CARDIOVASCULAR PARAMETERS AND
STATIC ELASTEC MODULI OF THE

TURKEY AORTA

Thesis for Hie Dede-u 0‘ Db. D.
MICHIGAN STATE UNIVERSETY

Elwood William Speckmnnn. Jr.
1962

0-169

This is to certify that the

thesis entitled

CARDIOVASCULAR PARAMETERS AND STATIC

ELASTIC MDDULI OF THE TURKEY AORTA

presented by

Elwood William Speckmann, Jr.

has been accepted towards fulfillment
of the requirements for

M— degree in

Poultry Science -

Animal Nutrition

Date 2 1962

Major profeslsori/j

,«.———-——- —~*—a———

 
  
 

LIBRARY

Michigan State
University

  

    

 

 

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ABSTRACT
CARDIOVASCULAR PARAMETERS AND STATIC ELASTIC
MODULI OF THE TURKEY AORTA

by Elwood'William Speckmann, Jr.

Under commercial rearing conditions, turkeys are Spontaneously
affected by a fatal condition known as aortic rupture. Investigations
in this laboratory have indicated that the cause of the aortic rupture
syndrome may be of a physiological nature rather than of a nutritional
deficiency. Cardiac and circulatory dynamics were recorded under nor-
mal conditions and following epinephrine injection. The association of
atherosclerosis with plasma cholesterol and aortic elasticity and the
relationship of these values to the cardiovascular parameters was
evaluated.

Plasma cholesterol level was found to increase with age in both
male and female Broad Breasted Bronze (BBB) turkeys from 4 weeks of
age to approximately 16 weeks of age after which age the plasma cholesterol
level plateaued. The adult plasma cholesterol level was determined as
249:8 mg percent for commercially purchased poults and BAQ113 mg percent
for EXperiment Station stock. There was no sexual difference in plasma
cholesterol levels at any age.

In these experiments atherosclerosis began early in age, for by
8 weeks of age all turkeys had either microscopic or macroscopic
atherosclerotic lesions. The males exhibited a greater atherosclerotic
severity than did the females. Reserpine administration at the level

of 0.1 ppm and 0.2 ppm in the feed did not offer any protection against

 

 

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Elwood William Speckmann, Jr.

the increase in plasma cholesterol or the severity of atherosclerosis
with advancing age.

The cardiac output of untreated mature male BBB turkeys was de-
termined by an isotope dilution technique using radioactive-phosphorus
(P32) as the indicator. Common carotid and popliteal arterial blood
pressures were measured directly and were recorded simultaneously with
the cardiac output determinations pre- and post-epinephrine injection
by means of two strain guages connected to a recording polygraph.

From the cardiovascular measurements systemic resistence was
calculated. The mean cardiac output of mature male BBB turkeys was
231148 ml per Kg0'73u per minute. The cardiac parameters were not
affected by strain but were significantly influenced by atherosclerotic
severity. TurkeyS'with a higher incidence of atherosclerosis had a
greater minute volume, cardiac output and stroke volume than turkeys
with little or no atherosclerosis. The injection of 0.5 ml of 1/25,ooo
epinephrine caused a negative cardiovascular response; minute volume,
cardiac output and stroke volume decreased.

Blood pressures increased with advancing age in both male and
female BBB turkeys. Several of the hemodynamic parameters were in-
fluenced both by strain and atherosclerotic severity. The M.S.U.
strain of turkey had a significantly higher systolic blood pressure
than did the commercial strain of turkeys with the cross between the
two strains of turkeys falling in between. The group with the highest
atherosclerotic score also had the highest systolic blood pressure.
The popliteal arterial blood pressures were consistently lower than

their common carotid artery counterparts and were not influenced as

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Elwood William Speckmann, Jr.

much by strain and atherosclerotic severity. The injection of epinephrine
caused a pronounced elevation of blood pressure. This was accompanied by
a negative cardiovascular response and a concomitant increase in systemic
resistance which elevated blood pressure. Reserpine significantly re-
duced blood pressure whereas BAPN and vitamin C had no affect.

A method for the determination of the static modulus of elasticity
for the thoracic and abdominal aorta and an equation rearranged for
elastance calculations as a function of change in volume were described.
The aortic segments were most distensible in the physiological blood
pressure range, the pressure-volume curves being sigmoid in nature.

The vessel segments also exhibited hysteresis. The thoracic aortas
were much more distensible than the abdominal aortas; the elastances
of untreated male BBB turkeys being in the neighborhood of 3.28:0.11
and 13.95i0.24 dynes/cm2 X 105 respectively in the physiological blood
pressure range. This difference becomes more pronounced at higher
pressures.

Partial correlation coefficients of cardiac, hemodynamic and
elasticity parameters were calculated to evaluate their inter-

relationships.

CARDIOVASCULAR PARAMETERS AND STATIC ELASTIC

MODULI OF THE TURKEY AORTA

by

Elwood William Speckmann, Jr.

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY

Department of Poultry Science

1962

 

525434

571.: l {.3 3

This dissertation is dedicated to my
father, whose last wish has been fulfilled
and to my mother, whose sacrifices and en-

couragement made this endeavor possible.

 

 

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ACKfiOWLEDGfiEK

The author wishes to express his most sincere appreciation and
gratitude to Dr. R. K. Ringer of the Department of Poultry Science
for his invaluable guidance, constant assistance and encouragement
throughout the course of this study and for his critical evaluation
of the manuscript.

Further acknowledgment is also extended to Mrs. T. Tetzlaff,
technician for preparation and staining of aortic tissue and to Mr.

J. wolford, graduate student, for his aid in construction of the
elasticity apparatus. The author wishes to thank Dr. L. F. Wolterink,
Department of Physiology and Pharmacology for the development of the
formula for the determination of cardiac output and to Dr. B. Rosenburg,
Department of Biophysics for rearrangement of the formula for deter-
mining vessel elastance.

The author is also indebted to Dr. H. C. Zindel, Head, Department
of Poultry Science for his cooperation in making funds and facilities
available for this investigation and to Dr. T. H. Coleman, Department
of Poultry Science, for his helpful suggestions and critical review
of the manuscript. The author wishes to thank Mr. E. Niemala and his
staff for their assistance in the care and management of the turkeys.

The writer is also beholden to his committee, Dr. P. E. Reineke,
IDepartment of Physiology and Pharmacology, and to Dr. D. E. Ullrey,
Department of Animal Husbandry, for use of radioisotOpe equipment and
for their recommendations toward the composition of this manuscript

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and to Dr. R. J. Evans, Department of Biochemistry, for his constructive

review of the thesis.

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Elwood W. Speckmann, Jr.
Candidate for the degree of

Doctor of Philosophy

DISSERTATION:
Cardiovascular Parameters and Static Elastic Moduli of
the Turkey Aorta
OUTLINE OF STUDIES:
Major area of study: Poultry Science (Avian Physiology)
Supporting areas of study: Biochemistry, Kutrition
BIOGRAPHICAL ITEMS:
Born: January 10, 1936, Brooklyn, New York
Undergraduate studies: Rutgers University, New Jersey
1953-1957
Graduate studies: Hichigan State University, Michigan
1957-1962
“YPERIEUCE:
Graduate Research Assistant, Hichigan State University
1957-1960
Dr. Salsbury Graduate Research Fellow, hichigan State
University, 1960—196?
MEI-1B BR :
Poultry Science Association

Society of Sigma Xi

 

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TABLE OF COHTEHTS

Introduction . . . . . . . . . . . . . . . . . . . . . . . .

Review of Literature . . . . . . . . . . . . . . . . . . . .

 

A. Problem of Aortic Rupture in Turkeys. . . . . . .
1. History. . . . . . . . . . . . . . . . .
2. Nutritional Research . . . . . . . . . . . . .
B. Atherosclerosis - Cholesterol - Hemodynamic Complex
1. Atherosclerosis. . . . . . . . . . . . . . . .
2. Cholesterol. . . . . . . . . . . . . . . . . .
a. Plasma Cholesterol Lowering Agents .. . .
3. Hemodynamics . . . . . . . . . . . . . . . . .
a. Carotid and Popliteal Hemodynamics.
C. The Aortic Rupture Syndrome . . . . . . . . . . . .
1. Attempts to Produce Aortic Rupture . . . . . .
a. BAPN. . . . . . . . . . . . . . . . . . .
2. Attempts to Stop Aortic Rupture. . . . . .
a. Tranquilizers . . . . . . . . . . . . . .

3. Physiological Parameters Associated with the
Aortic Rupture Syndrome. . . . . . . . . . .

a. Cardiac Output. . . . . . . . . . . . . .

b. Elasticity. . . . . . . . . . . . . . .
Objectives . . . . . . . . . . . . . . . . . . . . . . . . .
Experimental Procedure . . . . . . . . . . . . . . . . . . .

A. General a o o o o o o o o o o o o o o e c o 0

Vi

43’wa

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1. Cholesterol Determination . . . . . . . . . . .
2. Blood Pressure Determination. . . . . . . . .

3. Cardiac Output Determination. . . . . . . . . .
4. Elastance Determination . . . . . . . . . . . .
5. Atherosclerosis Determination . . . . . . . . .

6. Statistical Analysis. . . . . . . . . . . . . .

Results and Discussion. . . . . . . . . . . . . . . . . . . .

A.

B.

EXperiment I Age, Plasma Cholesterol, and
Atherosclerosis. . . . . . . . . . . . . . . . . .

Experiment II Age, Plasma Cholesterol, Hemodynamic
Parameters, and Atherosclerosis. . . . . . . . . .

Experiment III Effects of Intravenous Injection
of Epinephrine on Hemodynamic Parameters of
Untreated and Reserpine-Treated Hale BBB Turkeys .

Experiment IV Determination of Cardiac Output and
Simultaneous Measurement of Cardiovascular and
Hemodynamic Parameters Pre- and Post-Epinephrine
Injection in Adult Hale BBB Turkeys. . . . . . . .

Experiment V Determination of Thoracic and
Abdominal Aortic Elastance at Pressures Below,
Equal to and Above the Physiological Blood
Pressure Range . . . . . . . . . . . . . . . . .

DiscuSSion O O O O O O O O O O O O O O O O O O O O O O O 0 O

 

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . .

Literature Cited. 0 O O O O O O O O O O O O O O O O 0 0 O O 0

AB Bendix O O O O O O O O O O O O O O O O O O O O O O O O O O 0

vii

Page
28
28
3O
35

38
39

39

47

63
93
115
119

137

Table

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LIST OF TAPLBS

Determinations of initial and final body lHOi hts,
the monthly we'ght gains and the feed efficiency of
PPl B turl :eys fed Scrpasil from 1 (W 2 weeks of

.44

at” e O O O O C O O O O O O O O O O O O I O I O O O O O O O

lean monthly plasmac holesterol levels (m5 percent)
of PEP turkeys from )—.;h weeks of afo wit 11 Serpasil
administration from 1 ”a; through 2'+ wee ks of aQG . . . .

Co 1mon carotid henodvnailc rarer wt ers and mean scores

of andominal aortic athero sclzrotic plaques of PPR
turkeys at 27 weeks of mmlrltl Sergasil adr.im stration
from 1 day trough 2% w eke of age. . . . . . . . . . . .

Bi —we,kl ; measurement of hemodynamic para
plasma cholesterol and a 4erinal atlQPOS
5

worth I, ml,

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Conmon carotid 1,.o-rnam1c paran hers pre— anl pose-
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crinonh ine of acult male TT' turJBSS (die 21 kce.S)
.:,,. r‘ _ z. . n . n ””1.
foll owllg Serrasil “dnlnisol clan lo: 1“ Leexs. . . . . .
. .. rt. 1 1,1,, 1, e ' r _, ,.,.L.‘., . I. ....‘ . l
COT l lOLL 0.1.- O CiCE - 1.31-10bu71r11 llC i.'n.rc1lu~"} u- .i‘b “I" ._;‘- 3.211.-. 1.10." C-
1 v 7" -~-. r\ ‘
onenen rine of acrlt male QB“ turkeys (Age 11 hangs)
' ‘r r1 , - :s a ' ' ~ . -~ '. 'l' 2,-- -' -.! -‘ , [‘1 v :-\ fl, '
fOl_._O‘:iLlL) 51);." ‘38.;1 (.‘L'I 1.12.1123 all 7‘ t/-_'Ol. 123:“ .C I - .3 o o o o o o
r‘ “’3. "10011 1“ YN {37‘ WC‘ ‘ T’fi 't‘ '1 ‘ “(‘3' ‘ 1U}? 1 \ “W": a
1.1.1 \ilOV CCU Cl .L x at . N-JCII .3 1‘- ..- ( AIL. 1':th \J—‘Jirngi J Li -21“.-
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\ '0 ‘l L \‘ "“"“ '1‘ .3 31— \‘PT
“plWOpl"lW“ 01 adult male ._- ch -rvs . . . . . . . . . .
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Cardiovascular IRPCHFEDTS of adrlt male

C rilovoocn'“*‘1va“rh:ters followinf tfl~ in eticn of
- ,: . . .L «our: ”n.1, .-.,.
OfJJlO}:H.1nC} to ellrl.t IHlle . :_= t l;.CXLv . . . . . . . . . .

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Percent change in cardiovascular parameters
following the injection of epinephrine to adult
male BBB turkeys . . . . . . . . . . . . . . . . . . .

Common carotid hemodynamic parameters of adult
male BBB turkeys O O O O O O O O O O O O O O O O O O 0

Common carotid hemodynamic parameters following
the injection of epinephrine to adult male BBB turkeys

Percent change in common carotid hemodynamic
parameters following the injection of epinephrine
to adult male BBB turkeys. . . . . . . . . . . . . . .

Pepliteal hemodynamic parameters of adult male
BBB turlfheys O O O O O O O I O O O O O O O O O O O O O O

Popliteal hemodynamic parameters following the
injection of epinephrine to adult male BBB turkeys . .

Percent change in popliteal hemodynamic parameters
following the injection of epinephrine to adult
male BBB turkeys . . . . . . . . . . . . . . . . . . .

Mean values for static modulus of elasticity
(Dynes/cm2 X 105) for the thoracic aorta of adult
male BBB turkeys below the normal physiological
systolic blood pressure range (25-150 mm Hg) . . . . .

Mean valugs for static modulus of elasticity
(Dynes/cm x 105) for the thoracic aorta of adult
male BBB turkeys at the normal physiological

systolic blood pressure range (175-350 mm Hg). . . . .

Mean valugs for static modulus of elasticity
(Dynes/cm X 105) for the thoracic aorta of adult
male BBB turkeys above the normal physiological
systolic blood pressure range (375—300 mm Hg). . . . .

Mean valufis for static modulus of elasticity
(Dynes/cm X 105) for the abdominal aorta of adult
male BBB turkeys below the normal physiological
systolic blood pressure range (25—150 mm Pg) . . . . .

Mean valuSs for static modulus of elasticity
(Dynes/cm X 105) for the abdominal aorta of adult
male BBB turkeys at the normal physiological systolic
blood pressure range (175-350 mm Pg) . . . . . . . . .

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Correlation coefficients ("r“) of two variatns . . . . . 5Q

Correlacion coefficients ( r‘) of two variatoc . . . . . 1‘

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Close-up photograph illustrating continuous
bloOd £101! UTIdC-Z‘I‘ G-I: 1.411130 0 o o o o o o o o o 0

Photograph illustrating equipment for detection
and recording of primary radioisotope curve . .

Photograph illustrating primary dilution curve.

Photograph illustrating the ayparatus used to
determine elastance . . . . . . . . . . . . . .

Mathematical rearrangement of Love's elastance
equation. . . . . . . . . . . . . . . . . . . .

Photograph illustrating distensibility of the
thoracic aorta at 0 mm Hg and 500 mm hg . . . .

Photograph illustrating distensibility of the
abdominal aorta at 0 mm Mg and 500 mm H“. . . .

q

Three consecutive pressure-volume curves of the

thoracic aorta of mature male hi? turkeys . . .

Three consecutive pressure—volume cvrves of the

T“

abdominal aorta of mature male LT: turkeys. . .

Pressure-volume curves of the thoracic aorta of

mature male BBB turkeys and the effect of EAPL
and vitamin C treatment . . . . . . . . . o o .

Pressure-volume curves of the abdominal aorta of

mature male BBB turkeys and the effect of PAPN
and vitamin C treatment . . . . , , “ , . . o .

