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THE CHARACTERIZATION OF SPONTANEOUS
IDIOPATHIC HYPERTENSION IN
A COLONY OF DOGS

BY
Fredrick Earl Tippett

A DISSERTATION

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

DOCTOR OF PHILOSOPHY

Department of Pathology

1984

ABSTRACT
THE CHARACTERIZATION OF SPONTANEOUS

IDIOPATHIC HYPERTENSION IN
A COLONY OF DOGS

BY

Fredrick Earl Tippett

This study documents spontaneous idiopathic
hypertension in the dog but, presently, only loosely
associates iJ: with underlying pathology. The
characterization of a dog model of primary hypertension was
undertaken after a 5 year old female siberian husky dog was
diagnosed as idiopathic hypertensive. Femoral arterial
systolic, diastolic, and mean blood pressures were 200 mm
Hg, 150 mm Hg, and 175 mm Hg, respectively, at the time of
admission to the Veterinary Clinical Center. Other
abnormalities included bilateral retinal hemorrhage with
papilledema, aortic enlargement and tortuosity, and slight
pulmonary arterial and cardiac enlargement.

The propositus was bred over a period of 5 years and
produced several offspring. Over 10 propositus-progeny and
progeny-progeny matings have taken place, producing 37
animals. Thirty of these animals were conditioned,
subjected to femoral arterial blood pressure determinations,

and placed into 4 groups based upon mean blood pressure

Fredrick Earl Tippett

(MBP) values: group I (MBP 128112 mm Hg, n = 4), group II
(MBP 121:8 mm Hg, n = 9), group III (MBP 114:9 mm Hg, n =
8), group IV (MBP 101:9 mm Hg, n = 9). Groups I, II, and
III were significantly different from group IV (p<0.05).
Group I and group III were significantly different (p<0.05).
However, group I was not significantly different from group
II and group II was not significantly different from group
III. In combined groups, there was a significant positive
correlation of systolic blood pressure (SBP), diastolic
blood pressure (DBP), and mean blood pressure (MBP) with
age, r values being 0.40, 0.47, and 0.44, respectively.
Ten.animals were randomly selected from grouszL,II,
and III and clinically evaluated. Using the clinical tests,
we have not been able to show distinct differences from
group to group, but there were a few individual animals with
abnormally high values of left ventricular wall thickness
(LVWT), left ventricular thickness/body surface area
(LVWT/BSA), and left ventricular wall thickness/body weight
(LVWT/BW), upon echocardiographic examination. The only
marker at present is differences in MBP from group to group.
We expect the eventual unmasking of other abnormalities as

time progresses.

To

My mother (Mrs. Macie Tippett),
in memory of my father (Mr. Sam Tippett),
and my brothers and sisters ‘
(Yvonne, Kenneth, Mattie, Langford, Veronica, Glenn, Kelvin,
and Anthony).

ii

ACKNOWLEDGEMENTS

First of all, I thank God, who through my Lord and
Savior Jesus Christ, made all of this possible. I wish to
express my appreciation to members of my graduate committee
(Drs. Thomas Bell, Gary Blanchard, George Eyster, George
Padgett, and Robert Stephenson) for their assistance in my
program.

Thanks are also extended to many others who assisted me
in other ways, whether in technical, financial, or
I inspirational capacities. The list would be too long if I

included them all by name.

iii

TABLE OF CONTENTS

LIST OF FIGURES . . . . . . . . . . . . . . . . . . .
LIST OF TABLES . . . . . . . . . . . . . . . . . . .
LIST OF ABBREVIATIONS . . . . . . . . . . . . . . . .
INTRODUCTION . . . . . . . . . . . . . . . . .'. . . .
LITERATURE REVIEW . . . . . . . . . . . . . . . . . .
MATERIALS AND METHODS . . . . . . . . . . . . . . . .

Animals . . . . . . . . . . . . . . . . . . . . .
Indwelling Catheter Blood Pressure De erminations
Dinamap Blood Pressure Determinations . . . . .
Ophthalmic Examination . . . . . . . . . . . .
Blood and Urine Examination . . . . . . . . . .
Femoral Arterial Blood Pressure Determinations
Nonselective Aortogram . . . . . . . . . . .
Selective Left Ventricular Angiocardiogram .
Thoracic Radiography and Electrocardiography
Nonselective Venous Angiogram . . . . . . . .
Tissue Biopsy . . . . . . . . . . . . . . .
Plasma Catecholamine and Renin Activity
Determinations . . . . . . . . . . .
Excretory Urogram . . . . . . . . .
Renal Arteriogram . . . . . .

Echocardiographic Examination . . . .
Cerebrospinal Fluid Examination . . .
Blood Cadmium and Lead Determinations
Blood Gas Analysis . . . . . . . . .
Data Analysis . . . . . . . . . . . .

RESULTS AND DISCUSSION 0 O O O C O O O O O O O C O O 0

Validation of Femoral Arterial Mean Blood Pressures
Blood Pressure Level in the Propositus . . . . . .
Groups, Based Upon Blood Pressure Determinations .

Dinamap Blood Pressure Recordings vs Femoral Arterial

Recordings . . . . . . . . . . . . . . . . . . . .
Ophthalmic Examination 0 O O O O O O O O O O O O 0
Blood and Urine Examination . . . . . . . . . . . .

iv

Page
vi

viii

Nonselective Aortogram . . . .

Selective Left Ventricular Angiocardiogram .
Thoracic Radiography and Electrocardiography

Nonselective Venous Angiogram .
Renal Biopsy . . . . . . . . .
Plasma Catecholamine and Plasma
Determinations . . . . .,. . .
Excretory Urogram . . . . . . .
Renal Arteriogram . . . . . . .
Echocardiographic Examination .
Cerebrospinal Fluid Examination
Heavy Metal Determinations . .
Blood Gas Anlysis . . . . . . .

SUMMARY AND CONCLUSIONS . . . . .
RECOMMENDATIONS . . . . . . . . .
LIST OF REFERENCES . . . . . . . .

VI TAE O O O O O O O 0 O O O O O O

Renin

Activity

Figure

‘LIST OF FIGURES

The atapetal subalbinotic left eye showing
indistinct disc margins indicative of
papilledema (arrowsk. A pre-retinal
hemorrhage (a) and deep dot retinal hemorrhage
(b) are present ...............

The fundus photograph of the right eye showing
papilledema lifting the retina at the disc
margins (arrow) and a deep subretinal
suffusion hemorrhage (c) . . . . . . . . . .

Left ventricular angiocardiogram showing
aortic enlargement (Open arrows) and a slight
anterior displacement of the ascending aorta
(closed arrrowsL. (a) Catheter within left
ventricle. (b) Normal lung field . . . . . .

Left renal excretory urogram demonstrating
that the left kidney is normal in size and
shape. There is a slight increase in diameter
of the left ureter (arrows), probably as a
result of abdominal compression during the
procedure. (a) Lumbar vertebral body. (b)
13th rib. (c) Catheter in abdominal aorta .

Left renal arteriogram outlining the left
renal parenchyma and vascular network which
appear normal. (a) Renal artery. (b) Renal
cortex. (c) 13th rib. (d) Catheter within
renal artery . .. . .. . .. . .t.. . . .

vi

Page

0 O 38

C O 38

. . 40

o o 42

O O 42

Figure

Echocardiographic analysis of normal vs colony
animals showing in”: non-significant
comparisons of representative animals from
groups I, II, III when compared to each other
and to the normal, control group when
considering LVWT, LVWT/BSA, and LVWT/BW.
Despite the non-significance between groups,
individual animals from groups I and II were
significantly different from the normal
control group for all three parameters .. .

Siberian husky pedigree chart showing the
familial pattern of hypertension distribution
within the colony of animals. The colony
consists of some related animals but‘with.no
available information, normal and affected
males and females, dead or unavailable
animals, and animals at the University of
Pennsylvania which are maintained there byaa
breeding agreement. The animals are numbered
individually with date of birth listed above
the various litters. There was a significant
positive correlation of age with SBP, DBP and
MBP within the colony . . . . . . . . . . . .

vii

Page

44

46

LI ST OF TABLES

Table Page

1 Colony animals' mean blood pressures over a
five month period by age and category . . .... . 47

2 Selected comparisons of femoral arterial and
Dinamap blood pressure determinations . . . . . . 49

3 Selected comparisons Of ophthalmic examination
results 0 I I O O O O O O O O O O O O O O O O O 0 so

4 Clinical laboratory data from propositus after
admission to clinic . . . . . . . . . . . . . . . 51

5 Selected comparisons Of colony serum chemistry
analysis . .. . .. . .. . .. . . . . . . . . . 52

53

6 Selected comparisons Of colony urine analysis .

7 Selected comparisons of colony hematologic
anaIYSis O O O O O O O O O O O O O O O O O O O O O 54

8 Selected comparisons of colony electro—
cardiography evaluation . .. . .. . .. . .. . 55

9 Selected comparisons of plasma catecholamine
levels between group representatives and
prOPOSitus O O O O O O O O O O O O O O O O O O O O 56

10 Selected comparisons of plasma renin activity
between group representatives and propositus .. . S7

11 Selected comparisons of echocardiographic
analysis of colony representatives and
propositus . .. . .. . .I.. .. .. .. .. .. 58

