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EFFECTS OF ELECTROLYTE AND
WATER ABNORMAUTES ON TOTAL
PERIPHERAL RESISTANCE AND OTHER
HEMODYNAMiC PARAMETERS IN DOGS

Thesis for me Beam of M. S
MICHIGAN STATE UNIVERSITY
GLENN W. IELKS
1973

ABSTRACT

EFFECTS OF ELECTROLYTE AND WATER ABNORMALITIES 0N
TOTAL PERIPHERAL RESISTANCE AND OTHER HEMODYNAMIC PARAMETERS
IN THE 006
by Glenn W. Jelks

Various electrolyte and water abnormalities alter arterial blood
pressure (ABP) in dogs (l7, 46, 64). Whether the changes in ABP are
the result of alterations in cardiac output, total peripheral resistance
(TPR) or both has not been clearly established. The present study des-
cribes the effects of electrolyte and water abnormalities on TPR. l29
experiments were completed in anesthetized dogs such that total steady
state venous return and cardiac output could be measured. Cardiac
output was maintained constant by means of a pump, changes in ABP thereby
directly reflected changes in TPR. .A 5 minute intravenous (IV) infusion
of isotonic KCl (N=ll) or MgClz (N=ll) solution at l.9l cc/min increased
plasma [K+] by 0.64 mEq/l and increased [Mg++] by l.83 mEq/l. These
abnormalities did not significantly alter_TPR. A 5 minute IV infusion
of hypertonic saline solution at 7.64 cc/min increased plasma osmolality
(Osm) 20 mOSm/l (N=l0). TPR decreased an average of 5% (p<0.05). Simult-
aneously increasing plasma [K+], [Mg++], and Osm (N=lO) 0.4 mEq/l,
l.95 mEq/l, and 22mOsm/l respectively, produced a decrease in TPR of ll%
(p<0.05). Identical experiments Here carried out in spinally anesthetized
(procainized) dogs. Singly increasing plasma [K+] (N=l0). [Mg++] (N=l0)
or simultaneously increasing plasma [K+] and [Mg++] (N=8), produced

significant decreases in TPR. Hyperosmolality (N=ll) and the combination

of hyperkalemia, hypermagnesemia and hyperosmolality (N=l0) prodbced
significantly greater decreases in TPR than seen in spinally intact
animals. Appropriate control solutions were infused for intact (N=l8)
and spinally anesthetized (N=20) dog experiments. These data strongly
suggest that part of the fall in ABP seen in intact dogs during various
acutely produced electrolyte and water abnormalities is due, at least

in part. to a fall in TPR. They also indicate that ABP responses in
intact dogs during various single electrolyte abnormalities may be masked

because of operable compensatory barostatic mechanism.

EFFECTS OF ELECTROLYTE AND WATER ABNORMALITIES ON TOTAL PERIPHERAL
RESISTANCE AND OTHER HEMOOYNAMIC PARAMETERS IN DOGS

By

Glenn W. Jelks

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements

for the degree of
MASTER OF SCIENCE
Department of Physiology

1973

TABLE OF CONTENTS

Page

DEDICATION ............................ v
LIST OF FIGURES .......... . ................ vi
I LIST OF TABLES .......................... vii
INTRODUCTION ........................... l
LITERATURE SURVEY ......................... 4
EXPERIMENTAL METHODS ....................... 30
RESULTS .............................. 35
DISCUSSION ............................ Sl
SUMMARY AND CONCLUSIONS .................... . 58
APPENDIX ............. . ................ 59
REFERENCES . . . . . ...................... 67

iv

DEDICATIONS

TO MY WIFE, ELIZABETH. TO MY CHILDREN, JENNIFER, DEBORAH,
AND MICHAEL.