K- J
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INTRODUCTION

Aortic rupture was first reported in turkeys in 1952. This
condition probably existed for some time prior to 1952 but had gone
unreported and/or unnoticed. Today, the turkey grower and breeder
are faced with narrowed margins and reduced income. Therefore, each
producer must scrutinize his losses from disease and poor management
practices.

Aortic rupture has been of utmost concern to turkey growers and
breeders because it is occurring under various systems of management
in widely scattered portions of the United States, Canada and England.
There are apparently no external symptoms to this malady prior to
death yet mortality may be as high as 20 percent. Males of the larger
varieties (Broad Breasted Bronze and Broad Breasted.White) are pre-
dominantly affected and die usually between 8 - 24 weeks of age,
representing a significant economic loss to the turkey raiser. Re—
ports from turkey raisers indicate the highest incidence of death
occurs following a "stress". In this dissertation, stress denotes
a physiological imbalance which causes a release of epinephrine.
Jumping off a roost, fighting, sexual play, undue medication, sudden
excitement, or other such stresses which are most frequent in growing
male birds reaching sexual maturity, are probable contributing agents
to aortic rupture.

Aortic rupture has been reported to occur in association with
ailuerosclerosis. The relationship of atherosclerosis to dietary

Pattmarns and lipid metabolism, particularly cholesterol, is well

known. Primary investigation of the aortic rupture syndrome in this
country, therefore, has been from the nutritional aSpect. Consider-
able literature exists as to the effects of various dietary regimes
on aortic rupture artificially produced with beta—aminopropionitrile,
few of which were beneficial.

The possible association of stress with aortic rupture, coupled
with the high blood pressure reported for the male turkey suggest
the cause of this condition to be of a physiological nature. The
successful use of reserpine, a hypotensive tranquilizer, in stepping
losses due to aortic rupture further documents this assumption. The
primary objective of the research reported in this dissertation was
to investigate the basic cardiovascular and hemodynamic parameters
which may contribute to the cause of aortic rupture in turkeys. In
addition, the elasticity of the thoracic and abdominal aortas was
measured to ascertain their distensibility under various physiological

conditions.

REVISJ CF LITERATKRE

Problem of Aortic Rupture in Turkeys
The incidence of aortic rupture in turkeys was first reported

in the United States in 1952 (Durrell, SE 31., 1952). However, some
growers have observed this condition since as early as 1940 (waibel,
1960). More recently, aortic rupture has been reported in Brown
Leghorn hens (Siller, 1962a; 1962 ; 1962c). Durrell gt El' (1952)
reported the malady to occur under various systems of management in
widely scattered areas of the United States. They found a wide varia-
tion in age incidence, with the condition occurring generally in
growing male turkeys between the ages of 8 - 24 weeks, of the Broad
Breasted Bronze (BBB) or Broad Breasted White (BBW) varieties. Aortic
rupture is not a condition of poor health as it is generally observed
in the largest males that are experiencing rapid body weight gains

and is, therefore, a significant economic loss to the turkey raiser.

Morrison (1960) indicates that aortic rupture occurs almost every

month of the year but is most prevalent from April to October, the
time when the largest number of turkeys are being raised. Although
aortic rupture usually affects more mature birds, it has been reported
by Morrison (1960) to occur as early as 5 weeks of age. He also rem
.pOrted that the condition occurs in both sexes but is more prevalent
Eflnong male turkeys. Losses from aortic rupture are generally under 5
.Percent; however, losses as high as 20 percent have been reported
Ciaitel, 1960). A survey reported by Ringer (1959) indicated that
the? incidence of death frequently occurred early in the morning when

Ia“? loird is jumping off a roost or disturbed by the producer.

3

Possibly other stresses such as fighting, sexual play, undue medica—

tion, or moving which are most frequent in growing male birds reaching
sexual maturity, are contributing agents to aortic rupture.

The aortic rupture syndrome is characterized by a rupture of the
abdominal aorta in the interrenal area resulting in a fatal hemorrhage.
IHcSherry §t_ El. (1954), described the degenerative changes of the
eulrta in detail and showed it to be precipitated by a dissecting
aruaurysm. Gottlieb and Lalich (195%), Carnaghan (1955) and Gibson

arui deGruchy (1955) reported that this syndrome is not only precipi-

‘tsrted.by a dissecting aneurysm, but occurs in association with Spon-

‘tsudeous atherosclerotic plaques. Siller (1962b), however, found

éuaxrtic rupture with and without atherosclerosis in chickens. Although

tJiea exact etiology of aortic rupture remains obscure, the foregoing
Stiggyests that a general weakening of the arterial wall may be involved
irl the condition (Barnett, 1960; Ringer, 1962).
The association between plasma cholesterol and atherosclerosis

0T1 one hand and plasma cholesterol and dietary regime on the other

318 idell known (Katz and Stamler, 1953; Kritehevsky, 1958; 1962).
Idleqwefore, research on the aortic rupture syndrome in the United
States has been primarily from the nutritional standpoint. ‘Waibel
(ISNSO) observed blood clots in the body cavity of turkeys which had
(iiexj from aortic rupture. This suggested that the blood clotting
meCthanism was involved in aortic rupture. Barnett 33 31° (1958)
reported that anticoagulants added to a beta—aminopropionitrile
CBAJWU)-containing diet increased, whereas, vitamin K added to this
CtiEf; reduced. mortality due to aortic rupture. Beta—aminOprOpioni—

-tr3¥Le, originally isolated as the principle in sweet pea seeds that

-5-

caused lathyrism, is a toxic substance used to produce aortic rupture
(Barnett §£.飰 1957). It will be explained more completely in sub-
sequent passages.

Van Itallie (1957) reviewed work which indicated that athero-
sclerosis in man is associated with a high level of dietary fat.

The incidence of dissecting aneurysms in turkeys has increased in

recent years. Also during the past few years the caloric content of

true diet has been increased, often by the addition of fat (Barnett
aIMiIMorgan, 1959). Since Gottlieb and Lalich (1954), Carnaghan (1955)
arui Gibson and deGruchy (1955) associated atherosclerosis with aortic
Inigrture, the emphasis of nutritional studies switched to fat supple-
Unarrtation. Pritchard gt al. (1958) reported that diets high in fat
EuaCi protein increased the incidence of dissecting aneurysms. Barnett
aihd.bkn}§u1(1959) reported that mortality was almost doubled in chicks
vflaewi 20 percent fat was isonitrogenously added to the diet. This in-
CIYaase in mortality occurred in Spite of an approximate 20 percent
reduction in BAPN intake on the high energy diet. 'Waibel and Pomeroy
(15I59) failed to confirm these results in turkeys; however, they re-
INDI“ted.that dietary fish meal hastened the appearance of BAPN-induced
Imortality. Lalich gt al. (1957) reported that they could not prevent
a‘xrtxic rupture in turkeys by feeding a high protein (28$) ration in
ass<Dciation with BAPN-HCl although rats exhibited a significant de—
Cr’eéise in aortic rupture when fed 20 percent protein diet plus BAPN.
StaLmiler gt 21° (1958), however, observed that high-protein diets appear
‘to Ilrotect chicks against atherosclerosis induced by cholesterol feed-
leg. Recently McDonald gt al. (1962) reported that the amino acids -

I‘ ‘ :lysine and L - cystine - and the related compound taurine potentiated

BAPH-induced dissecting aneurysms in turkeys. These amino acids,
however, occur in most all proteins and are essential to birds.

Drugs such as nitrofurazone and semicarbazide hydrochloride have
been shown to potentiate BAPN-induced aortic rupture (Roy gt_§l. 1960).
Work with vitamins by Barnett, as cited by Carlson (1959), showed that
vitamins B6 and B12 and fats increased the incidence of aortic rupture.
Increasing the vitamin level or lowering protein did not stop losses
from aortic rupture (Morrison, 1960). Recently, Thornton (1960) re-
ported that the addition of ascorbic acid at levels as high as 100
mg/lb feed did not improve BAPN-induced aortic rupture in turkeys.
Aortic rupture resulting from copper deficiency has been reported in
chicks (O'Dell gt 31., 1961) and in swine (Carnes gt gl., 1961).
Copper deficiency apparently results in a derangement of connective
tissue as extensive dissecting aneurysms were readily present in
both studies. The relationship of copper to aortic rupture in turkeys
is not yet known.

The occurrence of aortic rupture under diverse dietary regimes
and the failure of the nutritionists to prevent or stop aortic rupture
in the field support the concept that nutrition, other than its asso-
ciation with cholesterol and atherosclerosis, has very little to do
with the aortic rupture syndrome. The association of stress with
aortic rupture has prompted this author to attack the problem from

a physiological standpoint.

-7-

 

 

Atherosclerosis - Plasma Cholesterol — hemodynamic Complex
Atherosclerosis
Atherosclerosis is a distinct entity -- one among the arteri-

oscleroses and by far the most important (Stamler, 1962). It is a
syndrome with different pathogenic and etiological mechanisms, yet
it is interwoven with hypertension. Atherosclerosis is the chief
pathologic lesion in coronary heart disease in humans. It is a di-
sease, and not a manifestation of senescence, and therefore is pre-
ventable and to a certain point curable. Further, atherosclerosis
is a metabolic disease in which altered cholesterol-lipid-lipoprotein
metabolism plays a critical and decisive role (Kritchevsky, 1962).
Elevated levels of circulating serum cholesterol-lipid-lipoprotein
are cardinal signs of the abnormality and constitute the metabolic
prerequisites for atherogenesis in most persons afflicted during
middle age (Albrink gt 31., 1961). The pathological hall-mark of
atherosclerosis is the lipid-and cholesterol-containing, focal intimal
plaque (Katz and Stamler, 1953). Increased blood pressure is also
believed to be involved significantly in the pathogenesis of athero-
sclerosis in man (Anitschkow, 1933; Rosenthal, 1934; Moschcowitz, 1950;
Blumenthal, 1956c; Burch and Phillips, 1960; and Stamler, 1962) and in
aves (weiss and Fisher, 1959). Many theories have arisen concerning
the genesis of atherosclerosis (Blumenthal 1956a; 1956b; 1956c).

0f the species commercially used as laboratory animals, spontane-
ous atherosclerosis has been reported to occur in dogs (Lindsay gt 2l°
1952), cats (Lindsay and Chaikoff, 1955), rabbits (Bragdon, 1952),
rats (Humphries, 1957), chickens (Dauber, 1944), turkeys (Carnaghan,
1955), pigeons (Lofland and Clarkson, 1959) and baboons (Gillman and

Gilbert, 1957). Of these animals the atherosclerotic lesions of aves

 

 

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most closely resemble that of man (Dauber, 1944). The normal spon—

taneous develOpment of avian arteriosclerosis (Fox, 1933; Dauber, 1944;

weiss, 1959), its similarity to human atherosclerosis (Dauber, 1944),
and the ease with which cholesterol can induce this condition (Katz

and Stamler, 1953; Kritchevsky, 1958) have precipitated another wave

of nutritional research designed to produce or control atherosclerosis

by altering the plasma cholesterol level. It is not the sc0pe of this

dissertation to review the multiferous procedures for producing hyper-

cflaolesterolemia and atherosclerosis. Excellent reviews on the rela—

‘tionship between nutrition and atherosclerosis are reported by Katz

arui Stamler (1953) and Katz gt gt. (1958). More specific experiments

iri birds are reported by Kestern gt gt. (1936), Stamler and Katz (1950),

Eitarfler gt gt. (1957, 1958, 1959), Fisher gt gt. (1959, 1960), Leveille

e1; gt. (1960) and Siller and Bolton (1961). Needless to say, the type

(Df' dietary fat and amount of cholesterol influences blood lipids as

tveill as severity of atherosclerosis. Leveille and Fisher (1958) sug-

é:e£3ted that if fowl have an adequate protein intake they can metabolize

eDUCess dietary cholesterol. Stamler gt gt. (1958) confirmed these re-

Slrlts. Wbllenberger and Kossler (1960) reported that caged chickens

llaxi a higher incidence of aortic and coronary atherosclerotic lesions

‘tfuin did free birds allowed to exercise. Exercise, or rather metabolic

17ad;e, may have considerable influence on plasma cholesterol level.
LThen desiccated thyroid was fed to chicks it significantly decreased
‘tfhe incidence and degree of diethylstilbestrol—induced atherosclerosis
alibhough it was without sustained effect upon plasma and tissue lipids
(Eitamler gt gt., 1950). Thyroxine and thiouracil in small doses were

ITiported to aggravate Spontaneous atherosclerosis in cockerels

 

-9-

(Perttala, 1961). Perttala (1961) has an excellent review on the
role of the thyroid in atherosclerosis.

Although dietary or hormonal induced avian atherosclerosis re-
sembles the Spontaneously occurring malady in both chickens and man,
there are important differences in distribution and histological
structure between Spontaneous and experimental lesions. The Spontane-
ous lesion is primarily fibrotic and tends to localize in the muscular
abdominal aorta; whereas, the experimental lesion is characterized
initially by lipid deposition, mainly in the elastic thoracic aorta
(Dauber and Katz, 1942; 1943; Weiss, 1959). Fisher gt gt. (1959),
however, induced atherosclerotic lesions in the abdominal aorta of
chickens that were similar to Spontaneous lesions. Since aortic rup-
ture in turkeys concerns the abdominal aorta, Spontaneous lesions, or
lesions which can be induced in this area of the aorta have the greatest
Significance.

Lofland and Clarkson (1959) studied Spontaneous atherosclerosis
in pigeons. These workers found Racing Homers and Show Racers to
be resistant to atherosclerosis while the White Carneau and Silver King
had a high incidence of Spontaneous atheromatous lesions in the aorta.
The level of serum cholesterol and phospholipid and the cholesterol:
phospholipid ratio, however, were unrelated to the incidence and severity
of atherosclerosis. They, therefore, attributed the susceptibility to
atherosclerosis to be genetically determined. This concept was also
advanced by Prichard §£.él° (1962) in a more recent paper. In pigeons,
there is no sex difference in blood pressure (Ringer gt gt. 1955) or in
susceptibility to atherosclerosis (Lofland and Clarkson, 1960; Prichard

gt gt., 1962); whereas, in chickens (Pick gt gt., 1952c; Katz and Stamler,

 

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1953; weiss, 1959) and turkeys (Ringer and Rood, 1959) the male has
the higher blood pressure and is more prone to atherogenesis after
puberty (Speckmann and Ringen 1962).

Estrogens of the female pigeon apparently have no prOphylatic
value against the severity or incidence of spontaneous atherosclerosis
in this Species (Lofland and Clarkson, 1960; Prichard 22.§l°9 1962).
The prephylatic effect of estrogens in cholesterol-induced-coronary
atherosclerosis has been reported for chickens but it apparently does
not apply for the thoracic or abdominal sectors of the aorta, in fact,
in these latter areas, estrogen may actually potentiate atherosclerosis
(Pick gtht., 1952a; 1952b; Stamler gt gt., 1954; Peck gt'gt., 1961).
For further information on the role of hormones in atherosclerosis,

an excellent review is given by Pincus (1959).
Cholesterol

The involvement of an altered cholesterol metabolism further
complicates the study of the atherogenic syndrome. Excellent reviews
on the role of cholesterol in atherosclerosis are given by Katz and
Stamler (1953) and Kritchevsky (1958).

A thorough investigation into the sterol composition of athero-
sclerotic aortas Showed that cholesterol was the major constituent
(Hardegger gt_gt., 1943). The aortic cholesterol esters are deposited
from the plasma resulting in the arterial wall having a similar com-
position to the plasma (weinhouse and Hirsch, 1940; Bottcher gt gt.,
1960). Exogenous cholesterol also becomes deposited in the atheroma
of cholesterol-fed rabbits (Biggs and Kritchevsky, 1951). The arterial

wall of some Species is capable of snythesizing cholesterol (Chernick

 

-11...

gt gt., 1949; Siperstein gt_gt., 1951; Azarnoff, 1958; Field, 1960).
This has recently been reported for chickens (Dayton, 1959; 1961).
Dayton (1961) reported a decline in the rate of cholesterol synthesis
during maturation of the aorta. Perhaps cholesterol synthesis is
concomitant with growth rate, being more rapid in the growing chick.
In chickens, the age period rather than age itself seems to be a more
significant factor in atherogenesis. A report by Rodbard gt.gt.,(1951)
Showed that hypercholesterolemia occurred in chicks during embryonic
develOpment, yet no atheromas were found in newly hatched chicks. Dur-
ing the first two months of life the chick is resistant to hypercholes-
terolemia and atherogenesis. At the eighth week (corresponding to
puberty), plasma cholesterol increases markedly, despite an unchanged
dietary regime. Following this rapid increase in plasma cholesterol,
atherosclerosis proceeds rapidly and by 16 weeks the birds may be se-
verely affected.