12 Echocardiographic analysis of normal, non-
COlony Siberians O O O O O O O O O O O O O O O O O 59

13 Selected comparisons of colony cerebrOspinal
fluid examination data .. . .. . .. . .. . .. 60

14 Selected comparisons of plasma lead and cadmium
determinations O O O O O O O O O O O O O O O O O O 61

viii

Table Page

15 Selected comparisons of colony blood gas
analysis . . .. . .. . .. . . . . . . . . . . . 62

ix

LIST OF ABBREVIATIONS

BSA Body surface area

DBP Diastolic blood pressure

E Epinephrine

EH Essential hypertension

HR Heart rate

LVWT Left ventricular wall thickness
MBP Mean blood pressure

NE Norepinephrine

NSR Normal sinus rhythm

SBP Systolic blood pressure

INTRODUCTION

Systemic hypertension is an abnormal elevation in
arterial blood pressure, which if gone unchecked, usually
results in physiologic abnormalities and organ damage. It
is estimated that 16% of the American human population is
affected [1]. In human beings, the etiology is either
primary (essential) or secondary [2] [3] [4]. Secondary
hypertension constitutes approximately 5% to 10% of all
known cases and includes such subcategories as renal,
endocrine, neurogenic, mechanical interference, exogenous,
toxemia of pregnancy, and miscellaneous causes [5] [2] [6].
Primary, essential, or idiopathic hypertension comprises 90%
to 95% of all reported cases [5] [6].

The dog has long been used as an experimental model to
study various forms of secondary hypertension [7] [8] [9]
[10] [11] [12] [13]. However, in the dog, few cases of
naturally occurring secondary hypertension have been
reported [14]. No case of primary hypertension in the
canine has been clinically documented in the literature.

In this study, idiopathic hypertension was diagnosed in
a five year old female siberian husky dog after extensive
clinical evaluation. Representatives from the resulting

litters produced by the propositus were likewise evaluated

in order to identify, characterize, and further perpetuate

the condition in dogs.

LI TERATURE REVIEW

Hypertension in man has been studied and discussed over
a period of many years. Stephen Hale, in 1711 showed that
arterial pressure varied with the size of the animal,
excitement, bleeding and left ventricular stroke volume, and
noted the effects of hot water in relaxing and cold water,
quinine, cinnamon and alcohol in constricting the small
vessels [15]. Ludwig Traube, in 1856 proposed the associa-
tion of contracted kidneys with hypertrophy of the left
ventricle. He also noted the correlation of increased
arterial pulse tension and hemorrhagic retinitis [15]. TJL
Janeway published a classic, Clinical Study 2; Egg Blggd
Pressure in 1904, where he placed cases of normotensive
patients with atherosclerosis into the 'enfeebled heart"
category [15]. The syndrome of "essential hypertension" was
first named by Frank in 1911 [15]. Harry Goldblatt and his
coworkers became established figures in the history of
hypertension by discovering a workable method for the pro-
duction of experimental renal hypertension in 1934 [15]. By
restricting the renal artery pulsatile blood flow instead of
obstructing it entirely or damaging the kidney in other
ways, they could produce "benign” or "malignant" forms of
hypertension in the dog. Thus, they were responsible for
the return of emphasis to the kidney and one of its chemical

3

products (renin) in the genesis of hypertension. By the
early to mid 1900's, it was apparent to researchers that two
forms of arterial hypertension existed; one form was secon-
dary to a detected organic lesion but the second form was‘
not. Hence, the terms "secondary" versus ”idiopathic”,
”primary", or "essential".

Presently, hypertension has been reported worldwide and
believed to affect 15-20% of all adults [5]. It has been
estimated that hypertension afflicts 65 million Americans
‘with 25 million being borderline in pressure elevation. The
syndrome has been shown to cost the nation 20 billion dol-
lars in such areas as medical bills, lost wages, and lost
productivity [5]. The incidence of hypertension in the UJL
is 16%, 22% in blacks and 9% in whites [1].

There have been many defined and described secondary
causes of chronic blood pressure elevations. Ten to fifteen
percent of all cases Of hypertension have been shown to be
secondary in nature [5] with the majority of cases due to
renal abnormalities. Of the other secondary causes, endo-
crine etiologies have been defined.

Cases of pleochromocytoma have been shown to comprise
less than 1% of all the hypertensive population [16].
Sjoerdema gt 2l° found that 10% of these tumors were malig-
nant.and necessitated the use of alpha-methyl-tyrosine to
block synthesis of the increased catecholamines before

hypertension could be controlled [17]. Some of the benign

tumors detected were multifocal and apparently familial [16]
[18].

The adrenal cortex is an endocrine organ often
incriminated in the causation of various forms of secondary
hypertension. Cushings syndrome was first described by
Harvey Cushing'in 1932 [19]. It was held by Vetter gt’gl.
that 80% of all patients with Cushings syndrome had
hypertension [20]. Mendlowitz indicated that this syndrome
was associated with less than 1% of all hypertensive cases
[21]. It has been shown that the blood vessels become more
reactive to nonepinephrine [22] [23]. Also, there has been
shown to be an increase in renin substrate and angiotension
II [24]. However, the validity of this pathogenesis has
been challenged [25].

In 1955, Conn first described a patient with
hypokalemic hypertension due to an aldoesterone-producing
adenoma of the adrenal cortex [26]. Vetter reports that
primary aldosteronism is caused by an adenoma of the adrenal
cortex in 70-80% of these cases [25]. Idiopathic bilateral
adrenocortical hyperplasia has been thought to be the cause
of primary aldosteronism in 20-30% of the patients [25].
Hypertension due to glucocorticoid suppressable aldostere
onism has been shown to be amenable to glucocorticoid ther-
aPY [27].

Cases of hyperaldosteronism and hypertension have been
described as being associated with extra-adrenal tumors [28]

[29]. Two forms of adrenocortical hyperplasia accompanied

by hypokalemia and hypertension have been described in man:
ll-hydroxylase deficiency and 17-hydroxylase deficiency [25]
[30]. Virilization and excess androgens accompanied persons
affected with the former disorder while amenorrhea and male
pseudohermaphroditism was seen in those affected by the
latter defect [31]. I

The prevalence of hypertension in cases of parathyroid
hyperfunction ranged from 10% to 70% [32]. NevertheleSs,
the pathophysiologic association has not been made. In one
case, an underlying renal abnormality was observed but in
other studies, no linked organic abnormalities have been
determined [33] [34) [35].

In a study of 458 hyperthyroid patients, Hurxtal found
a systolic blood pressure of 150 mm Hg or higher in 26% of
the patients overall, and in 42% of those with severe hyper-
thyroidism [36]. Hypertension associated with this
condition was characterized by an accelerated peripheral
circulation arising from a dilation of arterioles and meta-
arterioles [37] [38]. Other clinical signs associated with
this disease state included tachycardia, arrhythmia, and
high cardiac output [37] [38] [39].

The central nervous system (CNS) has also been noted to
contribute to "secondary" hypertension. There has been much
speculation as to what extent the CNS and Specifically the
autonomic nervous system play in the development and
maintenance of high blood pressure. It is known that there

was elevation of sympathetic activity in hypertension, thus

strongly implicating the CNS as having a role in elevated
arterial pressure [40]. However, it could not be determined
whether this increased activity initiated or maintained it.
Cobb and Rose showed a significant correlation of increase
in hypertension in occupations of intense mental activity
[41]. Harris £5 31. Showed by epidemiological data that
individuals classified as tense developed hypertension more
frequently than those who were not [42]. It has been
documented that a specific emotional stimulus can result in
transient increases in blood pressure [43] [44]. Kaplan
indicated that hypertension may occur in association with
increased intracranial pressure from any cause [30].
Cameron and Daig observed a paroxysmal form of hypertension
in patients with tumors of the cerebellum [45]. Evans 35
_l, observed similar results [46]. Julius listed several
causes of hypertension due to neurogenic abnormalities:
brain tumors, encephalitis, bulbar poliomyelitis, familial
dysautonomia, acute porphyria, quadriplegia, and extra-
adrenal chromaffin tumors [2].

Conditions affecting the mechanical interference with
blood flow have been shown, likewise, to initiate secondary
forms of hypertension. Hypertension seen in cases of patent
ductus arteriosus and aortic insufficiency were shown to be
due to a compensatory increase in systolic blood pressure
[47). It has been shown that coarctation of the aorta
causes a rare but curable form of hypertension in children

[48]. Blood pressure elevationtin these cases is believed

to be caused in part by maladies within the renin-
angiotension system [6]. Kaplan reported an adult form of
this aortic narrowing as well as the infantile form [30].

Chobanian indicated that systolic hypertension is a
common clinical problem in the elderly [49]. Pure systolic
hypertension in the study was defined as a systolic blood
pressure equal to or greater than 160 mm Hg and a diastolic
pressure of less than 90-95 mm Hg [49]. Kannel indicated
that the chief cause of excess morbidity and mortality in
these hypertensives is an increased propensity to athero-
sclerotic disease and thus interference with blood flow
[50].

Zeigler and Mast noted that arteriovenous fistulas are
a rare cause Of hypertension but when present are accom-
panied by hypertension in 45% of the cases [51]. This
elevated blood pressure was thought to be due to a signifi-
cant increase in the circulating blood volume or renal
parenchymal ischemia causing an increase in renin release.
AV fistulas in the kidney have been described as congenital
or acquired.