LIST OF FIGURES

Figure Page

l. Tracing of experiment from the intact
dog series showing cardiovascular
effects of a five minute infusion
of electrolyte solutions which
created hyperkalemia, hypermagnesemia,
hyperosmolality and decreased pH .......... 44

2. Tracing of experiment from the spinally
anesthetized (procainized) dog series
showing cardiovascular effects of a
five minute infusion of electrolyte
solutions which created hyperkalemia,
hypermagnesemia, hyperosmolality and
decreased pH .................... 45

3. Summary graph of total peripheral resis-

tance changes observed in all experi-
mental groups studies ................ 49

vi

LIST OF TABLES

Table Page
l. Summary of Procedures utilized .............. 34
2. Average effects of intravenous

infusion of test solutions on

measured cardiovascular and

blood parameters .................. 36
APPENDIX

Table Page

I. The average effects of control NaCl

infusion at l.9l cc/min ............... 60
2. The average effects of control NaCl

infusion at ll.46 cc/min .............. 6l
3. The average effects of KCl infusion

at l.9l cc/min ................... 62
4. The average effects of MgCl2 infusion

at l.9l cc/min ................... 63
5. The average effects of hypertonic NaCl

infusion at 7.64 cc/min ............... 64
6. The average effects of KCl and MgClz

infusion at 3.82 cc/min ............... 65
7. The average effects of KCl, MgCl and

hypertonic NaCl infusion at -

ll.46 cc/min .................... 66

vii

INTRODUCTION

Stroke volume and cardiac frequency are direct determinants of cardiac
output. The stroke volume is influenced by myocardial contractile strength,
the level of arterial blood pressure the heart must work against, and
the diastolic ventricular volume. Diastolic ventricular volume is in
turn determined by diastolic ventricular compliance, resistance to blood
flow through the atria-ventricular values, filling time, and filling
pressure. An important determinant of filling pressure is venous return
of blood to the heart. Cardiac output and total peripheral resistance
are, of course. the direct determinants of systemic arterial blood pressure.
Surprisingly, few studies have been done on the effects of combined
electrolyte and water abnormalities on cardiac output, heart rate, systemic
arterial blood pressure, total peripheral resistance and venous return.
Furthermore, the direct effects of systemic electrolyte and water abnor-
malities on the aforementioned parameters have not been well delineated
due to operable neurological compensatory systems mediated via the
autonomic nervous system. There have been almost no studies on filling
time, ventricular compliance, resistance to blood flow through the atria-
ventricular valves and venous return during ionic abnormalities.

Studies of the local effects of increased plasma cationic levels on
vascular resistance in several isolated organs have demonstrated that
locally induced mild hypermagnesemia (8, ll, 20, 29, 33, 66. 68, ST, 91)
and hyperkalemia (8, ll, l2, l4, 20, 29, 33, 68, 80, 8l, 86, 9l) cause
vasodilation in most vascular beds studied. Hyperosmolality, produced
by local hyperosmotic infusion of NaCl, urea, glucose, mannitol or sucrose
also decreases vascular resistance (23, 24, 29, 50, 59, 60, 63, 68, 71,

81. 89) in isolated organs. Furthermore, it has been shown that combining

l

2

hypocalcemia, hyperkalemia, hypermagnesemia, hyperosmolality and
acidosis in isolated perfused organs produces much greater decreases in
vascular resistance than occurs with any single component of the combin-
ation (40, 47, 79). The opposite combinations of hypercalcemia, hypokalemia,
hypomagnesemia, hypoosmolality and alkalosis produce increases of
vascular resistance (47, 79). V