Azarnoff (1958) has divided experimental animals into two groups.
The first group consists of herbivorous animals such as rabbits, chickens,
guinea pigs, swine and calves. The aorta of these animals can incor—
porate acetate into cholesterol and it is these animals that can be made
atherogenic with relative ease by feeding a high cholesterol diet. The
second group consists of carnivorous and omnivorous animals such as
rats, cats, dogs and humans. The aorta of these animals cannot incor-
porate acetate into cholesterol and it is difficult to produce athero~
sclerosis in this group by a high cholesterol intake alone. The role
of the arterial wall in the maintenance of atherosclerosis is unknown,
yet it may contribute Significantly to atherogenesis. The fact that

atherosclerotic plaques contain carotenoid pigments (Blankenhorn, 1956)

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-12-

and linoleic acid (Battcher gt gt., 1960) which cannot be synthesized

in the body suggest that at least part if not most of the atherosclerotic
plaque is derived from the plasma. For further detail on the role

of the arterial wall in atherogenesis, the reader is referred to

Lansing (1959) and Kask (1962).

Windaus (1910) has shown that the atherosclerotic aorta contains
6 - 7 times as much free cholesterol and 20 - 60 times as much ester
cholesterol as does the normal aorta. These findings were confirmed
by Katz and Dauber (1945) and Buck and Rossiter (1951). Field (1960)
demonstrated a rapid turnover of cholesterol deposited in aortic plaques.
Therefore, atherosclerotic plaques may be reversible (Field, 1960).

The turnover of cholesterol in the chicken was found to be more rapid
in the thoracic than in the abdominal aorta (Dayton, 1959). The lower
ability to handle cholesterol in the abdominal aorta may be concomitant
with its higher susceptibility to atherogenesis.

Dauber (1944) reported that the incidence of Spontaneous athero-
sclerosis in chickens increases with age. The potentiating effects of
high plasma cholesterol levels on the development of atherosclerosis
(Katz and Stamler, 1953) suggest that the changes in plasma cholesterol
with age may be significant. Serum cholesterol increases with age
(after 30 years) in men and women (Keys, 1949; Keys §£.§l°9 1950;

Jones gt'gt., 1951). weiss (1957) reported that the average total
plasma cholesterol level of female chickens from 8 — 57 months of age
was 197 (180 - 210) mg percent and did not vary with age. On the

other hand, male chickens had an average plasma cholesterol level of

139 mg percent between 8 - 25 months of age, increased to 155 mg percent

by 35 - 38 months and reached a level of 209 mg percent by 45 months of

n .-

-13-

age. In this particular experiment, cholesterol did not seem involved
in the development of atherosclerosis, at least for the first two years
of age.

Very little work has been reported concerning the effect of age
on the plasma cholesterol of the turkey; waibel 33 al., (1960) re-
ported a very slight change in the plasma cholesterol levels of BBB
turkeys between the ages of 3 weeks (126 mg percent) and 5 weeks (129

mg percent). Speckmann and Ringer (1962), however, reported that

plasma cholesterol increased with age in both male and female BBB
turkeys from 8 weeks of age (149 mg percent) to 16 weeks of age (249
mg percent), after which age the plasma cholesterol level plateaued.

In man, attempts to control plasma cholesterol by decreasing
exogenous cholesterol intake fail because of the high rate of choles-
terol synthesis in the liver and other organs (Ruskin, 1960). Triparanol
(HER-29), a hypocholesterolemic drug, has been reported to lower serum
cholesterol in man (Ruskin, 1960) and in rats and monkeys (Blohm §t_§l.,
1959); Blohm and MacKenzie, 1959). 'When fed to turkey poults triparanol
also decreased serum cholesterol levels but it decreased growth and
failed to prevent mortality from BAPN-induced aortic rupture (Waibel
§t_al., 1960). Recent studies with triparanol in man have demonstrated
that this compound inhibits cholesterol biosynthesis by blocking the
reduction of 24-dehydrocholesterol (desmosterol) to cholesterol (Avigan
§t_al., 1960; Steinberg and Avigan, 1960). Desmosterol, however, ap-
pears to be more atherogenic in chickens than cholesterol (Wong and
Avigan, 1962). The prophylactic effects of triparanol on aortic rup—
ture in turkeys is therefore questioned. The feeding of bile acid

binding polymeric organic bases (Tennent gt gl., 1960) and ferric

 

,i

 

 

-14-

chloride, which precipitate bile acids (Siperstein gt.§l., 1953) have
been reported to inhibit the increase in serum cholesterol and athero—

genesis in cholesterol fed cockerels.
Hemodynamics

That hemodynamics play a role in the etiology of atherosclerosis
was first suggested by Anitschkow (1933) and Rosenthal (1934). Al- 5‘
though hypertension alone may not lead to atherosclerosis, it is more 1
prevalent in the descending stage of life and then coupled with hyper-
cholesterolemia, may play a decisive role. The rapid increase in
blood pressure (Ringer and Rood, 1959) coupled with rapidly increasing
levels of plasma cholesterol (Speckmann and Ringer, 1962) in the grow-
ing male BBB turkey may therefore be prediSposing to the aortic rupture
syndrome.

It is also interesting to observe that the lesions of the aorta
are generally more severe than those of other arteries. The aorta
distends considerably during each systole and recoils during diastole.
It is possible that the recurrent stretching of the vessel may facili-
tate the rapid entry of lipids into the intima and media, especially
under the driving force of an increased arterial tension (Aschoff,
1933; Kuroyanagi, 1959). Rosenthal (1934) reported that the deposition
of lipid was closely related to the structure of the vessel and to
the infiltration and expression of fats. In this respect, the thoracic
aorta expresses cholesterol and lipids well; whereas, the abdominal
aorta does not (Aschoff, 1933). The higher blood pressure in the
aorta than in other areas of the circulation probably enhances lipid

infiltration into the vessel wall. Also, the absence of atherosclerotic

-15-

plaques in areas of relatively low pressures such as the pulmonary
or venous circuits further suggests a hemodynamic-atherogenic
involvement.

When cortisone was administered to cholesterol-fed chicks, it
produced moderate hypertensive effects concomitant with intensified
aortic and coronary atherosclerosis; whereas, the administration of
hydrocortisone and adrenocorticotropin to similar animals produced

hypercholesterolemia and hyperlipemia yet did not intensify aortic or

coronary atherosclerosis (Stamler §£.§l°9 1954).

Blumenthal (1956c) believes that atherosclerosis is a reparative
process to the wear and tear of an increasing arterial tension (with
age) on the vascular system. ‘Weiss and Fisher (1959) demonstrated a
relationship between blood pressure and aortic hydroxyproline (connective
tissue) concentration in the chicken; whereas, plasma cholesterol was
correlated with aortic cholesterol concentration. Thus, blood pressure
is a better measure of abdominal atherosclerotic severity and plasma
cholesterol a better measure of thoracic atherosclerotic severity.
These researchers also suggested that blood pressure was involved in
spontaneous avian atherosclerosis. Hemodynamic changes have also been
implicated as contributory agents in the aortic rupture syndrome
(Gibson and.deGruchy, 1955; Ringer and Rood, 1959; Speckmann and Ringer,
1961; Burger, 1962; Ringer, 1962) as well as reduced distensibility

tiue to atherosclerosis (weiss and Sheahan, 1958).

 

 

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_ 16 -
Aortic Rupture Syndrome
Attempts to Produce Aortic Rupture

The pathogenesis and etiology of the aortic rupture syndrome
have already been discussed. Much interest still remains as to the
cause of this malady, yet it is difficult to study field problems
in view of its Sporadic occurrence. That beta-aminopropionitrile
(BAPN) produces a similar dissecting aneurysm under predictable and
controlled conditions allows research in the laboratory. Ponseti
and Baird (1952) were able to show that dissecting aneurysms could
be produced in rats by feeding rations containing sweet pea seed
(Lathyrus odoratus). Subsequently, {cKay gt gl., (1954) and Schilling
and Strong (1955) identified the toxic substance in L. odoratus as
beta-(N-gamma-L-glutamyl)-aminopropionitrile. BAPH is also contained
in seeds of Caley pea (L. hirsutus) and singletary pea (L. pusillus)
as reported by Barnett (1960). The similarity of lesions produced
experimentally and those found in field cases of aortic rupture
(Pritchard gt.§l., 1958) suggested that BAPN might be contained as
some feed ingredient but the analysis of many legumes, common feed—
stuffs and even the feed used during an outbreak of aortic rupture
failed to detect the presence of BAPN (Barnett, 1960).

As time progressed, other investigators (Bachhuber and Lalich,
1954; Bachhuber §t_§l., 1955; Lalich, 1956) demonstrated that dietary
iBAPH produced aortic rupture and other signs of lathyrism in rats.
lhxrtality resulted from aortic rupture in the thoracic region of the
aorta.which was accompanied by hock and toe deformities and pericardial

euui pulmonary hemorrhages. Lalich gt §l°’(1956) have also shown that

 

 

 

 

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-17..

dissecting aneurysms as well as skeletal defects could be produced
in turkeys by feeding different levels of BAPN. Barnett gt gt., (1957),
Lalich gt‘gt., (1957) and Waibel and Pomeroy (1958) likened the naturally
occurring condition of aortic rupture in turkeys to the dissecting
aneurysms observed in rats fed BA N. Barnett gt gt., (1957) observed
that turkeys fed BAPN developed lathyrism with symptoms similar to
those induced in rats except aortic rupture in turkeys occurred in
the abdominal aorta, similar to field cases of the condition. The
field cases, however, were not accompanied by hook and toe deformities
and other complications (Barnett gt.gt., 1957). The use of BAPN does,
however, provide a valuable tool for the study of aortic rupture in
the laboratory.

The turkey is 4 - 8 times more susceptible to BAPN than is the
rat (Lalich gt_gl., 1957). The faster growth rate and greater feed
consumption may also contribute to the greater susceptibility of the
turkey to BAPN toxicity (Barnett gt gt., 1957). Age seems to be a
very important factor in susceptibility to BAPN toxicity (Geiger gt.gt.,
1933; Ponseti and Shepard, 1954;'Walker and Wirtschafter, 1956; Waibel
and Pomeroy, 1958). To obtain circulatory damage in rats, BAPN must be
fed during the first few weeks after birth when elastogenesis is par-
‘ticularly active. Rats over seven weeks of age are not subject to
dissecting aneurysms induced by BAPN (walker, 1957). Zahor and Machova
(1961) noted severe mortality in BAPN-treated chick embryos due to
extensive hemorrhaging and dissecting aneurysms. waibel and Pomeroy
(1958) found that higher levels of BAPU are required to produce
lmwmorrhaging when birds become older and the circulatory system is

morma completely developed. Ringer (1961) feeding 0.04 percent BAPN-

3.0!":
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- 18 -

fumarate to 3-week-old turkey poults for seven weeks could not produce
aortic rupture.

waibel and Pomeroy (1958) demonstrated that the severity of
BAPN toxicity was proportional to dosage level. Low levels of BAPN
(0.01 percent) fed to 4-day-old poults produced no aortic rupture to
21 weeks of age, however, a level of 0.02 percent BAPN fed to 4—day—
old turkey poults produced aortic rupture in 4 of 7 turkeys between
7 and 13 weeks of age. Higher dosage levels of BAPN increased and
hastened mortality. Sex is apparently not a factor in BAPN toxicity
as both sexes die. The males usually die first probably because of
their faster growth rate and greater feed consumption. Ringer (1961)
observed that dietary BAPN (at 0.04 percent) had no effect on blood
pressure. Kowalewski (1960) noted that when BAPN was fed to cockerels
it had no effect on lipid content in serum, liver or aorta thus BAPN
most likely causes aortic rupture by causing degenerative changes in
the aortic wall.

Investigations into the site of action of BAPN suggest that it
acts by interfering with connective tissue metabolism. Enzinger and
warner (1960) suggested that acetoaminonitrile interferes with the
formation and maturation of connective tissue fibers. More specif-
ically,‘Walker (1957) suggested that BAPN acts by inhibiting the
formation of elastic fibers rather than acting as a direct elastolytic
agent. There is no breakdown in connective tissue when BAPN is ad—
ministered as is evidenced by its lack of effect on the adult animal.
Van Den Hooff gt gt., (1959) demonstrated that BAPN inhibited the
crosslinking whereby tropocollagen is aggregated into insoluble fibers.

This evidence was confirmed by Martin gt gt., (1961) and Wirtschafter

F‘m"“'3’

 

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-19-

and Bentley (1962).

The lathyritic effects of BAPN may be potentiated by feeding
nicotinic derivatives which inhibit the enzyme monoamine oxidase
(Roy gt gt., 1959). honoamine oxidase catalyzes the metabolic break-

down of BAPN to cyanoacetic acid.
Attempts to Stgp Aortic Rgpture

Attempts to stOp losses due to aortic rupture have been essen-
tially via the feed as this is one of the easiest and most economical
ways to treat birds. The failure of voluminous dietary regimes to
prevent or stop mortality from aortic rupture have been previously
reviewed. Many drugs have been screened in an effort to reduce mor—
tality with but one real success, reserpine.

Reserpine (Rauwolfia serpentina), a hypotensive tranquilizer,
has been demonstrated to afford protection against aortic rupture in
turkeys (Carlson, 1959; Barnett, 1960; Morrison, 1960; Haibel, 1960).
Reserpine has been shown to decrease elevated serum cholesterol levels
and inhibit the develOpment of aortic atheromatosis in normotensive
and hypertensive rats maintained on an atherogenic diet (Smith and
Rossi, 1962). These investigators also demonstrated that reserpine
reduced blood pressure only in the hypertensive rats. They also found
that the hypertensive state increased the severity of atherogenesis
in cholesterolized rats which were not fed reserpine. Although re-
serpine has been demonstrated to reduce blood pressure in chickens
(Sturkie gt_gt., 1958; Bunag and Walaszek, 1962) and turkeys (Speckmann
and Ringer, 1961) it has neither an effect on the plasma cholesterol
level nor on the incidence of atherosclerosis in growing BBB turkeys

(Speckmann and Ringer, 1962).

-20..

The central action of reserpine, possibly at the hypothalamic
level (Plummer gt|gt., 1955) may be involved in the hemodynamic reSponse
to oral administration of reserpine to turkeys. Reserpine is an in-
hibitor of the serotonin-storing mechanisms of tissues (Shore 22.2l°’
1957). According to Shore gt_gt., (1957) reserpine in the body rapidly
enters the brain and irreversibly affects the serotonin binding sites
and then disappears. Consequently the serotonin in various depots,
including the brain, is released and metabolized by monoamine oxidase.
The serotonin that continues to be made presents a persistent low con-
centration of free serotonin to the brain tissue. It is this free
serotonin that is considered to exert the actions attributed to reser-
pine (Cronheim and Gourzis, 1956). Although reserpine disappears
quickly, its effects persist for some time until the binding sites
have recovered or until new ones are formed. Reserpine administration
affects chickens similarly to mammals by releasing bound serotonin
(Huber and Link, 1962). Excellent reviews on serotonin are given by
Page (1958) and Lewis (1958).

The prophylactic action of reserpine on field cases of aortic
rupture may not be due entirely to its hypotensive action. Burger
gt gl,, (1961), fed various tranquilizers, a ganglionic blocking agent,
auinnammalian hypotensive drugs to turkey poults and observed no sig-
nificant effects on blood pressures with any of the drugs, including
reserpine, yet all drugs but the mammalian hypotensive drugs were
effective in curtailing mortality due to BAPN toxicity. Krista gt gt.,
(1961) treated a natural outbreak of aortic rupture in turkeys and
observed.that diethylstilbestrol implantation increased the incidence

of aortic rupture by more than 60 percent; whereas, daily injection

WAyA-A' 2.1
A
.
.

-21..

of testosterone propionate reduced the incidence of aortic rupture by
75 percent. Diethylstilbestrol decreased blood pressure by 16 percent
while testosterone had no effects on blood pressure values. Ringer

and Rood (1959), however, could not decrease blood pressure in turkeys
with large amounts of diethylstilbestrol. Perhaps hypertension is an

aggravator rather than a cause in the aortic rupture syndrome.