Another condition in man which has been known to cause
interference with the mechanical flow of blood and resulting
in secondary hypertension is Pagetfs disease. This disorder
has been associated with hemodynamic changes characterized
by cutaneous vasodilation in the skin and subcutaneous

tissue overlying involved bones. .When 1/3 to 1/2 of the

skeleton was affected, the increased blood flow has been
linked to high cardiac output-hypertension [52].

Several exogenous causes Of secondary hypertension were
listed by Julius [2]. Poisoning with heavy metals, lead and
thallium, was reported to cause hypertension. Cadmium
induced hypertension in rats, rabbits and dogs, either when
injected intraperitoneally, or intraarterially or when
administered orally [53] [54] [55] [56]. However, the
significance of the relationship between cadmium and human
hypertension is uncertain. Low blood levels of zinc and
magnesium have been detected in some hypertensives [57]
[58].

A number of unrelated drugs have alsolbeen.associated
with hypertension. Weber indicated that monoamine oxidase-
inhibiting drugs prevented the wholesale degradation of
nonepinephrine in the postganglionic nerve fiber thus
potentiating the strong vasopressor response when such drugs
were administered with antihypertensive drugs such as
reserpine [59]. An association between the use of oral
contraceptives and the occurrence of high blood pressure was
reported in 1967 [60]. Since then, much discussion has
taken place concerning this relationship. The actual cause
of the hypertension has been suspected to be due to an
increase in the renin-angiotension system with increases in
renin substrate and aldosterone [61] [6]. Exogenous
administration of steroids in high doses have been known to

cause Cushing-like syndrome with elevation of blood pressure

10

and other complications [62] [63] [64]. Excess licorice
ingestion has been shown to cause hypertension due to the
sodium-retaining activity of glycyrrhizinic acid [65] [66].

Approximately 60% of all cases of hypertension during
pregnancy has been stated to be due to another secondary
form of hypertension, toxemia Of pregnancy [61]. Toxemia of
pregnancy has been described as a triad consisting of hyper-
tension, edema, and proteinuria Of which hypertension is the
most frequently demonstrable [61] [67]. Exogenous precursor
peptides formed in the placenta, renin-angiotension system,
vascular spasms, prostaglandin release» intravascular
coagulation, and specific glomerular renal lesions have all
been suggested as having impact on the develOpment of the
hypertension.

There have been many miscellaneous causes of secondary
hypertension reported in the literature. Hypertension asso-
ciated with a high hematocrit has been reported in two types
of patients. Gaisbock and others described a benign form of
polycythemia with a hematocrit near the upper limit of
normal and reduced plasma volume [68] [69] [70]. The bone
marrow, white blood cell count, and platelet count were
normal. While the cause is unknown, a ”stress factor“ was
suggested as a possible etiology. In a second group of
patients, polycythemia and hypertension were associated with
non-neoplastic renal disease such as hydronephrosis, poly-

cystic kidney or renal artery stenosis [71]. The specific

ll

nature of the increase in red blood cell production and bone
marrow stimulation is not known.

Lowery found sustained hypertension in 13 of 53
children with burns covering 10-75% of their bodies. The
cause of the hypertension was not ascertained, however [72].

Schwartz made an association of carcinoid syndrome with
essential hypertension [73]. The release Of vasoactive
amines were thought to be in part responsible for the
elevation in blood pressure.

Many types of secondary hypertension have a renal
parenchymal component. Hayduk stated that there are few
types of hypertension in which primary or secondary hyper-
tension can be excluded with certainty [74]. He further
stated that the mechanism of hypertension in acute glomer-
ulonephritis may involve sodium and water retention
resulting from the glomerular lesion. In one study, 20.3%
of patients with malignant hypertension were found to have
associated glomerulonephritis [75]. Hypertension was found
to be present in 60-75% of cases Of chronic atrophic pyelo-
nephritis [76] [77]. It has been suggested that an ischemia
induced increase in renin secretion may be responsible for
the hypertension in pyelonephritis [74]. Exposure of the
kidneys to radiation has been Shown to lead to the develop-
ment of hypertension weeks and even years after the exposure
[75] [78]. In one report it was indicated that a 39% inci-
dence of hypertension was Observed after irradiation [79].

Very severe hypertensive states have been known to result

12

from the adult form of cystic renal disease [74] [67].
Though the direct mechanism of the elevation in blood pres-
sure is not known, ischemia due to cystic renal changes is
considered possible. Sodium and water retention have been
known to occur. The renal parenchymal disturbance in lupus
erythematosus has also been associated with hypertension.
Some authors reported a 25.2% incidence of hypertension in
systemic lupus erythematosus based on an analysis of 520
cases [80]. A few cases of hydronephrosis have been asso-
ciated with hypertension [81]. The speculated mechanism of
hypertension could be ischemia due to pressure in the inter-
lobular arteries and/or the loss of prostaglandin-secreting
interstitial cells from the renal papilla. Similarly,
several tumors within the renal parenchyma with renin-
secretory function have been associated with hypertension
[71] [72] [73]. These tumors, though anatomically small,
have very high concentrations of renin. In addition, the
non-secretory tumors, Wilm's tumor and hypernephroma, have
been associated with hypertension [85] [86] [87]. Finally,
hypertension is reported to be present in between 60 and 78%
of patients with diabetic nephropathy [88] [89] [90].
Renovascular hypertension has been known to occur in
many forms. Most patients with polyarteritis nodosa and
renal involvement were Shown to be hypertensive [91]. The
mechanism was assumed to be due to ischemia of the areas of
renal cortex which lie distal to the affected arteries.

"True" renovascular hypertension, however, has been

13

associated with renal artery Obstruction by infarct,
thrombus or embolus involving the main artery or one of its
branches. The major cause of Obstruction of the renal
artery in old age has been reported to be the presence of
atherOsclerotic plaques whereas in the younger patient
(below age 40 years), the most frequent cause is a form of
dysplasia of the renal artery [92]. Other vascular
disorders of the kidney such as trauma, renal thrombosis and
renal arterial dissection have been associated with
hypertension [92].

All forms of hypertension for which no specific etio-
logical agent Or mechanism was determined were grouped into
a second major category called primary or essential hyper-
tension.

Essential hypertension was named by Frank in 1911 and
termed ”hypertensive cardiovascular disease“ by Janeway in
1913 [93]. Today, it has come to designate a condition
which constitutes an unidentifiable physiologic disturbance
or disturbances which leads ultimately to elevation Of dia-
stolic, systolic and mean blood pressures, anatomical
changes in the vascular tree, and functional impairment of
involved tissues. Hypertension is perceived to be a sequela
appearing during the progressive development of the disease
[94]. Essential hypertension (EH) has been estimated to
account for up to 90% of all cases of hypertension with the

secondary type believed to comprise 10% [5]. In the

l4

majority of the cases, the diagnosis of EH is made after the
exclusion of all known secondary causes.

For years, the problem with understanding essential
hypertension.centered around defining it. 1311955, Perera
indicated that hypertension existed if repeated‘ recordings
of casual diastolic pressures yielded values of 90 mm Hg or
above [95]. Systolic blood pressure (SBP)Iof 140 mm Hg is
generally regarded as the upper normal figure. However, the
age of the individual must also be taken into consideration.
Mean blood pressures (MBP) above 105 to 110 mm Hg have been
regarded as hypertensive [96]. An even less definable term,
“borderline hypertension" was coined by Conway gt at. in
1968 [97]. It was used to designate a group of patients who
had diastolic blood pressure sometimes below and sometimes
above the 90 mm Hg limit. It was also regarded as a
possible pre-stage to essential hypertension. A variable
proportion of subjects with borderline hypertension have
shown an elevation of cardiac output and heart rate [98].

As far as possible etiologies for EH, many theories
have been proposed. Pickering proposed that EH may repre-
sent a quantitative rather than a qualitative deviation from
the norm acquired through multifactorial inheritance and
modified by environmental factors [99]. Page has supported
the concept that EH is a disorder of cardiovascular regula-
tion originating from an altered interplay of a mosaic of
factors rather than in a single cause [100]. Both genetic

and environmental factors have been known to play a role in

15

hypertension but their relative contributions are not known.
In the autoregulatory hypothesis, it was proposed that the
level of blood pressure was determined by the amount of
blood pumped by the heart and the resistance to the flow of
this blood by the vascular'bed, ‘These two factors are, in
turn, affected by many other factors [3]. The sodium
transport theory held that patients with EH are in a state
of continuous correction of a slighty expanded extracellular
fluid volume [3]. Dahl and co-workers first proposed that
permanent hypertension might evolve through a genetic defect
in renal sodium excretion leading to an increase in body
fluid volume and, in turn, an increase in a sodium excreting
hormone and hypertension [101] . In support of the concept
of a sodium excreting hormone, it was suggested that
increased amounts of natriuretic hormone may be involved in
the pathogenesis of the disease. Other factors must also be
considered as possible components Of the EH syndrome. For
example, alteration.of pressor substances, defects in the
hereditable sympathetic nervous system and related.neural
mechanisms, imbalances in the renin angiotension and
vasodepressor systems, and obesity have all been associated
with EH [3].