In addition to their local effects on vascular smooth muscle, it
has long been recognized that plasma cationic and osmolar abnormalities
have important effects on cardiac muscle (2, 3, 21, 22, 27, 37, 47, 5l,
54, 56, 57, 6l, 62, 69, 74, 76, 82, 90, 92-94). For example, myocardial
contractile force is increased by local hypercalcemia or respiratory'
alkalosis.(47). Hypokalemia has recently been shown to increase myo-
cardial contractile strength (4). It has been well documented that
hyperkalemia or respiratory acidosis depresses myocardial contractile
strength (47). In addition, hypocalcemia (47) and hypermagnesemia (92)
have also been shown to decrease myocardial contractile strength. All
this information suggests that generalized blood electrolyte and water
abnormalities in an animal would change systemic arterial blood pressure
by effects on both the heart and peripheral vasculature. Previous studies
on the effects of single electrolyte (H+, K+ Na+, Ca++, MgTT) changes
on blood pressure have resulted in equivocal findings (37, 49, 61, 62,
69, 7l, 74, 76, 82, 87, 90, 93). An increase in arterial blood pressure
sometimes follows hypercalcemia and decreases occur during hypermagnesemia,
hypocalcemia or hyperosmolality. In several studies changes in arterial
blood pressure did not occur or were not impressive considering the
change in electrolyte concentration produced. It seems that the effects

of generalized, single electrolyte abnormalities on the heart and blood

3

vessels are buffered, possibly by activation of various compensatory
systems such as the barostatic mechanisms. In contrast to these earlier
studies, it has recently been shown that inducing small, multiple systemic
alterations in plasma electrolyte concentrations and osmolality in
anesthetized dogs can acutely affect arterial blood pressure (l7, 46, 64).
In these studies it appeared that the local actions of the ions dominated
any evoked compensatory reaction since the blood pressure responses were
enhanced in dogs with inoperable neurologic barostatic systems (46, 64).
The present study was undertaken to determine the degree of invol-
vement of total peripheral resistance in the arterial blood pressure re-
sponses during the single and multiple plasma abnormalities of hyperkalemia,
hypermagnesemia, and hyperosmolality in intact dogs. Experiments were
‘also carried out with the animals neurological barostatic mechanisms rend-
ered unresponsive, thus allowing the demonstration of any effects of the
abnormalities on mean arterial blood pressure, total peripheral resist-
ance, venous return and heart rate without the influence of compensatory

reactions mediated through the autonomic nervous system.

LITERATURE SURVEY

This survey focuses on the effects of acute single and multiple
increases in plasma potassium, magnesium and osmolality on vascular
resistance and arterial blood pressure. First to be presented will
be the effects of these electrolyte abnormalities on the myocardium
and coronary vasculature. Secondly, the effects of these electrolyte
alterations on vascular resistance of several other organs will be sum-
marized. Lastly, the effects of these electrolyte alterations on mean

arterial blood pressure.will be discussed.

The Heart

Classical experiments by Sidney Ringer in l883 (72) described the
influence various constituents of blood had on contracting amphibian
ventricles. In one series of experiments, ventricular contractions could
be modified by adding to a circulating 0.75% NaCl solution various sub-
stances known to exist in the blood, namely the dissolved cations. Util-
' izing contraction characteristics of the ventricle perfused with saline
as controls, Ringer was able to ascertain beneficial or deleterious effects
of added constituents. It was discovered "...that potassium chloride in
small quantities, much smaller than exist in serum, will completely and
speedily obviate the character of the trace occurring with saline solution,
and give a trace in all respects like that occurring when the ventricle
is supplied with blood mixture." Addition of 0.006-0.0l Gm. of KCl dis-