Physiological Parameters Associated.With the Aortic Rupture Syndrome

Cardiac Output

Ever since the discovery of the circulation by Harvey in 1628,
there have been voluminous investigations to determine cardiac output
under normal and stressing conditions in an attempt to more effectively
diagnose cardiac abnormalities. Many methods have been described in
the literature, few of which are accurate and constant enough to be
considered an infallible estimation of cardiac output. The most publi-
cized methods for determining cardiac output may be classified into
five general areas, namely the direct Fick, indirect Fick or foreign
gas, the dye dilution, physical methods and thermal methods.

The direct Fick principle was evolved by Fick (1870). It con-
cerns the measurement of arterio-venous oxygen differences with a
‘measurable oxygen consumption under basal conditions. The oxygen
cxnrtent of arterial blood was found by direct puncture whereas the
accurate measurement of oxygen content of venous blood proved diffi-
culi; in man until Forssmann (1929) demonstrated that catheterization of
the rigflm;heart was possible. Slightly over a decade later Cournand

(15flg5) and.Richards (1945) initiated the widespread use of right heart

 

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-22..

catheterization for the estimation of cardiac output. This procedure
was the most accurate and is still used as a standard today.

The difficulty of applying the direct Fick to man has promoted
much investigation into procedures whereby gaseous differences can be
determined without direct analysis of the blood. These indirect Fick
methods are theoretically successful but their application to man has
resulted in limited accuracy. The general deve10pments of indirect
methods for measuring cardiac output are described by Hamilton (1945).
The most successful of these methods were reported by Christiansen
gt‘gt., (1914) and Douglas and Haldane (1922) whereby C02 arterio-
venous differences were obtained without arterial puncture. The
acetylene method introduced by Grollman (1932) gave the most accurate
results and largely superceded older methods. The chief error in all
of these methods seemed to lie in the rebreathing procedure as many
investigators believe recirculation occurs and induces underestimation
of the pulmonary blood flow during the test period.

Closely correlated to the usage of foreign gasses for cardiac
output determinations is the injection of a substance directly into
the blood stream and analyzing its dilution in samples of blood. As
with the Fick principle, the onset of cardiac catheterization had aided
the accurate measurement of dye concentration. Until 1950, the dye in-
jection method was limited in use because the construction of dye dilu-
tion curves required laborious, time-consuming spectrophotometric
determinations of 30-40 blood samples. The introduction, however, of
apparatus for automatic registration of dye concentration in whole
'blood has greatly facilitated routine application of this method. A

complete review of dye injection methods is given by Falholt (1958).

' "‘13

F .1-

-23-

In this researcher's investigation of the aortic rupture syndrome
in turkeys it became evident that measurement of cardiac output may
elucidate some of the problems associated with this condition. Funda-
mental studies in determining the cardiac output of animals began as
early as 1897. Stewart (1897) initiated the measurement of cardiac
output by the injection method using sodium chloride as the indicator.
Henriques (1913) introduced a colorimetric procedure for determining
cardiac output. Hamilton gt gt., (1928a; 1928b; 1932), Hamilton (1953)
and Kinsman gt_gt., (1929) improved Stewart's technique by using rapid
intravenous injection and serial sampling of peripheral arterial blood.
This method permitted an emperical replotting of the data to separate
the primary dilution curve from subsequent recirculation curves. Moore
gt gt., (1929) reported that the injection method was very accurate when
compared with the direct Fick procedure. Since that time, the Stewart-
Hamilton dye dilution technique has been employed for many types of flow
studies.

Several investigators have utilized radioisotOpes as indicators
for cardiac output determinations. Hahn and Hevesy (1940) described a
method for blood volume determinations using erythrocytes labeled with
radiophosphorus (P32). Later Hevesy gt gt., (1944) applied this method
to human subjects. Nylin (1945) and Nylin and Celander (1950) also used
erythrocytes labeled with radiophosphorus for cardiac output determina—
tions. They injected the labeled cells into an arm vein and blood sam-
ples were taken from the artery of the opposite arm. From the concen—
tration of the indicator as a function of time the cardiac output was

determined.

 

_24-

Recently Sapirstein and Hartman (1959) reported the cardiac output
of sodium pentobarbital anesthetized chickens as 218 ml per Kg of body
weight per min. These investigators used rubidium (Rbaé) as an isotope
tracer. Also in 1959, the cardiac outputs of adult male and female
chickens were reported as 143 and 173 ml per Kg of body weight per min,
reSpectively, by Sturkie and Vogel (1959). The latter authors used
Evans Blue (T-1824) in a dye dilution technique. Lawson gt gt., (1952)
found very little difference in cardiac outputs calculated from dye
(T-1824) or radiOphosphorus (P32) labeled erythrocyte dilution curves.
Sapirstein and Hartman (1959) and Sturkie and Vogel (1959) collected
numerous arterial blood samples to obtain a dilution curve. Haclntyre
gt_gl., (1951, 1952), and Pritchard EE.§l°9 (1952) outlined a procedure
for the determination of cardiac output by injecting radioiodinated
(1131) human serum albumen (RISA) and continuously recording the dilu-
tion curve. Hilnor Ei.él°9 (1953) described a photoelectric ear
densitometer for continuously recording the arterial concentration of
T-1824 in the dye dilution method. Sturkie is using a linear densi-
tometer now to obtain continuous measurements of changes in indicator
(T-1824) concentration (Personal Communication).

The physical methods of measuring cardiac output include mainly
ballistocardiography and the pulse contour method. Ballistocardiography
was first introduced by Henderson and Haggard (1925) but the method was
developed more fully by Starr gt gt., (1939), Starr and Schroeder (1940),
and Starr (1944, 1945). The principle involved in this method was that
forces originating in the movement of blood were transmitted to the
body and could therefore be recorded. Cardiac output was determined

by the application of proper formulae to the ballistocardiograph.

-25-

When compared to standard methods of determining cardiac output under
resting conditions in normal subjects, it was quite accurate. However
the departure from basal conditions deprives this method of its accuracy.
The pulse contour method of determining cardiac output has been in the
literature since 1904, when Erlanger and Hooker (1904) suggested that
the output of the heart varies approximately as the product of pulse
pressure and pulse rate. The pulse contour method has been difficult
to apply and yields highly variable results. The distensibility of

the aorta varies and affects the pulse wave velocity; a constant must
be calculated to determine cardiac output. A review of the develop-
ment of this procedure is described by Hamilton (1945); Hamilton and
Remington (1947) designed a procedure which rests on the principle

that the uptake of blood during systole by various segments of the
arterial tree may be estimated directly from the aortic pressure pulse.
According to Huggins gt gt., (1948; 1949) the pulse contour method.
checks well with determinations by the Fick method; however, Brotmacher
(1957) and Bernstein and Evans (1962), making similar comparisons,
believe this method is only good for relative values but is not re-
liable for accurate estimations of cardiac output.

Another method used for determining cardiac output is the thermal
dilution method (Evonuk gt gt., 1961; Richardson gt_gt., 1962). The
method depends upon accurate recording of the changes in blood tem-
perature which occur in the pulmonary artery and the arch of the aorta
when cool isotonic saline is injected into the superior vena cava.

This method compares favorably with the Fick and dye dilution procedures

(Fegler, 1954; Goodyer gt gt., 1959).

- 26 -

Elasticity

 

The elastic stretching of the human vascular wall has long been
the subject of extensive studies. Many physical methods have been
deveIOped for examining the elasticity of the vascular wall (Hallock
and Benson, 1937; Nichol, 1955; Lawton, 1955; Weiss and Linde, 1960;
Bergel, 1961; and Balkrishna gt gt., 1961). More recently, elastance
has been determined in vivo in dogs (Remington, 1962) and estimated
from total perfusion of animals (Johnson gt gl., 1962). To the author's

knowledge there have been no elasticity studies in Aves.

:o

8.

10.

OBJECTIVES

To investigate the possible causes of aortic rupture in an at-
tempt to minimize losses due to this condition in the field.

To determine the normal plasma cholesterol level of the BBB turkey.
To determine the cardiac output of mature male BBB turkeys under

normal conditions.

. pm“?-

To determine the modulus of elasticity of thoracic and abdominal
aortic segments of mature male BBB turkeys.

To evaluate comparative blood pressure measurements, i.e., from
the carotid and popliteal arteries.

To study the effects of age, sex, and oral reserpine administration
on plasma cholesterol, hemodynamic parameters and atherosclerotic
severity.

To study the effects of injecting a known quantity of epinephrine,
simulating a stress, upon cardiovascular parameters.

To study the effects of atherosclerosis on plasma cholesterol,
cardiac output, elastance and hemodynamic parameters.

To investigate the effects of feeding reserpine, BAPN, vitamin C
and BAPN + reserpine and the effects of heat on cardiac output,
thoracic and abdominal elasticity and carotid and pOpliteal blood
pressures.

To determine the effect of strain on blood pressure, cardiac out-

put, and elastance.

-27-

EKPERIHEHTAL PROCEDURE

General:

The same general procedures were employed throughout the entire
research project. All of the experimental animals were turkeys of
the Broad Breasted Bronze (BBB) variety. All animals were hatched
in Michigan State University Poultry Science Department incubators
except for the cholesterol experiment where purchased commercial BBB
turkeys were utilized. All turkeys were reared in a commercial type
house and had access to a sunporch. All birds, treatments, and loca-
tions were randomized, where appropriate, as completely as possible

by the selection of numbers from a box.
Cholesterol Determination:

The quantitative estimation of cholesterol utilizing the Liebermann-
Burchard reaction was reported by Zlatkis gt gt. (1953). Modification
of this procedure for the estimation of plasma cholesterol in turkeys

is reported in the Appendix.
Blood Pressure Determination:

An identical method for determining arterial hemodynamic para-
meters was used throughout the experiments, namely, the direct tech—
nique. Direct measurements were taken in unanesthetized animals held

in a supine position on a wooden frame.

(‘0
C L)
I

.l'

T‘_— "t—

-29-

Hemodynamic measurements from the right common carotid artery
were recorded in a manner similar to that described by Weiss and
Sturkie (1951). The common carotid artery was exposed surgically by
a longitudinal incision in the neck. The artery was clamped and the
cranial end tied permanently. A small nick was made in the artery
between the tie and the clamp. A polyethylene tube (i.d. 0.045 in.

X o.d. 0.062 in. for young birds or i.d. 0.066 in. X o.d. 0.095 in. P
for mature birds) which was 30 cm long was inserted into the artery
and tied in place. The cannula system was connected to a Statham
pressure transducer, Model P-23 156—255, which in turn was connected
to a low level DC pre-amplifier of a Grass Model 5 polygraph. The
cannula was filled with 10 percent sodium citrate solution to prevent
clotting. The pressure equipment was calibrated through the same
transducer by means of a "three—way" valve which permitted connection
of a pocket model aneroid sphygmomanometer thus establishing a closed
air system. The pressure was increased and the levels were recorded
on the polygraph.

Popliteal arterial blood pressures were determined via a percu-
taneous vessel puncture technique similar to that described by Ringer
gt gt. (1955). The cannula (18 gauge hypodermic needle) was connected
to polyethylene tubing. The tubing in turn was connected to a separate
channel of the polygraph in the manner described for common carotid
arterial measurements, thus common carotid and popliteal arterial
hemodynamic parameters were recorded simultaneously.

Systemic resistance units for the common carotid and pOpliteal
arteries were calculated in terms of relative units by dividing mean

blood pressure (in mm Hg) by milliliters flow per minute. Units were

-30-

0.734

calculated either on a bird or on a Kg basis. Mean blood pressure
was determined by dividing systolic plus diastolic blood pressure by

two .

Cardiac output determination:

 

The well-known Stewart-Hamilton dilution principle was adapted
for using radiophOSphorus (P32) as a tracer and measuring its dilution,
similar to a procedure described by HacIntyre gt gt. (1951). Unanesthe-
tized BBB turkeys were immobilized in a supine position on a rigid
frame throughout the recording.

The right common carotid artery was exposed and cannulated with
polyethylene tubing (i.d. 0.070 in. X o.d. 0.110 in.). The tubing was
tied into each end of the cut artery and arranged in a 100p so that
continuous blood flow could be maintained. The loop of tubing was
passed beneath an end-window G-M (Geiger-Mueller) tube (Buclear Chicago)
and taped in place so that identical counting geometry could be used
for counting the standard (Fig. I). The G. H. tube was connected in
series to a Model 1620 rate meter (Nuclear Chicago) which, in turn,
was connected to an Esterline-Angus recorder. The arrangement of the
equipment is illustrated in Fig. II. The rate meter scale was set for
a sensitivity of 3 K and a time constant of 0.5 sec. The Operating
voltage was determined as 1050 V. The recorder was calibrated with
the rate meter and set at the fastest gear ratio (12 in. per min).

It had a curvilinear deflection of 6 in. Standard counts were deter—
mined by a Model 182 A scaling unit (Nuclear Chicago) via the same
G-M tube and bore of polyethylene tubing used for the actual deter-

minations. Approximately 40~60 pc of P32 (contained in an aliquot

r—“1

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MPH mefl

   
 

  

HimafiZSoa. :H:nn;:g coo L ho- law: A: a ,
mr4 amp :owim ARV ho.gaocup and w;..oH:; Btcaa; .AQV have .
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-33..

ranging from 0.01-0.10 ml) were injected into each bird via the brachial
vein and close to the body to give maximum deflection of the rate meter.
It was therefore possible in one experiment to simultaneously record
cardiac output and common carotid and p0pliteal hemodynamic parameters.
A typical primary dilution curve is shown in Fig. III. The curve
shows a rapid upswing reaching a peak in 3-6 seconds; the declining
limbs are not interrupted by recirculation for at least 10 seconds.
Unfortunately, recirculated blood generally appears before the down-
swing of the primary curve is completed, necessitating extrapolation
of the primary down-stroke. Since the down-stroke is assumed to closely
approximate exponential clearance of the isotope from the heart,
extrapolation on semilogarithmic paper completes the dilution curve
and if the original tracing is extended the area or average counts
of the curve may be accurately determined.
Cardiac output was determined by modifying the standard Stewart-

Hamilton dilution technique. It was established that:

 

MV = (cps inj) ‘Where MV = Minute volume
c 5 (min)
(ml cps = Counts per second
cps = Average counts per

second of primary
dilution curve per
milliliter of

 

blood
C0 2 MV min = Duration of primary
0.734 curve in minutes
BW
C0 = Cardiac output
EN = Body weight in

kilograms

r—— —l'.:'

.mpcooow :H pumma pm how coapdfizopflooa
,L powd:aampcfl pom mH ARV Lzfla QCHC.H00U 0:9 .mpcooom m cm xmcg m mcflzomop A<V mCHBmgs
paddy a popmppmcosop e>pso one .o>gzo COflwSHflU % V:HLL Hmoflghp w mCHpmppmJHHH :memopomm .HHH mmsmflm
mucooom

OH

 

ciao? .02 55.6 .

_ 35 -

Since metabolic activities such as cardiac output do not increase at
a linear rate with body size or weight, body weight raised to the 0.734

power was used (Brody, 1945).

Elastance Determination:

 

A method was devised whereby the elasticity of thoracic and
abdominal aortic segments of BBB turkeys could be accurately determined. F»
A 20 mm length of the aortic segment was tied at each end to rigid
polyethylene tubing. At one end the tubing was connected to a syringe
and Statham pressure transducer by means of a "three-way" valve. At
the other end of the segment the tubing was tied onto a tuberculin
syringe which in turn was attached to a micrometer. When the entire
system was filled with liquid, a calibrated volume of liquid was de—
livered to the vessel segment, the pressure recorded and the external
radius measured. Fig. IV shows a photograph of the apparatus.