Since the greatest proportion of all hypertension in
man is of the primary form, an animal model closely
simulating EH is highly desirable. Various animals have
been used to study the genetic aspects of hypertension

[102]. Mice, rabbits, chickens, turkeys and dogs have been

16

monitored as to the contribution of strain or breed to
elevated blood pressure. The most useful small animal model
has been the spontaneous hypertensive rat of which several
differentiated substrains have been produced. Other
developed strains include the New Zealand strain of
genetically hypertensive rat (GHR), Milan hypertensive
strain (MHS), and Brookhaven strain of hypertensive-
sensitive rats (HSR). However, the knowledge Obtained from
these models has been fragmentary, and the results obtained~
in each strain were usually concentrated on only a few
aspects of the multifaceted problems oflflh In addition,
each substrain had its individual, unique defect which did
not include many aspects of the primary hypertensive human
patient.

The dog has long been used as an experimental model to
study various forms of induced secondary hypertension [7]
[8] [9] [10] [11] [12] [13]. Few cases of primary hyperten-
sion have been reported and no cases have been clinically
evaluated and documented. It*was against this background
that a case of primary hypertension in a siberian husky
female dog was diagnosed. Subsequent mother-son, father-
daughter, Sister-brother matings have been done and colonies
of affected or potentially affected animals have been pro-

duced and clinically evaluated.

MATERIALS AND METHODS

Animals

Forty-one conditioned siberian husky, golden retriever,
and mixed breed (siberian husky x Labrador retriever) dogs
were used in the study; The dogs were free of intestinal
parasites and heartworms and were vaccinated against rabies,
distemper, leptospirosis, hepatitis and parvoviral
infection. The colony animals colony ranged in age from 3
months to 8 years at the initiation of the study, and
included 21 males and 20 females. Two unrelated siberian
husky dogs (1 male and 1 female) and five golden retriever
dogs (4 females and 1 male) were utilized during one phase
of the experiments to establish a working normal blood
pressure for siberian husky dogs. Three additional, non-
colony siberian husky dogs consisting of 2 females and 1
male were used to establish normal echocardiographic values.

The propositus was bred to her male progeny and
produced 5 litters. One other litter was produced as a
result of a breeding to a hypertensive male labrador
retriever who was diagnosed at the College of Veterinary
Medicine at the University of Pennsylvania. A number of
sibling matings have taken place, further enlarging the
colony. The propositus and 10 colony animals were primarily

selected for the present study. However, ancillary data

17

18

from other colony and non-colony animals were used on

occasions.

Indwelling Catheter Blood Pressure Determinations

Three colony dogs were subjected to general anesthesia
using barbiturate anesthesia and maintained on halothane
gas. Surgically, the omocervical artery was isolated and an
indwelling catheter was directed through the artery and into
the aortic arch. The catheter contained heparin (1,000
units/ml) and crystalline penicillin (66,666 units/ml) in a
saline solution. It was then externalized and secured
through a skin incision on the dorsal neck. One week after
the surgery, separate blood pressure and heart rate
determinations were made simultaneously utilizing this
catheter and the direct femoral artery puncture. Both were
attached to transducers which were in turn connected to the

DR8 Blood Pressure Monitoring device.

Dinamap giggg Pressure Determinations

Blood pressure determinations were obtained on colony
dogs utilizing the Dinamap Research Monitor 12553.
Pressures were ascertained according to catalogue
specifications with cuff size and gain settings
corresponding to animals' limb circumference and body

weight, respectively. The test was performed on awake,

 

aDinamap Research Monitor Model 1255, Critkon, Inc.,
Tampa, FL.

l9

conscious dogs who were in left lateral recumbency. Five to
ten minutes later, blood pressure determinations employing
the direct method of arterial puncture were made and

comparisons evaluated.

Ophthalmic Examination

The 11 animals were examined using direct
ophthalmoscopy. The ocular media and retinae were
evaluated for any abnormal findings suggestive of hyper-
tension by viewing the eye grossly and by use of an
ophthalmoscope. The ophthalmOSCOpic examination was done in
a dark room with the animals being minimally restrained by

an assistant.

gtggg‘gtg‘gtttt Examination

Whole blood, serum, and urine were evaluated by stan-
dard clinical methods and reported in standard units for
both the propositus and colony animals semiannually. Since
the data were considered ancillary: the methods, which are
standardized 1J1 the Clinical Pathology Laboratory,
Veterinary Clinical Center, Michigan State University, East
Lansing, Michigan, are not reported. A representative set

of these data is reported with the results.

Femoral Arterial Blood Pressure Determinations

The systemic arterial blood pressure for each dog was
determined by femoral arterial puncture. A 22-gauge needle
was attached via a heparinized saline-filled plastic tube to

a Statham P23D6 pressure transducer which was in turn.

20

connected to an Electronic for Medicine DR8 Multichannel
Recorderb. The dogs were manually restrained in left
lateral recumbency and no anesthetics were used. The mean
blood.pressure was electronically calculated. Diastolic,
systolic, and mean blood pressures with electrocardiograms
were printed on the machine oscilloscope and recording
paper. Heart rates, using the ECG tracings, were determined
before, during, and after arterial puncture to provide an
assessment Of the level of excitement. However, after no
difference was found among rates in the three time periods,
only the heart rate nun during the arterial puncture was

utilized.

NOnselective Aortogram

This procedure was performed only on the propositus of
the colony. Here, via a midline incision through the
peritoneum, the abdominal aorta was exposed. Radiopaque dye
was injected through a catheter which was placed in the
abdominal aorta cranial to the branching of both renal

arteries. Radiographs were taken afterwards.

Selective Left Ventricular Angiocardiogram
Each animal was anesthetized with 5 cc/lb of sodium
pentobarbital intravenously. A catheter was placed via the

left carotid artery into the left ventricle. With the aid

 

bModel DR8 Recorder, Electronics for Medicine, Inc.,
White Plains, NY.

21

of fluoroscopy, contrast agent was injected and serial
radiographs taken over a period of 5 seconds. Visualization
of the size and shape of the left ventricular cavity, left

ventricular wall, and vascular components was possible.

Thoracic Radiography and Electrocardiography

At 3 months of age, all colony dogs had routine chest
radiography performed. Both ventrodorsal (VD) and lateral
(L) views were taken to get some assessment of cardiac size,
blood veSsel size and Shape, and noticeable lung lesions.
At.6 months of age, they were subjected to electrocardio-
grams to detect heart rhythm, electrical activity, and

possible cardiac enlargement.

Nonselective Venous Angiogram

This technique was utilized on the propositus, only.
Fourteen m1 of Hypaque M-75 was injected via the right
jugular vein and radiographs were taken over a period of 9

seconds based on a technique used by Fox 2£.él [103].

Tissue Biopsy

A wedge biopsied section of kidney from the propositus
was surgically removed, fixed, and processed for light and
electron microscopic examination. Five other colony animals
had sections of skin and Skeletal muscle similarly
evaluated, as well. Wedges of skin from the left lateral
flank and strips of the left external abdominal oblique

muscle were Sites of biopsy. The kidneys of the 5 animals

22

were needle biopsied during the time of wedge removal from

the skin and muscle.

Plasma Catecholamine 22E.§22£2 Activity Determinations
Plasma renin activity was determined by the technique
described in the Angiotensin-I-Squibb Radioimmunoassay Kitc.
During routine semi-annual evaluations, whole blood was
collected from the external jugular vein and placed into
pre-chilled, evacuated tubes containing EDTA. These blood-
containing tubes were then centrifuged at a temperature of
0° C. The plasma was transferred into plastic tubes and
immediately placeron ice for analysis. Those samples not
analyzed were kept frozen for later evaluation. Plasma
catecholamine levels were determined utilizing the
Catecholamine Radioenzymatic Kit [3H]d. Blood obtained via
jugular vein puncture was collected into chilled, evacuated
tubes containing EGTA and glutathione in concentrations of
90 mg/ml and 60 mg/ml, respectively. These tubes were
centrifuged at 0° C for 15 minutes and the plasma was
removed and stored at -20° C until used. These determina-
tions were made on blood obtained from the caudal vena cava

left renal vein and right renal vein. The methods of sample

collection are described in the section, BlOod Gas Analysis.

 

cE.R. Squibb Diagnostics, New Brunswick, NJ.

dThe Upjohn Company, Kalamazoo, MI.

23

Excretory Urogram

Three ml/kg of 75% Hypaque in an equal volume of 5%
dextrose were administered intravenously to the propositus.
Radiographs of the abdomen were taken following compression
placed across the caudal abdomen. The other colony dogs
subjected to this procedure received contrast agent injected
from a catheter which was placed into their renal arteries

via fluoroscopic guidance through the left carotid arteries.

EEEEl Arteriogram

In the propositus, following an abdominal incision, a
catheter was placed selectively in the left renal artery.
Five ml of 75% Hypaque was injected and serial radiographs
taken over a 7 Second period. The 10 other colony animals
had the same procedure performed but with a different
technique. A catheter was placed via a small incision into
the left carotid artery. Through fluorOSCOpy, it was guided
into the right renal artery and radiopaque dye injected.
Radiographs were immediately taken. The same procedure was

performed on the left kidney.

Echocardiographic Examination

M-mode echocardiograms were obtained using an
Electronics for Medicine Honeywell Echo IV System with a
2.25 megahertz transducere. The animals were awake and in

left lateral recumbency. Echocardiograms were obtained from

 

eHoneywell Echo IV System, Electronics for Medicine,
Inc., White Plains, NY.