solved in distilled water was sufficient to produce the augmentation of

5

ventricular contraction. Furthermore, it was shown that normal contractions
could be evoked with addition of potassium solutions of chloride, phos-
phate, sulphate, citrate, bicarbonate, chlorate, nitrate, acetate, or
carbonate as the anion. Therefore. the changes observed in ventricular
contractions were produced by potassium and were not a function of any
anion tested. When 2 cc of 10% KCl was added to the circulating saline
solution, it was observed that "...in a few seconds the ventricle became
arrested with some persistent spasm, which, however, soon disappeared."
Dr. Ringer concluded this first series of experiments by stating that
the "...excellent circulating fluid for maintaining ventricular contraction
in an isolated heart included one ten-thousanth part of potassium chloride
dissolved in-0.75% saline." I
A second series of experiments by Ringer in l884 (73) were necessitated
due to the fact that, unknowingly, his control saline solution was pre-
pared with ordinary pipe water instead of distilled water. Traces of
various inorganic substances were found to be present in this pipe water,
and therefore, some of the effects observed in the previous study were
possibly due to these additions. The results of the second series of
studies demonstrated that excellent ventricular contractions could be
obtained by supplying the heart with an artificial circulating fluid
containing a mixture or "...lOO cc saline, 5 cc sodium bicarbonate solution,
5 cc calcium chloride solution with l cc potassium chloride solution.”.
Thus, it was Sidney Ringer in the late l9th century who recognized
that combined plasma cations, namely potassium, sodium and calcium could
have measurable effects on the performance of the heart. Subsequent studies
have shown that other ionic and osmolar abnormalities also effect the
performance of the myocardium (2, 3, 2l, 22, 27, 49, 54,‘57, 62, 63, 69,
74, 76, 82, 90, 92, 94). However, few studies reveal a systematic

6

approach to the analysis of the effects single or combined electrolyte
and osmolar abnormalities may have on cardiac output, venous return or
total peripheral resistance. I

Numerous studies on the effects of electrolyte and osmolar abnormal-
ities on the coronary vasculature have been completed. A summary of .
selected studies pertinent to this thesis follows.

In l938, Katz and Lindner (5l) studied the effect of various ions
including potassium on the intact coronary vascular bed. These experi-
ments utilized a blood perfused Langendorff preparation during ventri-
cular fibrillation of the dog heart. In this preparation an increase
in coronary blood flow was indicative of coronary vasodilation and a
decrease in coronary blood flow reflected vasoconstriétion. Addition
of potassium in a concentration of l.5 to 2.5 times the concentration
of potassium present in the perfusate caused a vasoconstriction with re-
sultant decrease in coronary blood flow. Indeed, it was found that
potassium may cause constriction, dilation or both, even in the same
preparation, with addition of potassium within the range of 0.5 to 0.67
times the normal potassium content of the perfusate. An explanation of
these complex results may be that careful attention to the tonicity of
the perfusate and the possible interaction of direct and indirect effects
of the potassium ion was not manifest in these experiments. The tonicity
of the perfusate greatly exceeded the physiological range. Also, alter-
ation in fibrillatory beating characteristics of the heart was noticed
during hyperkalemia suggesting a cardiac muscle excitability and contract-
ility effect. Effects on these two parameters may indirectly influence
coronary vascular resistance (37, 40).

Studies by Bass gt 21;.19 l958 (2) also neglected possible contrib-

7

utory factors of tonicity and calcium concentration upon measured
coronary vascular responses to hypermagnesemia in the isolated beating
rabbit heart. In these experiments rabbit hearts were perfused with
oxygenated Lockes' solution. An increase in coronary flow, reflecting
coronary vasodilation, was observed with addition of MgCl2 to the perfusate.
Since there was a concomitant increase in perquate tonicity by addition
of this magnesium salt, the direct effect of each could not be accurately
ascertained.

McKeever gt._1;_in l960 (65) using a Langendorf preparation similar
to Katz and Lindner l938, found coronary dilation and constriction following
induction of small and large changes respectively, in perfusate potassium
concentration.

Read and co-workers in l960 (71) studied the effects of infusing
5-15 ml/Kg isotonic and molar solutions of NaHCO3, NaOH, NaCl, Na Lactate,
and 50% glucose or 50% urea solutions on systemic and coronary vascular
resistance in dogs. Total body constant flow perfusion was carried out
following induction of ventricular fibrillation to obviate any residual
cardiac output. Systemic and coronary blood flows were measured as well
as aortic and venal caval blood pressures. Systemic and coronary vascular
resistances were calculated. Infusion of all aforementioned solutions
at rates of 3 to 60 ml/min into the arterial inflow pump resulted in a
decrease in systemic and coronary arterial pressures reflecting decreases
in total peripheral and coronary vascular resistances, respectively.
Changes in resistances appeared to be a function of the rate of solute
injection. The greatest decrease in resistances occurred at a rate cor-
responding to 2 mOsm/Kg/min, which increased plasma osmolarity by 25 mOSm/l.