An equation for the calculation of elastance (E) of an isotrOpic
tube which does not change in length upon inflation was given by Love
(1927):

E = .29 x 2(1.02)R§RQ
"RO R2 R2
O_* l

 

Tfhere JIRO is the change in external radius following a pressure
change 13p, Ri is the internal radius and j is known as Poisson's
ratio. Poisson's ratio is the ratio of transverse to longitudinal
strain and has been taken as 0.5 for the arterial wall which has been
shown to extend isovolumetrically. The measurement of internal radius,
however, when the aorta was in a closed system, could not be easily

determined. Love's equation was rearranged (see Fig. V) so that

 

 

-37-

Figure V Mathematical Re-arrangement of Love's Formula Substituting
Volume for Radius

[*1

9 '7
= A2 K 2 (1 «6w ) :11 “RC
A Ro (Roi—Rx

 

1. v = fi’Roh

2 77’ 11:20 11,110

"J
C:
x,
O
H

3. ARC = AVo

2 TI' hRO

4. Substituting:

 

 

 

 

3 = _Q.E__ x 2(1-62)RA2RO
AVO 2 2
57m; (Ho -‘f’~ >
v _ q 7 2,2 2
5' u h 42%- (W Inc-m 1; o.
0 Roz-RA?
o_ 0 —7—R02R*2
ROZ-RAZ Roz—RA: Roz - 1x4 R02 _ R 2 1 - 1 (
R03R&Z ROZRAZ R0234? ROZRAZ 3‘2 E32
7. __1__= run
3‘2 Vin

\ Vin RON /

raj
H

-38..

elastance became a function of the change in volume with a given pres-
sure change. Changes in volume and pressure were accurately measured
with this apparatus. The final rearranged equation, for the determina-

tion of elastance (E), is given as:

:3“

E = A f \K “L \-1
(“5%)W’Th,1—02)/ .. _ 1 =.-
of‘ ,\ ’ K 1 R0,/

<1

:5

Where AXVO is the change from initial volume Vin with a pressure change

:3?“ “"‘““““1

13p. The h refers to height or length of the vessel and R0 is the out-

side radius.
Atherosclerosis Determination:

Following each experiment, the abdominal aortas were removed and
visually scored for atherosclerotic plaques in the manner described by
Katz and Stamler (1953). Scores range from 0 (no incidence) to 4 (high

incidence).
Statistical Analysis:

All of the data were statistically analyzed using the Analysis
of Variance or the Student "t" test (Snedecor, 1956). The treatment
'means were compared by the Duncan Multiple Range and Multiple F test
(Duncan, 1955). Other data were subjected to correlation analysis

(Simpson e]: _z_1_l_., 1960).

RESULTS AND DISCUSSION

Experiment I: Age, Plasma Cholesterol and Atherosclerosis

 

The first experiment was conducted on 360 commercially purchased
BBB turkey poults. These turkeys were utilized to study plasma choles-

terol, atherosclerosis and hemodynamic parameters together with growth.

2'7”“?

There were three treatments: 0.1 ppm and 0.2 ppm reserpine administered
in the feed as Serpasil (reserpine, CIBA) and untreated controls. Each
treatment was separated into a male group and a female group and these
groups again divided into two replicates resulting in twelve pens of
thirty birds each. The position of the treated groups was randomly
selected. After the birds were sexed, they were sorted and assigned
to treatments based on a one percent level of non—significance in initial
body weights. The experiment was initiated on February 25, 1959, at
which time the poults were hatched. Serpasil was incorporated into
the feed at one day of age and continued until September 10, 1959 when
the birds were sacrificed. The turkeys were fed starter, grower and
finisher rations from 2-8, 9—16, and 17-27 weeks of age, respectively.
Ilka turkeys were raised on the floor throughout the entire experiment,
ruui access to a sunporch during the summer months and received feed and
waiter fig libitum. Individual body weights and feed weights were recorded
UKNTthly'and feed efficiencies were calculated from these data.

.At the same time that the monthly body weight recordings were taken,
a two Ufld sample of blood was withdrawn from each of eight birds in each
replixxite for plasma cholesterol determinations.

-39-

-40..

At the end of the experiment (27 weeks of age) blood pressures
were taken directly from the common carotid artery of unanesthetized
birds. Only those birds from which plasma cholesterol samples had
been withdrawn were used. Following the blood pressure determinations,
the abdominal aortas were removed and visually scored for atheroscler-
otic plaques.

The initial and final body weights, the monthly weight gain and
feed efficiencies are shown in Table 1. The initial body weights and
the final body weights between treatments within sex were non-signifi-
cantly different at the 5 percent level. Analyses of these data
revealed that differences between the weight gains of the replicates
were not statistically significant. Therefore, the replicates were
pooled within each treatment.

The results of the monthly plasma cholesterol determinations by
sex are presented in Table 2. The data were pooled as the differences
between replicates were not statistically significant. Plasma choles-
terol levels of both males and females rose from 8 weeks of age to 16
weeks of age, after which age the plasma cholesterol level plateaued.
At any particular age, however, the plasma cholesterol levels of the
two sexes were not statistically different. The differences between
plasma cholesterol levels in any of the treatments were not statis-
tically significant at any age.

The mean common carotid hemodynamic parameters and atherosclerotic
scores of the abdominal aorta are presented in Table 3. The blood
pressure values obtained differed from those previously reported for
Iflfi3 turkeys (Ringer and Rood, 1959) but were similar to blood pres-

sures reported for Jersey Buff turkeys (Weiss and Sheahan, 1958).

_ Q1 _

Also in this study, male and female hemodynamic parameters were not
statistically different. The males demonstrated a higher incidence

of atherosclerotic plaques in the abdominal aorta than did the females.
This is in agreement with evidence obtained in humans and in chickens.
There was no difference between the control group and the Serpasil-
treated groups within sex. In this study, Serpasil at the levels
employed did not significantly influence plasma cholesterol, hemo-

dynamic parameters or atherosclerotic severity.

Aor Sc

BAPN

BBB

BPM

BVT

Chol

CO

Comm

DBP

Ht wt

M

NP

NV

PP

SBP

SRU

S.E.M.

SV

H

_ 42 -

Key for Tables

Abdominal

Aortic score
Beta-aminopropionitrile
Broad Breasted Bronze
Beats per minute

Blood vessel thickness
Body weight

Carotid artery
Cholesterol

Cardiac output
Commercial

Diastolic blood pressure
Elastance

Female

Heart rate

Heart weight

Male

Mean pressure

{inute volume

Pulse pressure

Systolic blood pressure
Systemic resistance units
Standard error of mean
Stroke volume

Thoracic

Change

_ 43 _

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-47-

Experiment II: Age, Plasma Cholesterol, Hemodynamic Parameters and
Atherosclerosis

 

In this experiment, BBB turkeys hatched in M.S.U. Poultry Science
Department incubators were utilized. They were raised in the conven-
tional manner, indoors, receiving feed and water ad libitum. At bi-
weekly intervals beginning at 4 weeks of age and extending through 24
weeks of age, 6 male and 6 female untreated turkeys were removed from
the group. Blood pressures were determined and 2 ml of blood was re—
moved for cholesterol determination. The birds were then sacrificed
and the abdominal aortas removed and scored to ascertain the onset and
severity of atherosclerosis.

The bi-weekly measurements of hemodynamic parameters, plasma
cholesterol, and abdominal atherosclerotic severity of untreated BBB
turkeys from 4-24 weeks of age are presented in Table 4. Hemodynamic
values of male and female turkeys rose from 4 weeks to 24 weeks of age
reaching a peak at approximately 20-22 weeks of age. The blood pres-
sures of the males were significantly higher than those of the females
after 16 weeks of age.

Plasma cholesterol levels again rose significantly in both males
and females with advancing age and again there was no significant
tiifference in plasma cholesterol level between males and females at
awry age. The plasma cholesterol levels were, in general, higher than
those reported for male and female turkeys in Experiment I but the
'turkeys were of a different strain.

At 8 weeks of age, all aortas had either microscopic or macro-
scopic atherosclerotic lesions. Most of the lesions were protruding

int&>‘the blood vessel lumen and were thus partially obstructive to the

rim-“ma

_ 48 -

flow of blood. The plaques occurred as streaks of fatty material

on the ventral aspect of the aorta. Very rarely were the streaks
accompanied with carotinoid pigment as is frequently reported in
chickens. The tom turkeys were affected with a more severe incidence
of atherosclerosis which increased with advancing age. Sporadically,
certain individuals showed evidence of severe atherosclerosis, es—

pecially the older males.

‘mel

Biuweekly measurement of hemod

Table 4.

ynamic parameters,

severity of BBB turkeys from 4-24 weeks of age

plasma cholesterol and abdominal atherosclerotic

Mean Rarametersi S.E.M.

 

 

 

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14 wk

12 wk

10 wk

8 wk

4 wk

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-51..

Experiment III: Effects gf Intravenous Injection gf Epinephrine 93
Hemodynamic Parameters 9f Untreated and Reserpine-
Treated Male BBB Turkeys

 

This experiment was essentially an exploratory trial to determine
the effects of an intravenous injection of 0.5 ml of 1/25,000 epinephrine
on the hemodynamic parameters of untreated and reserpine-treated male BBB
turkeys. This experiment was conducted in two phases, the second phase
being a refinement of the first phase. The two phases will therefore be
discussed together.

The turkeys were hatched and raised by conventional means by mem-
bers of the M.S.U. Poultry Science Department. At nine weeks of age
the turkeys were separated into 3 lots (untreated, 0.5 ppm and 1.0 ppm
reserpine) in the first phase and 4 lots (untreated, 0.1 ppm, 0.5 ppm,
and 1.0 ppm reserpine) in the second phase. Each lot consisted of 10
toms. After subsistence on this regime for 12 weeks (age 21 weeks)
common carotid hemodynamic parameters were recorded pre- and post-
epinephrine injection.

The hemodynamic parameters of the turkeys in the first phase are
presented in Table 5 whereas the hemodynamic parameters of those in
the second phase are presented in Table 6. Reserpine administration
at the level of 0.5 ppm and 1.0 ppm of the ration significantly de-
creased all hemodynamic parameters. Reserpine at the level of 0.1 ppm
of the ration did not alter hemodynamic parameters.

Following the injection of epinephrine, the percentage change
values were indexed by using 1.00 percent as the base value. Thus a
percent change of 174 indicates the value as 1.74 percent of the origi-

nal value or a net increase of 74 percent whereas a percent change of

-52-

0.89 indicates the value is only 89 percent of the original value or
a net decrease of 11 percent. This method of indexing will be used
for the remainder of the tables concerning percent change in cardio-
vascular parameters following the injection of epinephrine.

In all lots, epinephrine injection significantly elevated all
hemodynamic parameters. Following epinephrine injection heart rate
fluctuated, being elevated in some birds, but decreased in others;
the net result being no change in the heart rate of untreated lots,
but a slight decrease in heart rate of the reserpine-treated lots.
The reserpine-fed turkeys demonstrated a greater percentage change
in systolic blood pressure, and especially pulse pressure, than did
the untreated turkeys following the intravenous injection of epine—
phrine. Although the percentage increase in systolic blood pressure
and pulse pressure was considerably greater for the reserpine-fed

turkeys than for the untreated turkeys, the initial and final mean

systolic blood pressures and pulse pressures were significantly lower

than those of the untreated lot.

Theoretically, if this amount of epinephrine injected corresponds

to the amount of epinephrine released in the body when the tom experi—

ences a."stress," then following a "stress," depending on its nature

euwi severity, systolic blood pressure may be elevated in the neighbor-

kxxxi of 30—35 percent. Individual birds have been observed to reach

500 nun Hg and above following the same 0.5 ml injection of epinephrine.

Reseujiine therefore does exert some protection against stress by virtue

of its hypotensive action.

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Experiment IV: Determination 9f Cardiac Output and Simultaneous Kea—
§p£§ment 9f Cardiovascular and hemodynamic Parameters
Pre- and Pest-Epinephrine Injection i3 Adult hale BBB
Turkeys
.—————-fl_

 

 

 

 

The purpose of this experiment was to determine the cardiac output
and to ascertain the effect of an intravenous injection (0.5 ml of
1/25,000 dilution) of epinephrine on cardiovascular and hemodynamic
parameters of adult male BBB turkeys. Carotid and popliteal arterial n:
blood pressures were recorded simultaneously with the cardiac output
determinations. The turkeys were hatched and raised by conventional it
means by members of the h. S. E. Department of Poultry Science. At
30 weeks of age the turkeys were divided into 3 strains; the H.S.U.
inbred strain, a commercial strain, and a cross between the M.S.U. and
commercial strain. Each strain consisted of 10 male BBB turkeys. At
this time, cardiovascular parameters were recorded pre- and post-
epinephrine injection.

The cardiovascular parameters and atherosclerotic scores, and the
common carotid blood pressures pre- and post-epinephrine and the per-
cent change in these parameters are presented in Tables 7, 8, and 9
reSpectivelV. Analyses of the hemodynamic data indicated a statistical
difference between strains, therefore, the data for each strain are
listed separately in each table.

There was no strain difference in cardiovascular parameters or
atherosclerotic scores or in the cardiovascular response to epinephrine.
An average of the three strains established the cardiac output for the

h

N Z .
untreated mature male BBB turkey as 231 ml per Lg0‘73P/min. In general,
epinephrine injection caused a decreased cardiovascular reSponse.

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_ 59 -

increased slightly but not sufficiently to maintain the pre-epinephrine

cardiac output/Kgo'734.
The M.S.U. strain had a significantly higher carotid and popliteal

blood pressure than did the commercial strain. The systolic blood pres-

sure of the commercial-M.S.U. cross was intermediate between the two

strains alone. The pulse pressures were high eSpecially in the M.S.U.

strain; however, this is apparently normal for the adult tom. It was I-

also observed that the common carotid arterial systolic blood pressure

was consistently higher than the systolic blood pressure in the popliteal

artery. Since the birds were in a supine position during the blood

pressure determinations, the difference between carotid and popliteal

arterial blood pressures was attributed to the greater peripheral re-

sistance encountered by the blood passing from the heart to the pepliteal

artery. Perhaps this increased resistance is encountered in the ab-

dominal aorta, a major site for obstructive atherosclerotic lesions.

Following the injection of epinephrine, systolic and diastolic blood

pressures increased about the same in the common carotid and pepliteal

arteries. Pulse pressure increased most in the group with the highest

pulse pressure (MSU group). Common carotid pulse pressures also ex-

hibited a greater percentage increase following epinephrine injection

than did the popliteal pulse pressures. This further indicates an area

of reduced distensibility between the heart and the popliteal artery.
The marked difference in aortic atherosclerotic severity may have

'been.influential in the cardiovascular and hemodynamic response to

epinephrine injection. Hence, the results were divided into two groups,

runnely, these birds with an aorta score less than 2.00 and these birds

wiiji an aorta score of 2.00 or greater.

_ 60 -

The cardiovascular parameters of adult male BBB turkeys with an
aorta score above or below 2.00 and their response to epinephrine in-
jection are presented in Table 10. The group with the higher aortic
score had a significantly higher minute volume and a significantly
higher cardiac output than did the low incidence group. Since the heart
rates of the high and low incidence groups were essentially the same,
the stroke volume was higher in the group with the higher incidence of
atherosclerosis. Following the injection of epinephrine, the group
with the higher aortic score demonstrated the greater cardiovascular
response. This response was noted only in minute volume and cardiac
output which decreased 25 and 27 percent respectively as compared to
the low incidence group which decreased only 17 percent for both minute
volume and cardiac output.

The common carotid and popliteal hemodynamic endpoints of adult
male BBB turkeys with an aorta score above or below 2.00 and their re-
sponse to epinephrine injection are presented in Table 11. The group
with the higher aorta score exhibited a higher mean common carotid
blood pressure which was due mainly to an increased systolic blood
pressure. Pepliteal blood pressures did not exhibit as noticeable
an increase as did the common carotid blood pressures. The group with
the least severity of atherosclerosis demonstrated a significantly
greater percentage increase in common carotid and pepliteal mean blood
pressure following the injection of epinephrine than did the high in-
cidence group. The greatest percentage increase was in systolic blood
pressure which was reflected by an elevated pulse pressure. It was
also noted that the injection of epinephrine increased the difference
between common carotid and popliteal hemodynamic parameters whether

in the high or low incidence group.

F.

- 61 -

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-03-

Experiment V: Determination g; Thoracic and Abdominal Aortic Elastance
gt Pressures Below, Equal £9 and Above the Physiological
Blood Pressure Ragge

 

For this study, 120 mature male BBB turkeys were divided into 6
groups and placed on experiment. They were reared in conventional hous-
ing and they received feed and water gd libitum. The study was designed
to accomplish several objectives at the same time. Group 1 was a heat __
treatment group. Untreated toms were taken from the outside during the

winter (temperature range -100 F to 200 F) and subjected to a tempera-

F

ture of 1000 F and a relative humidity of 65-75 percent for four hours.
Circulatory dynamics were recorded immediately after the heat treat-
ment. In chickens an increase in body temperature has been reported
to decrease blood pressure (Rodbard and Tolpin, 1947) and cardiac out-
put, but increase systemic resistance (Sturkie and Vogel, 1961). The
turkeys in Group 2 were placed on a 0.05 percent BAPN supplemented
ration for four weeks. BAPN interferes with normal collagen metabolism
and has been demonstrated to produce aortic rupture in turkeys. Group
3 was actually a subdivision of Group 2. After 4 weeks on a BAPN sup-
plemented ration one-half the turkeys in Group 2 were placed on a 0.05
percent BAPN plus 1 ppm reserpine supplemented ration for one week.
Reserpine, a commercial tranquilizer, at 1 ppm in the ration, has been
shown effective against aortic rupture in the field. The turkeys in
Group 4 were placed on a 1 ppm reserpine-supplemented ration for one
‘week. The turkeys in Group 5 were placed on 100 mg of ascorbic acid
(Viteumin C) per pound of feed for four weeks. Ascorbic acid is essen-
tdefl.;for normal collagen metabolism. Group 6 consisted of untreated

toms VflIlCh were used only for elastance studies.