24

a window located in the region of the right ventricular
apex. Measurements of left ventricular wall thickness were
obtained from a recording taken immediately below the
anterior leaflet of the mitral valve. Electrocardiograms
were obtained simultaneouslyu In addition tolcolony dogs
and propositus, this procedure was performed on 5 adult
unrelated siberian husky dogs to give some assessment Of

average values for this breed.

Cerebral Spinal Fluid Examination

Ten colony dogs were anesthetized with barbiturate
anesthesia, placed in right lateral recumbency and
surgically prepped. After flexion of the neck, a 22 gauge
spinal needle with stylet was inserted into the cisterna
magnum. After the flow of spinal fluid was seen, a spinal
manometer was attached and cerebrospinal fluid pressure
measured. One to two ml of free flowing CSF was later
collected and cytologically evaluated. Specific gravity and
total protein determinations were made on each sample as

well.

Biggg Cadmium and Lead Determinations

Whole blood from each of 10 dogs was collected from
each dog via the external jugular vein. These samples were
placed.into]evacuated.EDTA-containing tubes and submitted
for cadmiunland lead analysis. .Each anticoagulated blood

sample was separated into 100 pl aliquots and diluted with 1

ml 0f 0-1% HNO3. For cadmium analysis, the solution was

25

directly placed via an autosampler into the graphite tube
for flameless spectroscopy on a Polarized Zeeman Effect
Atomic Absorption Spectrophotometer, Model 180-80 Hitachif.
Lead samples were first diluted 1:1 with a solution
containing 2 mg/ml NH4NO3. Ten ul of this sample was dried
using a 75 second sampling procedure with a maximum
temperature of 1000 C. Absorbances were compared with
standards made from standardized stock solutions from
Scientific Products. Cadmium was determined at 228.8 nm and

lead at 283.3 nm.

Blood Gas Analysis

Ten colony dogs were anesthetized with barbiturate
anesthesia and the right neck region surgically prepped for
the eventual use of the right jugular vein and carotid
artery. Small incisions were made in both vessels and
catheters placed accordingly. Both catheters were carefully
advanced and guided by fluorOSCOpy with continous electro-
cardiographic monitoring. One ml blood samples from the
aorta and right atrium were taken in heparinized syringes,
air removed, placed on ice, and taken to the blood gas
analyzer for blood gas and pH determinations. Also,
anterior vena cava, posterior vena cava, right renal vein,

and left renal vein blood samples were collected through the

 

intachi Scientific Instruments, Nissei Sangyo Ltd.,
Mountain View, CA.

26

jugular vein catheter and analyzed according to previously

described methods.

Data Analysis

Student's t-tests were used to analyze the data.
Significance was accepted at a probability level of g 0.05.
Analysis of variance for blood pressure group designations
and simple correlations for age and blood pressure
comparisons were utilized and significance was accepted at

a probability level Of §_0.05.

RESULTS AND DI SCUSSION

Validation gt Femoral Arterial Mean Blood Pressures

Mean arterial blood pressures Obtained using the direct
puncture technique were validated based upon a comparison in
3 dogs. Measurements of blood pressure were simultaneously
monitored and recorded from the femoral artery and the
aortic arch. These animals had aortic mean blood pressures
of 10517 mm Hg (number of trials [n] = 4), 10316 mm Hg (n -
3), and 10718 mm Hg U1==3). Their corresponding femoral
arterial mean blood pressures were 11516 mm Hg (n a 4),
107:11 mm Hg (n = 3), and 112:16 mm Hg (n a 3),
respectively. Each comparison was found to be insignificant
at pK0.05. Average femoral arterial pressures were 6 mm Hg
higher than the corresponding aortic pressures. This could
have been due to transducer calibration error, as one would

expect a slightly higher pressure within the aorta.

gtggg Pressure EEXEl.££ the Propositus

Femoral arterial blood preSsures recorded upon initial
examination were 200 mm Hg (SBP), 150 mm Hg (DBP), and 175
mm Hg (MBP). The pressures recorded on subsequent tables in
this text are those obtained after the animal had been

therapeutically maintained on diuretics and a low salt diet.

27

28

Groups, EEEEQ Uppp Blood Pressure Determinations

Direct systemic arterial blood pressures were obtained
in 30 dogs (excluding the propositus) over a 5 month period
and the animals classified based upon their mean blood
pressures (Table 1). The animals were segregated and
arbitrarily placed into groups such that groups I, II, III,
and IV had average MBP"S of 128112 mm Hg (range, 125-131 mm
Hg): 121:8 mm Hg (range, 118-124 mm Hg): 11419 mm Hg (range,
110-117 mm Hg): and 10119 mm Hg (range, 91-109 mm Hg),
respectively. There was at least a 7 mm Hg difference in
MBP from group to group when standard deviations were not
considered. Individual differences within each of the
groups I, II, and III were 5 7 mm Hg when the highest and
lowest values were compared. Group IV animals were removed
from group III by at least 7 mm Hg. However, intra-group
difference between the highest and lowest group IV values
exceeds 7 mm Hg. There was no significant difference in age
between the 4 groups. However, there was a positive
significance correlation of age with SBP, DBP, and MBP when
all groups were combined. The values for r were 0.40, 0.47,
and 0.44, respectively. The mean blood pressure of Group I
was not different from group II but was different from group
III and group IV (p<0.05). There was no difference between
groups II and III but there was a significant difference
between groups II and IV and between III and IV (p<0.05).
The combination of groups I and II was significantly

different from the combination of groups III and IV. Two

29

unrelated, physically normal siberian husky dogs were tested
and found to have 11213 mm Hg (MBP), 12916 mm Hg (SBP), 9614
mm Hg (DBP), and 9117 beats/min (HR) at 48 months of age.
Their individual values after 5 trials were: 11114 mm Hg
(MBP), 12816 mm Hg (SBP), 9813 mm Hg (DBP), 9717 beats/min
(HR) and 11313 mm Hg (MBP), 13116 mm Hg (SBP), 9515 mm Hg
(DBP), 8518 beats/min (HR). Based upon our previous
groupings, these animals would be placed within group III.
After conducting another independent study of 18 trials in 5
golden retriever dogs, MBP of 10419 mm Hg was found.
Individual mean blood pressures were: 9417 mm Hg U18 3),
10413 mm Hg (n = 4), 10418 mm Hg (n = 4), 104111 mm Hg (n =
4), 112114 mm Hg (n = 3). When considered as a group, these
unrelated animals have an‘average MBP within the range of
group IV. However, the one animal with a MBP of 112114
could be placed within group III.

Dinamap Blood Pressure Recordings y§_ Femoral Arterial
Recordings

 

Six animals representing groups I, II, and III had
their blood pressures compared using the automatic cuff
technique of the Dinamap and femoral arterial puncture.
Three groups of data were col lected. on three separate days
but a consistent number of trials using the Dinamap recorder
could be obtained only on one day due to mechanical
difficulty (Table 2). The utilization of the Dinamap
recorder for blood pressure determination has been reported

to be accurate in anesthetized animals [104] [105].

30

However, wide variations in SBP, DBP, MBP and HR have been a
problem when conscious, unanesthetized dogs were subjected
to this technique [105]. Our data (Table 2) indicates that
values for SBP, DBP, and MBP were generally lower than
corresponding values for femoral arterial puncture.
However, heart rates obtained while utilizing the Dinamap
recorder were generally higher than those obtained using the
femoral arterial puncture technique. So, when considering
heart rate, it would appear as if there is a higher
sympathetic tone with Dinamap use. Yet, there is no
resultant increase in blood pressures over those recorded
using the femoral arterial puncture. Additionally, when a
total of 18 MBP'S were obtained by femoral puncture on three
separate days and compared to 87 MBP”s obtained using the
Dinamap recorder over the same 3 days, there was an average
standard deviation of 6 mm Hg when using the former and 12
mm Hg when using the latter method. These findings tend to
indicate that the Dinamap pressures are less precise. Our
values for femoral artery puncture determinations (Table 2)
in this comparison are not outside the mean 1 standard
deviation of the individual values recorded on Table 1.
These data suggest the consistency of femoral arterial
puncture pressures. However, forty-three percent of all
parameters measured under the femoral arterial pressures
category were different from those in the Dinamap category
(Table 2), being at least one standard deviation out of

range when compared.

31

Ophthalmic Examination

Propositus - There was bilateral pupillary dilation
with negative pupillary light reflex. The left eye had
serous retinal elevation at the level of the optic disc.
Both eyes had retinal hemorrhage and papilledema at the
optic discs, as well (Figures 1 and 2). The intraocular
pressures were normal.

Colony - All 10 animals examined had normal ocular

structures irrespective Of the various groupings (Table 3)..

tlppg‘tpg,gttpg Examination

Propositus - Whole blood, serum, and urine were
evaluated and largely found to be unremarkable. The T4
value of 8.2 ng/ml was depressed below our laboratory range
of 15-40 ng/ml. However, T3 was within normal limits (Table
4).

Colony - Tables 5, 6 and 7 depict the findings of the
various groups relative to urine, chemical, and hematologic
analysis. No obvious group differences existed at this
time. However, individual animals had values which were

slightly above or below the normally reported values.