Evidence for direct effects of hyperosmolarity on vascular smooth muscle

8

was also presented in this study. Similar hypertonic infusions were
made following destruction of the CNS, ganglionic blockade, and cooling
to 5° centegrade. Not one of these procedures interferred with the
hypotensive effects of the hypertonic solutions. However, the hydrogen
ion concentration of the hypertonic infusates was not controlled and part
of the fall in coronary vascular resistance may have been due to assoc-
iated acidosis (37, 40). The hypotensive effects did not result entirely
from a passive decrease in resistance due to hemodilution and decreased
viscosity, since distilled water and isotonic solutions infused as controls
produced no hypotensive effect. Bellet gt.gl;_in 1957 (3) also described
coronary vasodilation in dogs following injection of molar sodium lactate
solutions.

Scott gthgl;_in 1961 (81) demonstrated that a small local increase
in plasma potassium or magnesium concentration decreased coronary vascular
resistance in the intact, beating dog heart. Furthermore, coronary vascular
resistance decreased as a function of the infusion rate of isotonic KCl,

MgSO or MgClz. Appropriate control infusions of isotonic NaCl did not

4
alter coronary vascular resistance. Care was taken to maintain isotonicity
of the infused solutions to avoid any vascular effects of tonicity on

the coronary bed. These studies were performed by by-passing the heart
with a pump oxygenator system and perfusing the coronary vasculature at

a constant rate with arterial blood at rates between 60 and 90 mllmin.
Perfusion pressure, which directly reflects coronary vascular resistance

in this constant flow preparation, decreased more during infusion of M9504
than MgClz. This was attributed to the fact that an isosmotic solution

as MgSO supplies more magnesium ion at a given infusion rate than MgClz.

4
The calcium ion was also studied in these experiments and perfusion

9
pressure increased slightly as a function of CaClz inquion. Infusion
of hypertonic NaCl (350 mOSm/l) at sequentially faster rates from 0.5 to
4.0 ml/min increased coronary venous plasma sodium concentration an average
of 16 mEq/l at the highest infusion rate. There was no consistent effect
of hypertonic NaCl on coronary vascular resistance; resistance fell in
seven and rose in 3 experiments. Therefore, these studies showed that
the coronary vasculature is directly dilated by infusion of isotonic
KCl, MgC12,or M9504 and constricted by infusion of isotonic CaClz.
Hypertonic NaCl decreased coronary vascular resistance in some instances
and increased it in others.

Maxwell gt_al;_in 1965 (61) studied the hemodynamic effects of hyper-
magnesemia on the general and coronary vasculatures of the dog. Injections
of 10% MgClz and infusions at 2 m1/Kg body weight of 10% MgCl2 were made
in anesthetized adult mongrel dogs. Cardiac output was determined by
the Pick method and coronary blood flow by the N20 saturation method.

Serum ionized Mg++ concentration increased an average of 2.62 mEq/l and
serum K+ decreased an average of 0.5 mEq/l. Serum osmolarity, [CaTT],
[Na+] and [Cl-] concentrations did not change. Associated with the serum
changes in [Mg++] and [KT] was a significant increase in heart rate and
decrease in systemic arterial blood pressure. However, there was no
significant change in coronary blood flow. Infusion of CaClz in the dogs
made hypermagnesemic caused a return of blOod pressure to normal levels
and a reduction of the tachycardia. The authors concluded that the de-
crease in arterial blood pressure and increase in heart rate was a result
of alterations of the Mg++ICa++ ratio which interferes with acetyl choline
activity at autonomic nervous system ganglia. This is necessary for the

excitation process at sympathetic ganglia and the release of adrenal

lO
medullary hormones. It was believed that hypermagnesemia decreased
acetyl choline activity resulting in an interference with the release
of adrenal medullary hormones that would act to raise arterial blood
pressure to normal levels. The heart rate would then fall to previous
levels by reflex barostatic mechanisms. The inability of hypermagnesemia
to increase coronary blood flow in the studies by Maxwell gt_al;_may be
due to the concomitantly produced hypokalemia. Hypokalemia increases
coronary vascular resistance and ventricular contractile force in the
jn_§1tg.canine heart, (4).