1‘

_ 64 -

At the end of the treatment period, the toms were individually
placed on a wooden restraining holder and the cardiac output and common
carotid and pepliteal arterial blood pressures recorded simultaneously.
Following these measurements 0.5 ml of a 1/25,000 dilution of epine-
phrine was injected into the bird and the same cardiovascular parameters

were measured. Each bird therefore served as its own control. When

i

these measurements were completed, the turkey was sacrificed and the

entire aorta removed. Thoracic and abdominal aortic segments were re-

ti Old: ”E015."

moved, cleaned, their branches tied and their elasticity measured.

The remaining portion of the aorta was cut Open and visually scored

for atherosclerotic severity. Following the determination of elastance,
the abdominal aorta was also scored.

The results are presented in Tables 12—30. Cardiovascular and
elasticity parameters will be discussed separately. The correlation
tables will also be discussed separately to relate these parameters
to each other. Since there was no interaction between strains and
treatments, in any of the evaluations, it is assumed that all the
strains reacted similarly to the treatments. BAPN does not influence
hemodynamic parameters (Ringer, 1961) therefore the BAPN group could
be used as a control for the cardiovascular and hemodynamic determinations.

The cardiovascular parameters of adult male BBB turkeys pre- and
post-epinephrine injection and their percent change are presented in
Tables 12, 13 and 14, respectively. Before the injection of epinephrine
the only strain difference that existed was in heart rate and stroke
volume. In this respect, the M.S.U. strain had a higher heart rate and
therefore a lower stroke volume than did the commercial strain. The

heart rate of the heat and BAPN groups was highest; however, reserpine

 

-05-

alone or when added to the BAPN group significantly decreased the heart
rate. Although reserpine lowered the heart rate, stroke volume was
increased sufficiently to produce a significantly higher cardiac output
per Kg0°73# than was found in the other treatments. Heart weight was
lowest in the BAPN group and the weight was not altered by reserpine
administration.

Following the injection of epinephrine there was no strain differ-
ence in cardiovascular parameters. In general, all cardiovascular
parameters decreased, probably due to the increased peripheral resist—
ance. Minute volume was significantly decreased in the BAPN group which
was not mediated as much by a reduction in heart rate as it was by a
reduction in stroke volume. The BAPN group, therefore, had the lowest
cardiac output per Kg0°734. Reserpine and vitamin C did prevent minute
volume and hence cardiac output per Kg0'73br from drOpping as much as
that in the BAPN and heat groups following the injection of epinephrine.

The common carotid and popliteal hemodynamic parameters of adult
male BBB turkeys pre- and post-epinephrine and their percent change
are reported in Tables 15-17 and 18-20, respectively. Prior to the
injection of epinephrine there were strain and treatment differences
in all of the carotid and popliteal hemodynamic parameters. The M.S.U.
strain had the highest hemodynamic parameters and the commercial strain
the lowest with the cross between the two strains falling somewhere in
between.

In general, before the injection of epinephrine, the popliteal
hemodynamic parameters were lower than those of their carotid artery
counterparts. Again, this may well reflect a pressure reduction over

an area of increased resistance such as the atherosclerotic lesions

-66..

which develOp spontaneously in the abdominal aorta during aging. In
both the carotid and popliteal blood pressures, the BAPN and heat
treated group had a normal mean blood pressure; whereas, reserpine
alone or in combination with BAPN, significantly reduced the mean
blood pressure. Reserpine accomplished this decrease in mean blood
pressure principally through a reduction in diastolic, and to a lesser
extent, systolic blood pressure. Reserpine also significantly lowered
the systemic resistance. Pulse pressures were significantly lowered
in the vitamin C group. This was accomplished through a reduction in
systolic blood pressure and an increase in diastolic blood pressure.
Since diastolic blood pressure is dependent upon the elastic recoil

of the aorta and since vitamin C promotes collagen anabolism, the in-
creased diastolic pressure was most likely brought about by the in-
creased number of collagen fibers in the thoracic aorta.

Following the injection of epinephrine, significant strain dif-
ferences were found only in systolic, diastolic and mean pressures.
Again in both carotid and popliteal arteries, the M.S.U. strain reached
higher pressures following epinephrine injection than did the commer-
cial strain, probably because they were higher initially. When epine-
phrine was injected, the hemodynamic parameters of all treatments
increased. Although the reserpine treated group had one of the greater
percentage increases in mean pressure following the injection of
epinephrine, it began at a lower level and the absolute value attained
still tended to be lower than the mean pressures of the other treat-
ments. Heat for some reason significantly elevated the epinephrine-
inducemilnean pressure above all other treatments. This was accomplished

mainljr'through an increased systolic blood pressure. Heat, however,

 

-07-

did not significantly alter the heart output (minute volume) in relation
to the other treatments and, therefore, did not lower the calculated
systemic resistance. Since epinephrine is a peripheral vasoconstrictor,
carotid and popliteal systemic resistance units increased as expected,
but less so in the BAPN and vitamin C groups. This increased systemic
resistance had a negative affect on cardiovascular parameters.
In reporting the static elastic preperties of the arterial wall, ?-

the values were divided into three pressure ranges. Elastances were

a. rmfi'; 17.7 7

calculated at 25 mm Hg intervals at pressures below the normal physio-
logical systolic blood pressure range (25-150 mm Hg), at the normal
physiological systolic blood pressure range (175-350 mm Hg), and above
the normal physiological systolic blood pressure range (375-500 mm Hg).
The mean elastance values under the various treatments at pressures
below, at and above the physiological systolic blood pressure range
are presented in Tables 21-23 respectively for the thoracic aortas

and in Tables 24-26, respectively for the abdominal aortas.

In general, throughout all the pressures the thoracic aortas were
more distensible than the abdominal aortas and this became more pro-
nounced at higher pressure values (Figs. VI, VII). These results were
expected as collagen has a much higher elastance value when compared
to elastin (Bergel, 1961) and collagen comprises the majority of the
abdominal aorta whereas elastin predominates in the thoracic aorta
(Hass, 1942). All values reported herein are for a 20 mm length of
aorta. Increasing the length to 30 mm lowers, whereas decreasing the
length to 10 mm increases, the elastance value (personal observation).
A piece of pure rubber tubing 20 mm in length and of the same approxi-

mate diameter and thickness as that of the average aorta was subjected

 

 

(A

-70-

to pressures and the elastances calculated. The rubber tubing was
much more elastic than either the thoracic or abdominal aortas, es-
pecially at higher pressures where it was 2.5 times more elastic than
the abdominal aorta and over 10 times more elastic than the thoracic
aorta.

The data agree with elastances calculated for thoracic aortas of
rabbits (Balkrishna gt al., 1961), and dogs (Peterson, gt él- 1960)
but not with elastance values reported by Bergel (1961) for dogs.
Bergel (1961) used 60 mm lengths of aorta, which were much longer than
those used in this experiment and may account for the differences.
Bergel also reported no difference between elastances of the thoracic
and abdominal aorta whether below, at or above the systolic blood pres-
sure of the dog. The data of this experiment demonstrates a slight
difference in elastances between thoracic and abdominal aortas at low
pressure ranges. This difference becomes magnified as the pressure
is increased until at 500 mm Hg the abdominal aorta is 5-6 times more
elastic than is the thoracic aorta.

At pressures below the normal physiological systolic blood pres-
sure range of the adult male BBB turkey the untreated and vitamin C
group thoracic aortas had the highest elasticity. The vitamin C group
had significantly higher elastances at pressures above 100 mm Hg than
did the other groups. BAPN decreased elasticity and reserpine added
to BAPN or reserpine alone improved the elastance values, especially
at the higher pressures, but they did not approach the untreated
elastance values. In the abdominal aorta, reserpine alone maintained
elastance at the untreated and vitamin C level but it did not overcome

the lowering of elastance by BAPN. In the abdominal aorta, however,

-71-

heat treatment tended to improve elastance whereby it decreased elastance
in the thoracic aorta.

At pressures within the normal physiological systolic blood pressure
range both vitamin C and heat treated thoracic aortas had improved
elastances over the untreated values. BAPN or reserpine at this pres-
sure range apparently did not influence elastance values although re-
serpine tended to decrease elastance. In the abdominal aorta BAPN
again lowered elastance values and reserpine in combination with EAPH
offered no protection. Reserpine alone, however, maintained elastance
values at the untreated level which differed from its effect on the
thoracic aorta. Vitamin C and heat treatment again significantly im-
proved elastances.

Tables 23 and 26 may be termed stress tables for these present
the pressures attained by tom turkeys during stress or excitement. In
our laboratory, temporary pressures up to and in excess of 500 mm Hg
have been produced in mature male BBB turkeys by injection of 0.5 ml
of 1/25,000 epinephrine. At pressures above the normal physiological
systolic blood pressure range the beneficial effect of vitamin C on the
thoracic aorta was most noted. Heat treated groups still remained
higher than the untreated lots, but did not reach the vitamin C values.
BAPN did not seem to decrease elasticity whereas reserpine did tend to
reduce elasticity. When the thoracic aortas were subjected to pressures
above 400 mm Hg, however, 30 percent of the aortas ruptured in the BAPN
lot, 25 percent in the BAPH plus reserpine lot, 10 percent in the re—
serpine lot and only 5 percent in the untreated and vitamin C lot. He
aortas were ruptured in the heat treated lots. In the aodominal aorta

the vitamin C let had the highest elastance value. The aortas of the

“.E'...fiU-L('
L.
|

fr"

-72..

birds in the untreated and heat treatments had the same elastances.

BAPN alone and in combination with reserpine continued to significantly
lower elastance values. The reserpine group had elastance values be-
tween the BAPN and the untreated groups. Also of interest was the fact
that it was not possible to rupture any abdominal aorta under any treat-
ment, even when pressures of 500 mm Hg were exceeded.

The results of three successive pressure volume (Hysteresis) curves
obtained from the same segment of thoracic and abdominal aorta are pre-
sented in Figures VIII and IX, respectively. During successive infla-
tions, all vessels became progressively larger. In the thoracic aorta
the first cycle of inflation and deflation resulted in a wide loop,
and at the end, the zero-pressure volume had increased considerably.
The width between the initial inflation and deflation was not as wide
as the initial cycle reported by Bergel (1961), however, the size of
the aortic segment was also smaller (20 mm) than that reported in 1961
by Bergel (60 mm) for dogs. The inflation curve of the initial cycle
demonstrates that the thoracic aorta of the male BBB turkey has a
linear distensibility up to a high pressure range and that the thoracic
aorta was most distensible in the physiological systolic blood pressure
range. As the hysteresis 100ps were repeated they became closer to-
gether until after the third cycle they were almost identical.

Analysis of the hysteresis curve for the abdominal aorta shows
that it is much more elastic than is the thoracic aorta, probably due
to its greater amount of collagen. Again the 100ps became narrower and
closer together with successive cycles. The abdominal aorta is quite
distensible up to a pressure of 100 mm Hg after which the pressure
volume curve begins to plateau as more and more connective tissue

elements are brought into play.

_ 73 -

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Typical pressure—volume curves of untreated, BAPN, and vitamin C
treated thoracic and abdominal aortas are presented in Figures X and
XI, respectively. A piece of pure rubber tubing, identical in size
to the aortic segment used is shown for comparison. Ascorbic acid
appears to have increased the elasticity of the thoracic and abdominal
aortas whereas BAPN treatment had no effect in the thoracic aorta but
did, however, decrease the elasticity of the abdominal aorta. Increas-

ing the length of either thoracic or abdominal aortic segments from

 

20 to 30 mm markedly increased their distensibility. Both aortic seg~
ments were considerably more distensible than a 20 mm length of pure
rubber tubing with a thickness comparable to the vessels used in this
experiment.

Partial correlation coefficients of three variates of cardiovascular
parameters are presented in Tables 27 and 28. Systolic blood pressure
was positively correlated with diastolic blood pressure, heart rate and
blood vessel thickness. Williams Ei.él' (1962) also found a significant
positive correlation between systolic blood pressure and total aortic
thickness or the ratio of intimal to total thickness. Fregly (1962)
found a positive relationship between systolic blood pressure and heart
weight in rats. Diastolic blood pressure was positively correlated
with heart rate and blood vessel thickness but demonstrated a negative
correlation with heart weight. Blood vessel thickness was positively
correlated with pulse pressure but negatively correlated with heart
rate. Pulse pressure, heart weight and percent change in systolic
blood pressure following the injection of epinephrine were all posi-
tively correlated with body weight whereas systolic blood pressure,

heart rate and thoracic elastance at 250 mm Hg were negatively correlated

 

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-78-

with body weight. Minute volume was positively correlated with stroke
volume and negatively correlated with heart rate whereas stroke volume
was positively correlated with heart rate but negatively correlated

with systolic blood pressure and blood vessel thickness. The percent
change in systolic blood pressure was negatively correlated with diastolic
blood pressure, pulse pressure, blood vessel thickness and thoracic
elastance at 250 mm Hg.

Correlation coefficients of two variates are presented in Tables

K‘s-"4mm,“ (n,
V

29 and 30. In general, it was found that pulse pressure was positively
correlated with diastolic blood pressure and thoracic elastance at 250
mm Hg but negatively correlated with the percent change in systolic
blood pressure subsequent to the injection of epinephrine. The percent
change in the systolic blood pressure of the popliteal artery following
epinephrine injection was positively correlated with minute volume and
negatively correlated with diastolic blood pressure. Abdominal elast-
ance or atherosclerotic severity could not be correlated with any

cardiovascular or hemodynamic parameters.

-79-

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- 83 -

 

 

 

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Hmmm.0 + 0mmfi.0 + *NH0H0.0 + ::mm.0 + N.mxh
wfimo.o + wawo.o I momm.o + mmmfi.o + m.NNN
NNNQQm.o + Hmmm.o + *Nmmom.o I NNommw.o I NNN.H
*imom.0 + mwwm.0 + *0mmd.0 I **mmmw.0 I %.pr
Hmfim.o I wwmm.o + *Nmmoo.o + *mwm:.o I N.axp
ammo.o I momm.o + mmom.o + *Nmmmm.o I N.NNN
>m u m mmm n m 3m n m 3m u m
szmuN mmmqwmnN mmmquuN onmmmuN
mmm u % >2 u h A80 H>m u % Aevwm SE 0mm 00m u a
-3m n K .NH om po¢ n x .HHH> ADV mm H x .HH> onmmmnw.fi H x .H>
mmpmflpm>
whmpmswpmg amasomm>0flvpmo mo A:Huv mpcmflOfiMMmoo :0flpmfimhpoo Hmflppwm .wm manwe

-96..

Table 29. Correlation coefficients ("r") of two variates

 

 

Variates "r"

 

Carotid Artery

 

SBP VS Ht Wt + 0.1040
DBP VS PP + 0.5054*
PP VS E Q 250 (T) + 0.5598*
PP vs Aor Sc - 0.1500
PP VS NV + 0.0949
PP vs HR - 0.0441
PP vs % _~ SBP after epinephrine - 0.6789**
E Q 250 (T) vs Aor Sc - 0.0477
E o 250 (T) vs MV + 0.0753
BVT (T) VS Ht Wt - 0.0444
BVT (T) vs MV - 0.1822
Ht Wt VS MV + 0.0987

 

* Indicates significance at the P 0.05 level.
** Indicates significance at the P' 0.01 level.