Nonselective Aortogram
Propositus - No apparent abnormalities were Observed in

the distribution of the dye in the right or left kidney.

Selective Left Ventricular Angiocardiogram
Propositus - The size and shape of the left ventricular

cavity appeared normal, as did the thickness of the left

32

ventricular wall. The aortic arch, however, was enlarged
and displaced anteriorlyu This enlargement.extended into
the brachiocephalic trunk and there was some tortuosity of
the descending aorta (Figure 3).

Colony - The size and shape of the left ventricular
cavity and thickness of the left ventricular wall appeared
normal. NO absolute statements could be made about the
aortas. However, 1 animal from group I, 2 from group II,
and 1 from group III appeared to have slight dilation and

tortuosity of the post valvular aorta.

Thoracic Radiography gpd Electrocardiography

Propositus - The cardiac silhouette was slightly larger
than normal. There was some evidence of right atrial
enlargement as evidenced by a tall p-wave (0.6 mv) upon
electrocardiographic examination.

Colony - One animal in group I had a mild generalized
cardiac enlargement upon radiography but all other animals
of this group were unremarkable. NO significant lung
changes were observed. Groups II and III had no major
cardiac nor pulmonary abnormalities. Table 8 depicts a
summary of the normal electrocardiographic data observed

within the colony.

Nonselective Venous Angiogram
Propositus - Passage of contrast agent through the

heart appeared to be unimpeded. The main pulmonary artery

33

was judged to be slightly enlarged. The right ventricular

cavity and wall thickness appeared normal.

Renal Biopsy

Propositus - Bowman's urinary space was normal in all
glomeruli examined and there was no evidence of fibrosis
within Bowman's capsule. In one section, two involuted
glomeruli were seen together, but associated arterioles were
not in the section. In general, arteries and arterioles
were well preserved with no evidence of hypertrophy.

Colony - The kidney, external abdominal Oblique muscle,
and skin were biopsied for histologic examination but poor
tissue fixation precluded an apprOpriate evaluation.

13131913 Qategholatine and 1131313 Renin Activity
Determinations

 

 

 

Propositus - Norepinephrine (NE), epinephrine (E) and
dopamine values were 210.1 pg/ml, 52.6 pg/ml and 21 pg.ml,
respectively. Left renal vein plasma renin activity and
right renal vein plasma.renin activity were 2.0 ng/ml/hr and
2.6 ng/ml/hr, respectively (Tables 9 and 10).

Colony - There were no significant differences in NE,
E, and dOpamine levels when comparing the three groups
(Table 9). These group values were also within the range
reported as normal in dogs. Also, there was no significant
difference in the plasma renin activity as measured in the
three groups. Sodium intake was approximately the same in
that the animals were fed the same laboratory chow. Sodium

excretion was not measured, however.

34

Excretory Urogram

Propositus - Renal size and shape were normal. Filling
of the diverticula and renal pelvis was achieved and the
anatomy of the collecting system within the kidneys was
‘ judged to be normal. There appeared to be a slightly
increased diameter to the .left ureter. However, this
finding may have been due to the unequal application of
pressure over the abdomen (Figure 4).

Colony - Renal Size and shape were normal for all
animals except one dog in group III. This animal (Avalon)
had one radio-dense area involving the left kidney. The
area was consistent with a renal infarct, as the opaque dye
was not able to penetrate, probably because of a lack of a

sufficient blood supply.

32221 Arteriogram

Prgpositus - There was no parenchymal nor vascular
architectural abnormalities Observed (Figure 5).

Colony - There were no evidences of vascular
abnormalities within the kidneys of these animals. However,
an area consistent with an infarct was seen in the left
kidney Of one animal (Avalon) from group III and in the

right kidney of an animal from group II (Folgers).

Echocardiographic Examination
Propositus - The propositus had values which were
higher than the range for normal siberians in the categories

of left ventricular wall thickness (LVWT), left ventricular

35

wall thickness/body surface area (LVWT/BSAL, left
ventricular wall thickness/weight (LVWT/weight) and septal
thickness (Tables 11 and 12).

Normal Siberians - Five normal adult Siberian husky
dogs unrelated to our colony and weighing‘18 to 25 kg were
examined by echocardiography to establish normal values for
this breed. Values for left ventricular wall thickness
(LVWT) were indexed to weight (kg) and body surface area
(M2) by dividing LVWT by these two parameters (Table 12).

Colony - When the various groups were compared,
considering LVWT, LVWT/BSA, and LVWT/weight, there was no
significant difference between the groups (Tables 11 and 12,
Figure 6). However, 3 animals from groups I and II had
higher values than the normal siberians when LVWT was
compared: 5 of 8 animals in group I and II had larger values
for LVWT/BSA; and 6 of 8 dogs from groups I and II had
larger values for LVWT/kg. Though there is not a
significant difference for LVWT/BSA and LVWT/kg between the
groups (Table 12), both groups I and II have a tendency at
this time to be higher than the normal siberians and group

III.

Cerebrospinal Fluid Examination

Colony - Examination of cerebrospinal fluid (CSF)
pressure, cytology, Specific gravity and total protein was
unremarkable. All values were within the reported normal

range for dogs (Table 13).

36

Egg y Eptgl Determinations

Colony - Values for lead and cadmium were within the
normal range for the canine. Group differences for cadmium
were insignificant and lead levels could not be detected

(Table 14).

Blood Gas Analysis

Colony - No significant distinctions between the groups

nor individual animals were apparent (Table 15).

37

Figure 1. The atapetal subalbinotic left eye showing
indistinct disc margins indicative Of papilledema (arrows).
A pre-retinal hemorrhage (a) and deep dot retinal hemorrhage
(b) are present.

Figure 2. The fundus photograph of the right eye
showing papilledema lifting the retina at the disc margins
(arrow) and a deep subretinal suffusion hemorrhage (c).

 

39

Figure 3. Left ventricular angiocardiogram showing
aortic enlargement (Open arrows) and a slight anterior
displacement of the ascending aorta (closed arrows). (a)
Catheter within left ventricle. (b) Normal lung field.

 

41

Figure 4. Left renal excretory urogram demonstrating
that the left kidney is normal in size and shape. There is
a slight increase in diameter Of the left ureter barrows),
probably as a result of abdominal compression during the
procedure. (a) Lumbar vertebral body; (b) 13th rib. (c)
Catheter in abdominal aorta.

Figure 5. Left renal arteriogram outlining the left
renal parenchyma and vascular network which appear normal.
(a) Renal artery. (b) Renal cortex. (c) 13th rib. (d)
Catheter within renal artery.

 

no.5

43

Figure 6. Echocardiographic analysis of normal vs
colony animals showing the non-significant comparisons of
representative animals from groups I, II, and III when
compared to each other and to the normal control group when
considering LVWT, LVWT/BSA, and LVWT/BW. Despite the non-
significance between groups, individual animals from groups
I and II were significantly different from the normal
control group for all three parameters.

ECHOCARDIOGRAPH ANALYSIS
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familial pattern of hypertension distribution within the
colony of animals. The colony consists Of some related
animals but with no available information, normal and
affected males and females, dead or unavailable animals, and
animals at the University of Pennsylvania which are
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a ahead danced HHHGMH «Ahead an z\umaoasm
a mHHNH Ahmed mavens «ahead as =\mummH0E
a summa SMASH mused mflumma as z\o:osmao
m ~H+¢~fl HH+SOH HH+M¢H ma.~ma as z\mes»
mflama mm: I .mHmEHCO m. HH msouo
Hus .mflnw~a Hanefla vauoefl aHHmmH eaumm cm H com:
a Ammoaa mMam Swama mHMMOH mmfl E\+umxon
a oahmma AMHHH canned «Huang ma z\mxome .<
m enema sHoHH nausea Hammad an E\gasmgwm
a cauomfl SAHARA Nausea NHHHvH «m m\mgmum.<
a ma+ama ma+sda -+om~ m~+m~H ma m\.oumem
Nanmmd mm: u AmHMSRBE a. H dsouo
Amameuuc Am: as. .m: as. .m: as. Agas\mumonc .mnucoec xmm\~mSH:<
: mm: mmo mmm mums Dune: mama

 

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48

.Ousuocsm Hmfiuouum

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a odmmofl mamas onMNH «NMoqfi ca L\moamua
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a mega puma sewed sahoaa ca s\maumo
v mums mums omega mahma. ca z\sxuoa
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a oaumoa cause manage ~mucmH ca z\ummnsxosm
m Nausea Edema AHANH edema“ ma E\xflua
m oH+moa oa+mm m+maa ma+mma Hm :\:mnx

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m HNMNHH ommSm asmmma ownma m E\Bm=m
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a ahead mnaoa whens manmma Hm :\numAHoO
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m «meda cause mflnmma enema am e\:meozumo
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a munda canes enema mauvaa He z\mx:mm
a m+oHH m+mm o+¢ma oa+m~H em a\:ofim><
aueafi am: I AmHmSHcm m. HHH asouo
.mflmauu. .me SB. .m: as. .mm as. Agss\mummn. .maugoS. xmm\HmSHcm
: mm: mma mam mums Dumas some

 

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49

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a SHAH 2.3: an; :32 H on. 32 a: RE 8953
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a Ewan 3H5 SHRH 833 A 23 o2 o: «E 5:88
z E: E5 8: E5 5: 55 Am: 55 z 29.5 E: 55 Am: 55 8: :5 1.55
mm mm: m8 mam mm mm: Ha Ha
+ 8330.8 Omega 8.3305 .932 gauge
3035538 $38.... .803 usage 8.... "£85... Edema no 3833.28 380.3 .m «Ema

50

Table 3. Selected comparisons*'of ophthalmic examination

results.