Numerous experiments have been completed showing the effects of single
or multiple electrolyte and water abnormalities on other in.§1tu’isolated
organ vasculatures. The effects of hyperkalemia, hypermagnesemia and
hyperosmolality on the isolated forelimb, hindlimb, renal, skeletal
muscle, gastric, mesenteric, and hepatic vasculatures will be discussed

next.

Limb Vasculatures

Emanuel gt_gl;_in 1959 (14) studied the effects of locally induced
hyperkalemia on forelimb series coupled resistances. In this study the
forelimb was isolated and perfused through the brachial artery at constant
flow. Segmental resistances were calculated by dividing brachial artery,
small skin artery, small skin vein, and cephalic vein pressures by the
total forelimb blood flow(muscle flow and skin flow). However, muscle
Ivasculature was ignored because small muscle arterial and venous pressures
were not measured. Infusion of 10% potassium salts of chloride or phosphate
ar rates which did not measurably effect systemic plasma ionic concentrations,
resulted in a decrease and then an increase in total forelimb vascular

resistance. The decrease in resistance was due primarily to a decrease

11
in the small skin arteriolar vessel resistance and this occurred over
the entire range of infusion rates (0.3 to 2.2 ml/min). The potassium
concentration was locally increased by 0.4 to 3.0 mEq/min with KCl and
0.2 to 1.5 mEq/min with K2P04. When local potassium concentration was
increased to 8 mEq/l, an increase in total forelimb vascular resistance
occurred and was attributed to an increase in large arterial resistance.
Therefore, at the higher infusion rates the observed increase in fore-
limb vascular resistance was a result of an increase in arterial resis-
tance which overrode the decrease in small artery (arteriole) resistance.
These authors also found that the responsiveness of the vascular smooth
muscle to injected norepinephrine and acetyl beta methylcholine chloride
decreased during hyperkalemia induced by potassium infusion over the
’ range of 0.4 to 1.3 mEq/min. The authors concluded that locally induced
hyperkalemia, within physiological ranges, causes an active vasodilation
of the forelimb small artery vasculature. Unfortunately, as previously
mentioned, the contribution of muscle vasculature to the resistance change
was not measured. Also, the potassium solutions used in these studies
were hypertonic to plasma. Other authors have shown that intraearterial
infusions of hypertonic solutions per se can decrease peripheral vascular
resistance (3, 48, 60, 71). Therefore, although the results of Emanuel
gt al;_are suggestive of a direct effect of'K+ on vascular smooth muscle,
the data are not conclusive.

Similar studies to those of Emanuel gt_gl;_were completed by Haddy
in 1960 (29) with particular attention to the local effects of Mg++, Na+
and Ca++. Again, however, careful attention to the problem of tonicity
was not adhered to and the results must by analyzed in view of this fact.
Separate infusion of 10% solutions of sodium chloride, sodium lactate,

sodium bicarbonate, and sodium sulfate into the brachial artery of isolated

12
dog forelimbs at rates of 0.3, 0.6, and 1.0 ml/min resulted in a pro-
gressive fall in brachial and small arterial pressures. There was no
effect on venous pressures. Also, the responsiveness of the forelimb-
to injected levarterenol and methacholine progressively decreased
as sodium concentration was elevated. Infusion of 10% MgSO4 at rates
of 0.3 to 2.3 ml/min resulted in a decrease in brachial and small artery
pressures which correlated with the increasing infusion rates. Total
forelimb vascular resistance decreased primarily due to a fall in small
vessel resistance. However, arterial and venous resistances also fell
slightly. The responsiveness of the forelimb to injected levarterenol
was decreased but not changed to methacholine during the hypermagnesemic
state.