-97-

Table 30. Correlation coefficients ("r") of two variates

 

 

Variates "r" value

 

Popliteal Artery

E @ 250 mm Hg (A) vs Aor Sc - 0.0660
E @.250 mm Hg (A) vs %.1 SBP after epinephrine — 0.2854
E33 250 mm Hg (A) VS DBP + 0.3436
E<® 250 mm Hg (A) vs PP + 0.3543
E o 250 mm Hg (A) vs IN - 0.2950
Aor Sc vs %.I SBP after epinephrine + 0.3075
Aor Sc vs SBP + 0.2220
Aor Sc VS DBP + 0.0960
Aor Sc vs PP — 0.2127
Aor Sc vs MV + 0.2888
33.3 SBP after epinephrine vs DBP - O.5873**
$30 SBP after epinephrine vs PP — 0.2678
%¢QSBP after epinephrine vs MV + 0.5099*
DBP VS PP + 0.1269
DBP VS MV - 0.4245
PP VS NV - 0.0890

3_

 

* Indicates significance at the P<< 0.05 level.
** Indicates significance at the P<: 0.01 level.

DISCUSSION

These findings reveal that the blood pressure of the turkey in-
creases with age, being higher in the male than in the female. This
confirmed work of Ringer and Rood (1959) and Speckmann and Ringer
(1961) who, with Gibson and deGruchy (1955) suggested that hemodynamic
parameters were associated with the aortic rupture syndrome. In one
experiment, however, there was no sex difference in blood pressure or
cholesterol at 27 weeks of age, yet the male turkeys exhibited a higher
incidence of atherosclerotic plaques in the abdominal aorta than did
the female turkeys. A plausible explanation for this as compared to
other blood pressure measurements may involve environmental tempera-
ture as similar effects of temperature on blood pressure were observed
in experiments conducted during summer months. It was during this
warm weather that the blood pressures were recorded. A similar effect
of temperature (weiss and Borbely, 1957) and season (weiss gt gl., 1957)
on blood pressure has also been reported for the chicken. It may well
be that the high temperatures cause extreme peripheral vasodilation
thus reducing the blood pressure. The fact that reserpine at low levels
did not significantly reduce the blood pressure is not surprising as
the pressure levels were already at a low point. A strain difference
in blood pressure has been shown to exist in turkeys and this may be
associated with a possible strain susceptibility to aortic rupture.

Blood pressure measurements in the turkey consistently show common

carotid systolic blood pressures higher than those of the popliteal

-98-

. _ "‘3

=5" .

 

-99-

artery. In chickens, Iaupp, (1923, 1924) reported femoral mean pres-
sures lower than carotid mean pressures reported by Stubel (1910).
In considering the influence of resistance on pressure one must keep
in mind the point of resistance and the point of pressure measurement.
If the resistance is peripheral to the point of measurement, then in-
creased resistance results in increased blood pressures. 0n the other
hand, consider a length of tube with fluid flowing through it. Pres-
sure at the upstream end is always greater than at the other end be-
cause of the dissipation of energy in overcoming the resistance offered
by the entire length of tube to flow. Perhaps the lower blood pres-
sures toward the periphery were caused by the spontaneous obstructive
atherosclerotic plaques found in the abdominal aorta of chickens (Katz
and Stamler, 1953) and turkeys (Ringer, 1960). These lesions possibly
increased vascular resistance between the heart and point of blood
pressure measurement.

The work of Kroeker and Neod (1955) compares simultaneously re-
corded central and peripheral arterial pressure pulses during rest
and in a supine position. These workers recorded pressures directly
by intra-arterial needles and catheters. In general they reported
that peripheral systolic and pulse pressures, i.e., arm and leg, were
the same at rest and uniformly exceeded central systolic blood pressures.
These workers, and recently Tjong and Verheugt (1960), found that
diastolic and mean blood pressures in humans at rest showed a smaller
but uniform decrease toward the periphery. This confirmed previous
work by Wood gt al. (1951). Other work by Hamilton gt gl. (1936) and
Schnabel 2£.El° (1952) also showed that there was an increase in systolic
blood pressure peripherally, but that diastolic and mean blood pressures

remained relatively constant.

.3.

-I.
.‘

 

{PSTH
._.
.

 

— 100 —

A more recent report on comparative indirect blood pressures of
humans by Spittel gt gt. (1961) showed that in a resting supine posi-
tion, thigh systolic blood pressures were considerably higher than
systolic blood pressures measured in the arm. These researchers found
that in the majority of patients with abdominal aortic aneurysms, both
thighs had low systolic pressures as compared to those in the arms;
in fact, more than half of these patients had a lower systolic blood
pressure in the thigh than in the arm. Perhaps such low thigh pressures
were also due to obstructive atherosclerotic lesions in the aorta.
Spittel gt gt. (1961), however, did not measure the atherosclerotic
severity of their patients.

Normal systolic blood pressures in the neighborhood of 300 mm Hg
for male turkeys seem phenomenal when compared to human systolic blood
pressures of 120-140 mm Hg; in fact, so far as the author knows, male
BBB turkeys have the highest normal blood pressure reported for any
animal. It is possible that blood pressure may be the initiating and
final cause of aortic rupture. Atherosclerosis in advanced stages is
characterized by lipid infiltration into the media causing vascular
weakness (Best and Taylor, 1956) and coupled with an increased pulse
pressure (as occurs in the male BBB turkey) and the erratic hemodynamic
fluctuations, as might occur during stress (epinephrine injection),
the vascular layers may become separated resulting in a dissecting
aneurysm. Blood under high pressure forces its way between the layers
causing a bulging of the wall. Since the tension on the wall of any
fluid-containing cylinder is proportional to the radius (law of Laplace)
a vicious cycle is established progressively weakening the wall until

a sharp elevation of pressure causes the final rupture.

_ “2.

F:

- 101 -

In view of the increased blood pressure of the BBB male turkey
above other animals, and the higher pressure attained during stress,
it is highly probable that blood pressure may be an important factor
in the aortic rupture syndrome. work reported by Speckmann (1959)
demonstrated that reserpine, a hypotensive tranquilizer, significantly
decreased blood pressure in the adult male BBB turkey. The birds
exhibited no tranquilization. Later, the finding that reserpine affords
protection against aortic rupture in turkeys (Carlson, 1959; Barnett,
1960; Morrison, 1960; and Waibcl, 1960) certainly suggests that hemo-
dynamic aspects are important in this condition.

Since systolic blood pressure was primarily influenced by reser-
pine, it was thought that reserpine may have had some effect on the
heart itself, possibly altering cardiac output to absorb the greater
work load during stress conditions. A method was devised for continu-
ously recording the primary dilution curve of radiOphosphorus. This
eliminated arterial sampling and allowed a more accurate evaluation of
the primary curve. The normal cardiac output of the male BBB turkey
was determined as 231 ml per Kg0'734 per min. This is slightly higher
than cardiac outputs reported for the chicken (Sapirstein and Hartmann,
1959; Sturkie and Vogel, 1959), but slightly lower than that reported
in rats, (Sapirstein and Hartmann, 1959).

In order to evaluate the effects of stress on cardiovascular
dynamics, epinephrine was injected and the parameters measured.
According to'Wiggers (1955) epinephrine injection in mammals caused
peripheral vasoconstriction but central vasodilation resulting in a
net vasodilation. Epinephrine excites the heart causing an increased

heart rate, cardiac output and force of contraction and it is these

 

 

 

'7

- 102 -

cardiovascular parameters which increase blood pressure in view of a
decreasing vascular resistance. In the turkey epinephrine injection
increased heart rate initially by direct stimulation of the heart but
also caused peripheral vasoconstriction. As heart rate increased,
blood pressures increased quickly causing the homeostatic blood pres-
sure mechanisms to decrease heart rate. Apparently the aortic arch
and carotid sinus bodies (assuming these receptors are present in the

turkey) are very sensitive to blood pressure fluctuations as heart rate

 

was decreased almost instantaneously. Blood pressure continued to
rise, however, due to constriction of peripheral vessels caused by
epinephrine. It was during this period of decreasing heart rate and
increasing blood pressure that cardiac output was determined. With a
decreased heart rate and increased venous return, stroke volume must
increase if normal cardiac output was to be maintained. Following the
injection of epinephrine, however, stroke volume decreased 20 percent
and consequently so did cardiac output. Apparently an injection of
0.5 ml of 1/25,000 epinephrine was too high for the turkey. The in-
creased venous return to the heart, concomitant with an increased ar-
terial pressure so that the left ventricle can put out only a small
stroke volume, caused blood to be impounded in the lungs (Johnson

gt gt., 1937). This probably resulted in such a diastolic enlargement
that the reserve power of the heart was surpassed causing the heart to
decompensate. Such cardiac decompensation decreased both systolic
discharge and minute volume; yet blood pressure was still increased
due to the intense peripheral vasoconstriction. The net effect of
epinephrine injection in the turkey was a negative cardiovascular re-

sponse, although blood pressure was increased.

-103-

When epinephrine was injected into reserpine-treated turkeys
blood pressure increased significantly showing a greater percentage
increase than in untreated birds injected with epinephrine; however,
the absolute blood pressure attained was significantly lower in the
reserpine—treated group than in the untreated group. Reserpine did
not alter cardiac output per Kgo°734 before or after the injection of
epinephrine but it did tend to lower systemic resistance. Systemic
resistance in the reserpine-treated group demonstrated a smaller per-
centage increase following the injection of epinephrine than it did
in the other groups. Considering hemodynamic parameters to be of prime
importance in the aortic rupture syndrome, the prophylactic action of
reserpine on aortic rupture in the turkey appears to be due to its
hypotensive action both in normal and stress conditions. Since it is
reported that reserpine indirectly depletes bound serotonin in the
chicken (Huber and Link, 1962) thus causing vasodilation and hypoten-
sion it is postulated that this relationship of reserpine and serotonin
also exists in the turkey and is the mechanism by which the blood
pressure is reduced and prevented from rising very much following the
injection of epinephrine.

Although the injection of 0.5 ml of 1/25,000 epinephrine was
undoubtedly a considerable strain on the cardiovascular system, the
turkey apparently was able to adjust successfully to the pressure
fluctuations as there were no apparent adverse effects. The successful

adjustment to hypertension produced by epinephrine plus the beneficial

effect of non—hypotensive tranquilizers on aortic rupture (Burger Ei.él°

1961) coupled with the failure to rupture abdominal aortas in the

elastance determinations, even though pressures of 500 mm Hg were

-O-IA It,

 

- 104 —

exceeded, suggests that hemodynamics alone are not the cause of aortic
rupture.

Work in other laboratories on chickens and humans has demonstrated
an association between hypertension, hypercholesterolemia and athero-
sclerosis (Katz and Stamler, 1953). Very little work has been reported
concerning plasma cholesterol level in turkeys. ‘Waibel gt gt. (1960)
reported that the plasma cholesterol level of BBB turkeys was 129 mg
percent at 5 weeks of age.

The plasma cholesterol level of the BBB turkey was found to in-
crease from 4 to 16-18 weeks of age after which it plateaued. These
values correspond to those reported by Baibel gt gt. (1960) and they
continued to rise with advancing age. The plasma cholesterol level of
commercial turkeys was lower than that of the M.S.U. stock. The aortic
atherosclerotic scores and hemodynamic values were also higher in the
group with the higher plasma cholesterol level. It is a common thought
that the differences between the plasma cholesterol levels of groups
of turkeys may result from different dietary regimes; however, in this
experiment the same commercial turkey feed was fed gg libitum to both
groups and blood samples were taken at the same time of day for both
groups. It is therefore suggested that in addition to blood pressure
there may also exist strain differences in plasma cholesterol and
susceptibility to atherosclerosis.

There are no sex or strain differences in blood pressures (Ringer
gt gt. 1955) or plasma cholesterol level in pigeons yet there is a
marked strain difference in susceptibility to atherosclerosis (Clarkson
gt gt., 1959; Lofland and Clarkson, 1960; Prichard gt_gt., 1962).

These authors believe that atherosclerosis in the pigeon is genetically

._.——.—__.
~ M A

‘F‘:

 

 

-105...

determined. Ringer (1962) believes that a vascular weakness may be
bred into turkeys susceptible to aortic rupture.

Perhaps in certain strains of turkeys the significantly higher
blood pressure of the male above the female accelerates atherogenesis
to the point where the aortic vessel is significantly weakened and the
additional hypertension experienced during stress is sufficient to
cause rupture of the aorta. If

p

There was no sexual difference in plasma cholesterol; however, r
the male BBB turkey after 16 weeks of age has been reported to have a
significantly higher blood pressure than the female BBB turkey (Ringer
and Reed, 1959; Speckmann and Ringer, 1961). The severity of aortic
atherosclerotic plaques increased with age, being more severe in males
than in females. The greatest increase in plasma cholesterol level
was between 12-16 weeks of age, the age during which blood pressure
has been reported to be increasing rapidly in BBB turkeys (Ringer and
Reed, 1959) and the age during which aortic rupture occurs most fre-
quently (Ringer, 1959).

The importance of plasma cholesterol in atherogenesis is stressed
in the following example. If a cholesterol fed cockerel has a plasma
cholesterol concentration of 100 mg percent, chances are 1 in 2 that
it will have atherosclerotic lesions. If, however, the plasma choles-
terol concentration is 300 mg percent, there is still 1 chance in 10
that it has no lesions at all (Tennent gt gt., 1957). If the theory
of Tennent gt gt., (1957) applies to turkeys, the mature BBB turkey,
with a plasma cholesterol level of 249 mg percent would have a very
good chance of getting atherosclerosis. Yet, in this work, there was

no sex difference in plasma cholesterol but the males had a significantly

 

- 106 —

higher incidence of atherosclerosis than did the females. Also in
pigeons, there is no difference in the plasma cholesterol level be-
tween birds susceptible and resistant to spontaneous atherosclerosis,
yet there is a marked difference in incidence and severity (Clarkson
and Lofland, 1961). The aortic cholesterol but not plasma cholesterol
was found to parallel the incidence and severity of atherosclerosis in
chickens (Fisher gt gt., 1959). Also in man there is a marked sex

differential in death rates from arteriosclerotic heart disease in

 

middle age, yet there is no apparent sex difference for blood pressure
or cholesterol level (Stamler, 1962).

Reserpine administration at the level of 0.1 ppm and 0.2 ppm in
the feed of BBB turkeys did not offer any protection against the in—
crease in plasma cholesterol level or the severity of atherosclerosis
with advancing age. Reserpine at 0.2 ppm and above in the feed did
reduce blood pressure.

Reserpine has been shown to decrease elevated serum cholesterol
levels and inhibit the development of aortic atheromatosis in normo-
tensive and hypertensive rats maintained on an atherogenic diet (Smith
and Rossi, 1962). These investigators also demonstrated that reserpine

decreased blood pressure only in hypertensive rats and that the hyper-

 

tensive state increased the severity of atherogenesis in cholesterolized
rats which were not fed reserpine. In humans with hypertension, aortic

cholesterol was significantly higher than in normotensive patients;

 

however, this same relationship was not necessarily true for the blood
(Rosenthal, 1934). In the case of hypertension, the accumulation of
cholesterol in the human aorta was predictable, and this accumulation

was a function of initial concentration (Holmes gt_gt., 1958). Aortic

-107-

cholesterol concentration has been reported to parallel plasma choles—
terol concentration in the chicken (weiss and Fisher, 1959). Blood
pressure itself was able to influence the metabolism of cholesterol

in the human aorta (Holmes gt gt., 1958) and elevated blood pressure
has been reported to accentuate atherogenesis (Daley gt gt., 1943).

If the theory of Daley gt gt. (1943) that hypertension accelerates
atherogenesis in humans is correct, then even though the plasma choles-
terol levels of male and female turkeys are not significantly different,
the higher blood pressure of the males will accentuate atherogenesis.

Growing male BBB turkeys are very susceptible to Spontaneous
atherosclerosis (Gottlieb and Lalich, 1954; Carnaghan, 1955; Gibson
and deGruchy, 1955; Speckmann and Ringer, 1962). These areas of
vascular degeneration are found in the same general anatomical loca-
tion of the aorta as that in which the rupture normally occurs. Early
reports by Gottlieb and Lalich (1954), Carnaghan (1955) and Gibson and
deGruchy (1955) suggested that aortic rupture is not only precipitated
by a dissecting aneurysm, but occurs in association with spontaneous
atherosclerosis. Vascular degeneration could weaken the vessel suf-
ficiently so that it may held under normal physiological pressures,
but during stresses, when blood pressure is elevated, the vessel rup—
tures. Ringer (1962) has likened the atherosclerotic blood vessel to
tubeless tires with a damaged sidewall. The tire will probably hold
up over the smooth highway, but over the rough dirt road, it blows out
as the bumps increase the pressure inside.