 

 

Animal Interpretation
Group I
Alfreda Normal structures
Penguin Normal structures
Joker Retinal hemorrhage; papilledema+
Pistol Normal structures
Group II
Apple Jacks Normal structures
Riddler Normal structures
Diamond Normal structures
Yuma Normal structures
Folgers Normal structures ’
Group III
Avalon Normal structures
Dion Normal structures

 

*These animals were randomly selected as representatives

from groups I, II,

and III.

+Observed upon initial examination at MSU Veterinary

Clinical Center.

51

 

SE in

finnfiofiu

 

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93mg 8m H28 2: 353836 a 8 >0:
mfiummo: um: 33: m .m vs 3%? 333mg
do 53:383 dim: 24 my mum u 3 mom
93mg 8on .80 £3 3” E8 «.3 .. am 80:
38%8 £323 8B: m m: 23 u 2: goes
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033mm: 88:8 83.. mg: mo 3% u won 8m
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Snug 3333 :29. a: 88:8 3.: >8
33% ~28 H29. S 28 83 We 589a H38.
manhunt: 3mg 3282.0:

 

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52

Table 5. Selected comparisons* of colony serum chemistry

 

 

analysis.

Group I Group II Group III

(n = 4) (n = 4) (n s 2)
BUN 13.5:5.S 15.3:4.2 19
Glucose 70.0:3.8 76.2110.0 86.016.0
Total protein 6.310.4 6.610.6 6.1:0.1
Albumin 3.510.2 3.q:o.1 3.5;0.1
Globulin 2.8:0.2 3.0:0.7 2.710.1
ALT 41.8:16.6 47.3113.7 S9.S;10.6
Alk phos 33.8:S.9 24.012.9 23.513.S
Na ‘ 147.3:1.0 147.5:1.3 147.5:0.7
C1 114.310.5 114.311.7 117
T Co2 18.1:1.5 18.3:1.7 16.512.1
Anion gap 14.511.9 l4.3:3.2 14.5:3.5
Serum app Clear Clear Clear
Ca 10.4:0.6 10.410.6 10.7
P . 4.1:0.3 3.310.3 3.210.S
Mg 2.310.2 2.210.2 2.1;0.1
Chol 225.0:21.2 153.0:10.8 195.5:44.6
Trig 35.0:5.5 37.3111.3 29.510.7
T3 1.1:0.3 1.0:0.1 0.810.1
T4 24.0:2.9 20.8:5.7 16.0:8.5
K 5.110.1 4.8:0.4 4.9:0.1

 

*The animals were randomly selected as representatives from
groups I, II, and III; data collection and analysis
utilizing standard units as mentioned on page 19.

53

Table 6. Selected comparisons* of colony urine analysis.

 

 

+Group I Group II Group III
(n=3) (n=4) (n=2)
Color . Yellow Yellow Yellow
Turbidity Clear Clear Clear
pH 9 7.811.S 7.0:1.4
Ca 2.5:1.S 2.8:0.9 3.4:1.S
P 55.6144.9 209.01109.9 161.0118.38

 

*These animals were randomly selected from the various
groups listed above; data collection and analysis utilizing
standard units as mentioned on page 19.

+Only 3 animals within this group were evaluated. They
included Penguin, Alfreda, and Pistol.

 

 

Thble'h. Selected comparisons* of colony hematologic
analysis.

Group I Group II Group III

(n = 4) (n = 4) (n 8 2)
plasma Tot. Prot. 63:27.0 6.o_+_o.5 6310.3
PCV (spun) 46.3:6.2 48.0:1.0 42.011.0
WBC 10.112.1 10.0:2.0 8.810.4
RBC 6.8:0.7 7.0:0.2 6.410.3
Hbg 15.8:2.0 16.0:0.2 14.010.1
PCV 47.4:5.0 49.011.0 44.011.0
MCV 69.3:2.4 71.0;2.0 69.011.0
MCH 23.0:0.8 23.011.0 22.011.0
MCHC 33.2:0.9 33.0:0.4 32.011.0
Seg 55.0110.0 67.0:9.0 57.0:6.0
N-Seg - - -
Lymph 30.3111.7 24.015.0 34.0:11.0
Mono 6.8:3.S S.012.0 5.5:2.1
Eos 7.813.0 4.0:2.0 4.512.1
Baso 0.3 0 0
Platelets Adequate Adequate Adequate

 

*Representative animals from the various groups were
randomly selected and compared; data collection and analysis

utilizing standard units as mentioned on page 19.

55

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.8 95 3535 mum 38 g

 

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56

Table 9. Selected comparisons* of plasma catecholamine levels between
group representatives and propositus.

 

 

DOPE-mine Epinephrine Norep
Animl (pg/m1) (pg/ ml) (pg/ ml)
Group I 41.8:17.0+ l99.8_f_56.4+ 411.0303.“
Alfreda 23 207 270
penguin 32 173 208
Pistol S4 144 629
Apple Jacks 58 275 537
Joker f 21 53 210
Group II 38.811631L 210.5169.0+ 373.5:94.9+
Riddler 36 146 284
Diannnd 53 264 300
m 17 156 . 468
Folgers 49 276 442
Group III 60.0:S.7l' l9l.0:_79.2+ 584.0:31141'
Avalon 64 135 804
Dion 56 247 364

 

*Animals within the various groups were randomly selected for
evaluation.

1‘Mean18D.

f The propositus, Joker, is considered as an individual case and is not
included in the calculations of group I.

57

Table 10. Selected comparisons* of plasma renin activity between group
representatives and propositus .

 

 

Left renal vein Right renal vein Caudal vena cava
Aninal (ng/ml/hr) (ng/mllhr) (rug/mllhr)
Group I 2.631.41' 2.211.21' 0.8:0.5+
Alfreda 4.3 3.7 1.5
Penguin - - 0.8
Pistol 1.7 1.5 0.5
Apple Jacks 1.9 1.5 0.4
Jokerf 2.0 2.6 1.2
Group II 2.011.4‘r 2.612.6’r 0.610.61-
Riddle: 3.9 6.4 1.5
Diamond 1.7 0.9 0.4
Yuma 1.6 1.2 > 0.5
Folgers 0.6 1.8 0.1
Group 111 1.510.“ 2.6+ 0.810.“
Avalon 1.2 - 0.4
Dion 1.7 , 2.6 1.2

 

*‘Deanimlsinttzedmeegramswererardomlyselectedmflmbjectedto
theabovedetenm‘nations.

+Mean_+_SD.

f The prepositus, Joker, was considered as an individual case and not
included in the calculations of group I.

58

000000000000 0 @0005 :0 0000005 00: 003 6000000000 05 3000002.

. 005000000 03 no 0000006 :0 05000000 MGBEC

.8 + 00002.0

60.39.00 0:0 00000000 30000500 0003 00050.00 300.09 05 0.00“ 000.508 05.0

 

 

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000.0 00.00 000.0 00.0 00.0 00.0 00.0 0000000
000.0 00.00 000.0 00.0 00.0 00.0 00.0 0000
000.0 00.00 000.0 00.0 00.0 00.0 00.0 0.0000000
000.0 00.00 000.0 00.0 00.0 00.0 00.0 0000000
+000.00000.0 00.000.00 +000.00000.0 0.00.0000.0 .000.0000.0 1.00.0000.0 +00.0000.0 00 00000
000.0 00.00 000.0 .00.0 00.0 00.0 00.0 .000000
000.0 00.0 000.0 00.0 00.0 00.0 00.0 00000 00000
000.0 00.00 000.0 00.0 00.0 00.0 00.0 000000
000.0 00.00 000.0 00.0 00.0 00.0 00.0 0 0000000
000.0 00.00 000.0 00.0 00.0 00.0 00.0 0 0000000
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59

 

 

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00.0 00.00 000.0 000.0 00.0 00.0 000.0 00000
00.0 00.00 000.0 000.0 00.0 00.0 000.0 000000
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Table 14. Selected comparisons* of plasma lead and cadmium

 

 

determinations.

Animal Lead (ug/dl) Cadmium (ug/dl)
Group I 0.5010.20+
Pistol 0 0.24
Alfreda 0 0.69
Penguin 0 0.61
Apple Jacks 0 0.47
Group II 0.74:0.64+
Yuma 0 0.24
Diamond 0 0.41
Folgers 0 1.66
Riddler 0 0.65
Group III o.27;o.1r+
Avalon 0 0.34
Dion 0 0.19

 

*Comparison was made between animals from groups I, II, and
III who were randomly selected for evaluation.

+Mean 1 SD.