In summary, this study showed that local hypernatremia or hyper-
magnesemia resulted in active vasodilation of the dog forelimb vasculature.
This decrease in forelimb vasculature resistance appeared to result
primarily from a decrease in small vessel (arteriole) resistance. The
results of this study are very suggestive of a direct effect of altered
cationic concentrations of hypernatremia (hypertonicity) and hypermagnesemia
on vascular smooth muscle. However, since careful attention was not applied
to the tonicity of the infused solutions the results are not conclusive.

In 1961, Overbeck g§_al;_(68) described experiments on the dog forelimb
that took into account the tonicity of infused electrolyte solutions.

In this study the local effects of Na+, KT, Mg++ and hypertonicity on

the dog forelimb vasculature were re-evaluated. The plasma osmolarity
and concentrations of K+ and Mg++ were individually increased in blood
perfusing the isolated intact farelimb. Locally increasing plasma potas-

sium concentration without changing plasma osmolarity over the range of

13

1—4 mEq/l produced a vasodilation of the forelimb vasculature. The major
site of dilation was limited to the small vessels just proximal to the
capillary. Upon increasing plasma potassium concentration above 10 mEq/l
a pronounced vasoconstriction of the large arteries was observed. Dawes
(12) also described a vasodilator action of K+ in larger doses in the cat
and dog hindlimb. Also, Frohlich gt al;_in 1962 (20) showed that increasing
plasma K+ over the range of 4-8 mEq/l caused a progressive dilation of the
arteriolar vessels of the dog forelimb. Increasing plasma K+ concentra-
tion above this level resulted in constriction of the large arteries causing
a marked rise in total forelimb vascular resistance in the face of arteriolar
dilation. In the kidney, locally induced hyperkalemia produced by infusion
caused active dilation when the serum concentration was elevated over
ranges which might occur naturally (0.11-0.69 mEqKTImin). An increase in
urine flow rate was associated with the vasodilation. When the potassium
concentration was elevated further, the dilation was replaced by active
constriction (80).

Lowe and Thompson in 1962 (58) demonstrated a vasodilator response
to intra-arterial infusion of isotonic KCl in the human forearm. Pro-
‘ gressive vasodilation was observed over the infusion range of 0.7-23 mg/min.
Larger doses of KCl could not be studied because they caused severe pain.
Glover gt_al;_in 1963 (26) demonstrated that infusion of 0.5 mEq/min KCl
produced no change in human forearm blood flow. However, infusion rates
of 0.1, 0.2 and 0.4 mEq/min increased blood flow progressively. Another
study (10) supports the findings that the potassium ion is a vasodilator
of vascular smooth muscle. In this study, the hindlimb vascular responses
to isotonic KCl infusion in genetically hypertensive and normotensive rats

were evaluated. Sequentially increasing KCl infusion rates produced a

l4

progressive decrease in hindlimb vascular resistance. In contrast to
data from men and dogs (66, 67, 68), the hindlimb vasoactive responses
of genetically hypertensive rats was not different from those of normo-
tensive rats (10).

Overbeck gt_gl;_in 1961 (68) demonstrated Mg++ to be a powerful vaso-
dilator of arterioles in the dog forelimb. Slight elevations of plasma
Mg++ concentration without changes in plasma osmolarity caused marked
vasodilation of arteriolar vessels in the isolated, intact, constant flow
perfused dog forelimb.

Other evidence that the MgTT ion is a vasodilator is provided by
Frohlich gt_al;_(20) in the dog forelimb and renal vasculatures, Haddy
(29) in the dog forelimb, Scott gt_al;_(81) in the dog coronary vascular
bed, and Overbeck gt_gl;_(66, 67) in the forearm of normotensive and hyper-
tensive men.

Increasing plasma tonicity by infusion of hyperosmotic solutions
of sodium, glucose, or urea results in arteriolar dilation in the dog
hindlimb (60),forelimb (34, 68), coronary and systemic vasculatures (3, 71),

and the renal vasculature (23, 24, 48).