When the turkeys were divided into two groups, one having a low
incidence (.< 2.00) and one having a high incidence (:> 2.00) of athero-

sclerosis, expected cardiovascular changes occurred with rising systemic

—108—

resistance. Turkeys with high aortic atherosclerosis had a higher
mean carotid blood pressure, which was due mainly to an increased
systolic blood pressure, cardiac output, and minute volume, than did
the low incidence group as the heart tends to overcompensate. This
means it is working harder. Since heart rates of the two groups were
essentially the same, the stroke volume was higher in the group with
the higher atherosclerotic severity. Popliteal blood pressures did

not exhibit as noticeable a difference as did carotid blood pressures

Ak' - ‘ F _V
-—a‘
I

”V
O.

 

when they were divided into groups based on atherosclerotic severity.
There were no apparent differences between popliteal hemodynamics in
the two groups. Following the injection of epinephrine, the low inci-
dence group demonstrated a marked increase in carotid mean blood pres-
sure. The greatest percentage inerease was in systolic blood pressure
which was reflected in an elevated pulse pressure. Systolic blood
pressure rose 37 percent as compared to only a 25 percent increase

in the high incidence group. Although there were no differences be-
tween pepliteal blood pressures of low and high incidence groups before
epinephrine, there was quite a difference following the administration
of epinephrine. Popliteal mean blood pressures demonstrated greater
percentage increases following the injection of epinephrine than did
carotid mean blood pressures. Again systolic blood pressure was re-
sponsible for the tremendous increase in mean blood pressure. The
popliteal systolic blood pressure increased 43 percent in the low
incidence group as compared to only a 25 percent increase in the high
incidence group. This was reflected in a greater percent change in
pulse pressure of the low incidence group (71 percent) as compared to

the high incidence group (52 percent). Perhaps the higher initial

{'1‘

-109-

blood pressure of the high incidence group was responsible for a lower
percentage increase following epinephrine injection. The decreased
cardiac output, however, was greater in the high incidence group (27
percent) than in the low incidence group (17 percent), possibly because
the high incidence group had a greater cardiac output at the beginning.
When vascular degeneration is produced by BAPN, which interferes
with connective tissue metabolism, a condition very similar to aortic

rupture occurs. Waibel (1960) and Barnett (1960) reported that re-

__- _ fl ‘.
J.

serpine retarded the onset of BAPN-induced aortic rupture. Reports
from Colorado indicate that vitamin C (Thornton, 1960) also delayed
the onset of BAPN toxicity and may possibly afford protection against
aortic rupture by its anabolical influence on collagen metabolism.
Collagen is responsible for most of the strength of blood vessels,
especially during hypertensive conditions. These findings place con-
siderable emphasis on vascular composition, both quantitatively and
qualitatively, and on their orientation.

Studies were therefore conducted to determine aortic elasticity
and to evaluate the influence of BAPN, ascorbic acid and atherosclerosis
on these values. Elasticity is that property of materials which en-
ables them to resist deformation by the development of a resisting
force or tension. The term must not be confused with distention.
Pressure and tension are the forces which determine the equilibrium
in a cylindrical vessel. The law of Laplace states that the pressure
and radius of a vessel determine the tension that is developed. The
greater the tension, the higher the elastance. Wolf (1952) believes
the phenomenon of aneurysmal expansion can be explained by the Laplace

equation. Pressure within a cylindrical vessel is the same in the

- 110 -

distended portion as it is in the undistended portion. Tangential
tension in the wall, however, varies with the radius, being very high
in the distended portion and low in the undistended portion. Rupture
therefore, when it occurs, will involve the distended portion. Ac-
cording to Hooke's Law, perfectly elastic or Hookean substances have
a linear stress-strain relationship. This proportionality is expressed
in familiar elastic moduli such as Young's modulus. The aorta, being
a viseo-elastic system, does not demonstrate such linearity between
stress and strain (Bergel, 1961). Assuming blood vessels to be cylindri-
cal and the evidence that the arterial wall is more extensible longi-
tudinally than circumferentially (Fenn, 1957), if change in length is
prevented, then the effective circumferential modulus becomes a function
of the radial and circumferential parameters (Lambossy and Muller, 1954).
The Young's modulus of an isotropic tube, which does not change
in length on inflation, was given by Love (1927). This equation was
rearranged into an incremental modulus by Bergel (1961). These re-
searchers, along with Burton (1951) and Balkrishna gt gt (1961) have
applied the law of Laplace to the aorta as they have used the change
in radius with a given pressure change to be indicative of the tension
developed. Love's equation has been rearranged so that a change in
volume with a given pressure change is indicative of the vessel's
elasticity. Although it is more practical to relate the modulus of
elasticity to pressure, the parallel arrangement and function of the
constituents in the arterial wall (Reuterwall, 1921) implies that the
properties of the arterial wall are more directly related to radius
than to pressure. Blumenthal (1956c) emphasizes this point as he

reports that blood pressure only changes by a factor of four between

 

 

- 111 -

the aorta and capillary bed whereas radius changes by a factor of 325.
Peterson gt gt. (1960) also related wall thickness and radius to
elasticity.

Reuterwall (1921) was the first to introduce the idea of "accommoda—
tion" that later became known as ”hysteresis" (Hood, 1954). Remington
(1955) and Bergel (1961) observed a gradual increase in vessel size
following several inflations and deflations which were accompanied by
narrowing of the hysteresis curve. Turkey aortas demonstrated their
greatest distensibility at the physiological blood pressure range.
Their extensibility was also impaired at pressures above and below
the physiological systolic blood pressure range. Roy (1880) studied
the relation between internal pressure and volumetric capacity and
also concluded that the aortic walls were most extensible at pressures
corresponding to the normal blood pressure of the animal and at higher
blood pressures the extensibility of the vessel wall was considerably
impaired.

Banga and Balo (1961) reported that the data for tensile strength
seemed to reflect more truly the severity of atherosclerosis than did
age, while the opposite was true for the modulus of elasticity. Burton
(1954), Peterson (1960) and Levene (1961) concluded that collagen
plays a direct role in the maintenance of tensile strength of the aorta
against abnormal stress. Lykke gt gt. (1960) found that the aortas
of BAPN~treated mice had lower breaking strains than did controls.
Levene and Gross (1959) had previously reported that the capacity to
maintain aortic tensile strength depends not only on the quantity,
but also on the state of aggregation of the collagen present.

The distensibility of the aorta, on the other hand, depends upon

- 112 -

the elastic properties of its components. The high degree of distens-
ibility of the aorta has been attributed to its large percentage (30-
40) of elastic tissue present (Hass, 1942). Nichol (1955) has shown
that the distensibility of the aorta of rabbits was increased in experi-
mental cholesterol atherosclerosis due to the deposition of cholesterol
and lipids in the intima of the arteries. Balkrishna gt gt. (1961),
also working with rabbits confirmed the work of Nichol (1955) but in
addition found that in the cholesterol fed rabbit, the distensibility
of the lateral diameter was increased whereas along the ventral diameter
the distensibility was decreased. Further, these researchers found
preferential sites for cholesterol deposition and plaque formation

along the areas of greater distention. Burton's (1951) theoretical
equilibrium diagrams further show how, in the presence of weakened
elastic tissue, as occurs in atherosclerosis, a slight increase in
pressure may cause the vessel to rupture.

There was a tendency for BAPN to decrease and vitamin C to elevate
the elastance values. This became more significant at elevated pres-
sures, when aortic rupture probably occurs. 0f significant interest
was the fact that the aortas from a high number of turkeys receiving
BAPN ruptured during the elastance determination. The rupture occurred
only in the thoracic aorta and could not be produced in the abdominal
aorta even when pressures of 500 mm Hg were exceeded. This suggests
that the tensile strength of the aorta may be more important than its
elasticity. This theory was also suggested by Mass (1942) and Banga
and Bale (1961).

'Further, histological examination of atherosclerotic and non-

atheroscleretic aortas by the author (not reported) showed that in

 

-113-

non-atherosclerotic aortas, the elastin and collagen components are
arranged in an orderly, laminated manner which is probably necessary
for their greatest strength as a visco-elastic system. In the aortas
affected with atherosclerosis, the vascular components were very dis-
organized with considerable lipid infiltration, reaching far into the
media. Vitamin C increased and BAPN decreased the number of collagen
fibers per unit area but did not correct this vascular disorganization.
'With vitamin C, elasticity is improved, but maximum tensile strength
is not attained.

Also of interest in the elasticity data was the fact that
elastances at lower pressures were high; they then decreased to a
point and then increased consistently with an increased pressure.

The increase in elastances at low pressures has been ascribed to the
muscular elements in the arterial walls. These are thought by Remington
(1957) to be less distensible than elastic tissues, but also to have

a larger viscous "dashpot" in series (Maxwellian element). This would
in time give a decrease in the effect of the muscle—restoring force at
a given length (Burton, 1954). This explanation, however, for the
increase in elastance at lower pressures is not in agreement with the
results of Alexander (1947) who found that the rate of distensibility
did not greatly alter the pressure-volume curve of an isolated dog
aorta, which in essence, tends to obliterate the significant dashpot
concept. The increase of elasticity at the higher pressure is thought
to be related to the increased stretch put on some of the connective

tissue elements in the arterial wall (Burton, 1954; Remington, 1957).

 

-114—

Although atherosclerosis seems to be involved in the aortic rupture
syndrome, the high blood pressure of the male BBB turkey may aggrevate
this condition by causing abnormal cholesterol metabolism in the aorta,
increased plaque formation and arterial degeneration thus reducing
distensibility and paving the way for rupture. The hypertension ex-
perienced following a stress may be the pressure-head necessary to
rupture the weakened aorta. The benefit of reserpine to the aortic
rupture syndrome may be due to its hypotensive action and ability to
smooth hemodynamic fluctuations which occur during stress rather than

its ability to alter cardiac dynamics or vascular components.

 

 

SUMMARY

Plasma cholesterol level was found to increase with age in both
male and female Broad Breasted Bronze (BBB) turkeys from 4 weeks of
age to approximately 16 weeks of age after which age the plasma
cholesterol level plateaued. The adult plasma cholesterol level was
determined as 249:8 mg percent for commercially purchased turkeys and
344:13 mg percent for M.S.U. turkeys. There was no sexual difference
in plasma cholesterol level.

In these experiments atherosclerosis began early in age, for by
8 weeks of age all turkeys had either microscopic or macrOSCOpic
atherosclerotic lesions. Atherosclerotic scores of the abdominal
aorta indicated a greater severity for the males than for the females.
Sporadically, certain individuals showed evidence of severe athero-
sclerosis. Individual aortas showed gradations in atherosclerotic
severity with aging of the birds. Reserpine administration at the
level of 0.1 ppm and 0.2 ppm in the feed did not offer any protection
against the increase in plasma cholesterol or the severity of athero-
sclerosis with advancing age.

The cardiac output of untreated mature male BBB turkeys was de-
termined by an isotope dilution technique using radioactive-phosphorus
(P32) as the indicator. Common carotid and popliteal arterial blood
pressures were measured directly and were recorded simultaneously with
the cardiac output determinations pre- and post-epinephrine injection

by means of two strain guages connected to a recording polygraph.

-115-

w

- 116 -

From the cardiovascular measurements systemic resistance was
calculated. The mean cardiac output of mature male BBB turkeys was
231:18 ml per Kgo°734 per minute. The cardiac parameters were not
affected by strain but were significantly influenced by atherosclerotic
severity. Turkeys with a higher incidence of atherosclerosis had a
greater minute volume, cardiac output and stroke volume than turkeys
with little or no atherosclerosis. The injection of 0.5 ml of
1/25,000 epinephrine caused a negative cardiovascular response;
minute volume, cardiac output and stroke volume decreased.

Blood pressures increased with advancing age in both male and
female BBB turkeys. Several of the hemodynamic parameters were in—
fluenced both by strain and atherosclerotic severity. The M.S.U.
strain of turkeys had a significantly higher systolic blood pressure
than did the commercial strain of turkeys with the cross between the
two strains of turkeys falling in between. The group of turkeys with
the highest atherosclerotic score also had the highest systolic blood
pressure. The popliteal arterial blood pressures were consistently
lower than their common carotid artery counterparts and were not in-
fluenced as much by strain and atherosclerotic severity. The injection
of epinephrine caused a pronounced elevation of blood pressure. This
was accompanied by a negative cardiovascular reSponse and a concomitant
increase in systemic resistance which elevated blood pressure. Reserpine
significantly reduced blood pressure whereas BAPN and vitamin C had no
affect.

Partial correlation coefficients of three variates of cardiovascular
and hemodynamic parameters indicated that systolic blood pressure was

positively correlated with diastolic blood pressure, heart rate and

-117-

blood vessel thickness. Diastolic blood pressure was positively
correlated with heart rate and blood vessel thickness but demonstrated
a negative correlation with heart weight. Blood vessel thickness was
positively correlated with pulse pressure but negatively correlated
with heart rate. Pulse pressure, heart weight, and percent change

in systolic blood pressure following epinephrine injection were all
positively correlated with body weight whereas systolic blood pressure,
heart rate and thoracic elastance at 250 mm Hg were negatively corre-
lated with body weight. Minute volume was positively correlated with
stroke volume and negatively correlated with heart rate whereas stroke
volume was positively correlated with heart rate but negatively corre-
lated with systolic blood pressure and blood vessel thickness. The
percent change in systolic blood pressure following the injection of
epinephrine was negatively correlated with diastolic blood pressure,
pulse pressure, blood vessel thickness and thoracic elastance at 250
mm Hg. Abdominal elastance or atherosclerotic severity could not be
correlated with any normal cardiovascular or hemodynamic parameters.

A method for the determination of the static modulus of elasticity
for the thoracic and abdominal aorta and an equation rearranged for
elastance calculations as a function of change in volume have been
develOped. The aortic segments were most distensible in the physio-
logical blood pressure range, the pressure-volume curves being sigmoid
in nature. The vessel segments also exhibited hysteresis. The thoracic
aortas were much more distensible than the abdominal aortas; the elastances
of untreated male BBB turkeys being in the neighborhood of 3.28:0.11 and

13.95:0.24 dynes/cm2 X 105 respectively in the physiological pressure

- 118 -

range. This difference becomes more pronounced at higher pressures.

At pressures below (25-150 mm Hg), at (175-350 mm Hg) or above (375-
500 mm Hg) the physiological blood pressure range, ascorbic acid treat-
ment tended to increase, whereas BAPN treatment tended to decrease,

elastance values.

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APPENDIX

I Modified Method for the Direct determination of Serum Cholesterol

REAGENTS

I

Standard Cholesterol Solution (1 mg per milliliter):
Dissolve 100 mg of pure, dry, ash-free cholesterol

in 100 ml of 100% glacial acetic acid (use only Merck
glacial acetic acid conforming to the dichromate test).

 

II Ferric Chloride Solution: Dissolve 10 gms. of ferric
chloride, reagent grade (Mallinckrodt ferric chloride)
in 100 ml of 100% glacial acetic acid (Merck).
III Color Reagent: Dilute 2.0 ml of the ferric chloride
solution to 200 ml with C. P. concentrated sulfuric
acid (Baker). To prevent ferric chloride from
precipitating, add 100 ml of sulfuric acid into volu-
metric flask then swirl while slowly adding 2.0 ml of
the ferric chloride solution. Then bring entire solu-
tion to 200 ml with sulfuric acid.
PROCEDURE:
Coleman Spectrophotometer
pc 14
Wavelength 560 millimicrons
Filter 14-214
Light path 13.5 mm
Amount of Standard Amount of Glacial Distilled Color
(1 mg/ml)_g Acetic Acid 'Water Reagent
0.1 ml 9.9 ml 0.1 ml 7.0 ml
0.2 9.8 0.1 7.0
0.3 9.7 0.1 7.0
0.4 9.6 0.1 7.0
005 905 001 . 700
Blank 10.0 0.1 7.0
Plasma (0.1 ml) 9.9 -- 7.0

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To 0.1 ml of plasma in a dry, clean 30 ml test tube add 10.0 ml
of Merck glacial acetic acid. To this add 7.0 ml of the color reagent
and mix immediately. It is desirable to run each tube in duplicate,
also each tube must be carried through separately and mixed immediately
by pouring from one tube to another several times to insure proper
mixing. Measure the percent transmission of the solution after it
has come to room temperature and determine the total cholesterol content
from a calibration curve. Cork test tubes while cooling to avoid loss
of mixture. The serum or plasma may be frozen once, but it must be

shaken after melting for accurate distribution of cholesterol.