62

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SUMMARY AND CONCLUS IONS

This study documents spontaneous hypertension in the
dog but only loosely associates it with an underlying
pathology [14]. A problem encountered when diagnosing
primary or secondary hypertension in non-human species is
determining a normal and an abnormal blood pressure range.
In dogs many techniques of blood pressure determination have
been used [14] [107] [108] but the generally accepted method
in conditioned dogs has been direct arterial puncture [109].
In one study utilizing the direct arterial puncture in 21
conscious, mongrel dogs, it was determined that normal
values for systolic, diastolic, and mean systemic arterial
pressures were 148:15.8, 8718.0, and 102.319.4 mm Hg,
respectively [110]. The propositus in our study far
exceeded that reported range upon initial examination (SBP,
200 mm Hg; DBP, 150 mm Hg; MBP, 175 mm Hg]. The ocular
lesion as evidenced by retinal hemorrhage, a condition
frequently associated with the malignant phase of
hypertension in man [111] [112], was a strong indication of
the significance of blood pressure elevation in the
propositus.

The cardiovascular abnormalities of this animal
included a slightly enlarged cardiac silhouette, right

atrial enlargement, slight pulmonary artery enlargement and

63

64

tortuosity and enlargement of the thoracic aorta. However,
there was no evidence of mechanical or congenital defects
contributing to these changes. Increased venous return or
central redistribution of blood may have contributed to an
excessive right atrial filling and subsequent enlargement.

A possible increase in cardiac output and relative lack
of significant renal pathology may indicate an early onset
phase of hypertension. Such changes have been shown to
occur in the early stages of essential hypertension in man
[98]. However, the ocular pathology suggests a more
advanced stage of the syndrome [111] [112].

In one study utilizing conscious alert dogs, average
plasma epinephrine (E) and norepinephrine (NE) values were
144155 pg/ml with a range of 40-241 pg/ml and 193:86 with a
range of 53-405 pg/ml, respectively [113]. The value for E
in the propositus was 52.6 pg/ml: lower than the average
value but within the reported range. The level of NE was
210.1 pg/ml; slightly higher than the reported average but
well within the accepted range. So, it doesnft appear that
significant sympathetic activity causing catecholamine
release ,was instrumental in the elevation of systemic
arterial blood pressure. However, urinary catecholamine
levels have not been determined.

There is insufficient available data on canine renal
vein renin levels to make an assessment of the significance
of our reported values. However, level of plasma renin

activity in sodium replete dogs after anesthesia and surgery

65

was reported to be 11230.1 ng/ml/hr (mean i SD) when caudal
vena cava blood samples were used [114]. The designations
of "high renin”, "low renin", and "normal renin” forms of
hypertension, as advocated by some, could not be used
because of intergroup similarities [115].

The T4 value of 8.2 ng/ml was lower than our laboratory
range of 15-40 ng/ml. However, T3, believed to be the most
metabolically active peripheral tissue hormone, was within
the normal range for the dog.

Based upon the absence of known secondary causes, the
propositus was diagnosed as having spontaneous idiopathic
hypertension. Realizing the necessity for animal models of
spontaneous primary hypertension, this animal was placed on
diuretic therapy (Diuril, 250 mg/bid)g and fed a low salt
diet (H/D prescription diet)h to maintain normal blood
pressure and survival. The animal has been bred to other
hypertensive or potentially hypertensive dogs, many of which
were her offspring. Various sister-brother matings have
been performed as well (Figure 7). .As a result of such
matings, 36 dogs have been added over a period of 5 years.
Many of these animals have been on contract by placing them
in homes of local residents to defray the cost of

maintenance. However, periodic clinical examinations are

 

gDiuril, Chlorothiazide, Merck, Sharp & Dohme, West
Point, PA.

hH/D dog food, Hills Pet Products, Inc., Topeka, KS.

66

mandatory. Other animals have been shipped to and are owned
by the University of Pennsylvania as a part of a
hypertensive breeding agreement.

In essential hypertension in man, it is generally
conceded that the genes play a fundamental role in blood
pressure homeostasis [116]. It is also known that
correlation coefficients for both systolic and diastolic
blood pressures are higher within families than in unrelated
individuals [3]. However, the mode of inheritance is not
known. With our limited numbers of available animals from
the several matings, we were not able to define a specific
mode of inheritance. However, the trait does appear to be
familial as 14 of 30 related animals (including propositus)
have hypertension. Additionally, there were significant
positive correlations of SBP, DBP, and MBP with age, r
values being 0.40, 0.47, and 0.44, respectively. On the
contrary, in 5 related golden retriever dogs, there was not
a significant correlation of MBP with age (r - -0.24).

Thirty animals in which MBP was measured, were used to
establish four animal groups. Group IV had the lowest MBP
and contained the majority'of the youngest animals. This
group had pressures which were compatible with those
obtained in such groups as the adult golden retriever and
other mongrel dogs. Group III largely consisted of adult
animals and had pressures similar to the unrelated normal
siberian husky dogs which were used to establish normal

adult siberian husky MBPu Group II animals appeared to be a

67

distinct group in that the MBP did not differ significantly
from group I or group III. However, group I was
significantly different from group III. This ”middle" group
(II) actually bridged the gap between group I and group III,
similar to what is done by the "borderline" hypertensives
relative to full-blown essential hypertension and
normotension in man.

After group establishment, 10 animals as
representatives from the three groups were further evaluated
because of the possibility that secondary organic lesions
could serve to further mark the condition in dogs. Upon
clinical examination and evaluation, groups I and II did not
differ significantly from group III, the normal siberians.
There were a few individual differences upon
echocardiographic analysis but no major group disparities.
So, at the present stage, at least, there aren't any
outstanding markers other than MBP that could be used to
further segregate the groups. We feel that with time, clear
group distinctions in terms of organic lesions and/or
clinical manifestations will be possible as in the case with
essential hypertension in man. Because of these
expectations, we have developed a protocol which can be used
to systematically evaluate existing colony animals as well
as those which will be born into the colony (see

recommendations).

RECOMMENDATIONS

Based upon our research findings, we’ve developed a
protocol to further characterize the hypertensive state in
our colony of dogs. The objective of this protocol is
fivefold:

1) Provide informationcnxblood pressure measurements so
that we can continually breed for the hypertensive
condition.

2) Serve as a data base for the further establishment of
normal and abnormal blood pressures in dogs.

3) Monitor blood pressures beginning at an early age in the
animal with the intention of tracking these animals into
maturity and determining any early inclination towards
hypertension development.

4) Using periodic clinical examinations to define possible
contributing lesions and time of onset of such lesions.

5) To rule cum: or identify secondary causes of
hypertension.

Table 1 should be used to screen all colony animals
through the age of 5 years or at which time systemic
arterial blood pressure is consistently elevated into a‘
range compatible, at least with our group II animals. Using
this table, one could detect the more prevalent secondary
forms of hypertension, if present. The primary form could

68

69

also be identified by the process of eliminating the
secondary forms.

Table 2 will be used to further define the hypertension
diagnosed using Table 1. Using this data in Table 2, a
clearer understanding of "borderline" versus full blown
essential hypertension may be achieved as the more subtle
changes in cardiovascular function and end organ structure

and function would be identified.

7O

 

 

Table 1. Preliminary protocol for all colony animals.
Ageat Emnwacy Tnxs
125thg of ofimsfls
Saxmdnywflnm (mmums) taming padbnmfl
Raul
Parenchymal 3 every 6 months urinalysis, BUN, cre-
atinine, serum and
urhErMaamiK
Rmrwmxmhmrami '
tnmma 6 eway'umeuhs DE’
Emkcnbe
Thyroid 3 every 6 months T3, T4 levels
Adrenal 3 every 6 months serum glucose, cate-
. cholamine, serum K,
Na,pkmmarEMn
Parathyroid 3 every 6 months serum and urinary Ca
aniP
Neurogenic 6 every 12 months blood gases, cerebro-
spinal fluid pressure
and cytology
Maiamkalinflaw
ferenoe with flow 3 every 6 months auscultation, tri-
ghcmddasanicmfles-
Unolenstmew
3 axehmmfliumfll
6 months old,
thaxewuy<nmer
wam fammalbkmdgmaxmna
Exogenous 3 every 12 months leadpadmium
Miscellamous 3 every 6 months hematocrit, red blood

cel 1 count, white
blood cell count,
platelet count

 

71

Table 2. Further definition of the primary form of hypertension.

 

 

Animals Type of tests Frequency of tests
All hypertensive echocardiogram every 6 months
All'hypertensive BOG every 6 months
All hypertensive cardiac output/total once at hyper-
peripheral resistance; tension diag-
renal arteriograms nosis and once
36 months later
All hypertensive fundusCOpic exam. emery'6 months
All hypertensive skin and skeletal every 12 months
muscle biopsy
All hypertensive renal biopsy every 12 months
All hypertensive femoral arterial blood every other week

pressure

 

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VITAE

The author was born in Birmingham, Alabama on April 7,
1955 to Mr. Sam and Mrs. Macie Tippett. In Birmingham, he
graduated from Sherman Heights Elementary School in 1969 and
Ensley High School in 1973. Post-secondary education began
when he enrolled at Tuskegee Institute, August, 1979.
There, he completed six years of training, after which he
received a Bachelor of Science degree in Animal and Poultry
Science (1978) and the Doctor of Veterinary Medicine degree
in 1979. His graduate study at Michigan State University in
the program or Veterinary Pathology began in September,
1979. During the course of his study for the Ph.D. degree
there, he was awarded the Charles In Davis Scholarship Award

for Veterinary Pathology.

82

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