The Renal Vasculature

Scott gt_gl;_in 1959 (80) described the effects of renal arterial
infusion of hypertonic KCl into the ig_§jtu, isolated, constant and nat-
urally flow perfused dog kidney. The experiments were designed to cause
deviations in local renal plasma potassium concentration with no alter-
ation in systemic plasma potassium concentration. In the constant flow
kidneys, renal vascular resistance was first lowered and then raised;

this response was not altered by phentolamine. Constant pressure perfused

kidneys exhibited an increase in urine flow rate during KCl infusion at

15

a rate that decreased resistance in constant flow kidneys. In the constant
flow kidneys, the vasodilation apparently resulted from a direct effect
of K+ on the renal arteriolar vascular smooth muscle. The subsequent
vasoconstriction at higher infusion rates may have been a direct effect
of K+ on larger renal arterial vessels, an indirect effect via a sympathico-
adrenal discharge, or a combination of both. As stated, these studies
did not account for the hypertonicity of the KCl solutions. Therefore,
further studies were completed using isosmotic solutions of KCl and other
cations (20). In these studies, renal vascular resistance was regularly
decreased by infusion of isosmotic KCl into kidneys with initially high
resistances. Kidneys with a low initial vascular resistance were, on
the average, unaffected. At the highest infusion rate (5 ml/min) the
calculated KT concentration in the plasma perfusing the kidneys was 8 mEq/l
and renal vascular resistance increased above control level. Therefore,
the precipitous rise in renal vascular resistance could have resulted
from potassium induced vascular smooth muscle contracture or possibly
adrenal discharge since systemic plasma-potassium concentration was ele-
vated.(37). Infusion of isosmotic MgClZ produced a regular decrease in
renal vascular resistance in initially high resistance kidneys. Kidneys
with a low initial vascular resistance were, on the average, unaffected.
Gazitua gt_gl;_(23, 24) studied the effects of locally increasing
renal blood osmolarity by intra-arterial infusion of dextrose, NaCl, and
urea solutions on renal vaScular resistance in the dog. Infusion of hyper-
osmotic solutions of dextrose, NaCl or urea produced decreases in renal
vascular resistance during the steady state. However, the time course
relationships of renal resistance changes were different between dextrose

and NaCl or urea infusions. Hyperosmotic dextrose infusion produced a

16
fall in renal vascular resistance that was sustained throughout the
entire infusion period of three minutes. Upon cessation of the instion,
renal vascular resistance returned to preinfusion control levels. On
the other hand, three minute infusions of hyperosmotic solutions of NaCl
or urea caused a fall in renal vascular resiStance that waned with time.
On termination of the infusions, resistance rose above control levels,

especially in the case of urea.

The Visceral Vasculature

The vascular effects of isotonic infusions of potassium and magnesium
salt solutions on gastric and superior mesenteric vascular beds of the
dog are similar to responses demonstrated in the forelimb, kidney and
coronary circulations. Chou gt al;_(9) studied the effects of Ca++, Mg++
and K+ on vascular bed supplied by the superior mesenteric artery in the
dog. Magnesium was found to be strikingly more potent as a vascular smooth
muscle dilator in the superior mesenteric bed than in the forelimb or
kidney vascular beds. Calcium was a less potent vasoconstrictor and pot-
assium seemed to cause less dilation in superior mesenteric bed than in
renal and coronary beds. Texter gt_al;, in 1967 (91), demonstrated that
infusions of isotonic KCl and MgC12 into the isolated, constant flow per-
fused superior mesenteric vascular bed caused a decrease in large and
small arterial vascular resistances. The same authors found similar results
in the isolated gastric circulation. However, at the highest rates of
infusion the characteristic biphasic response of vascular smooth muscle
to KCl infusion was not evident. This may be explained by the fact that
the infusion ranges utilized in this study only increased blood K+ con-

centration by 0.5-3 mEq/l. The increase in forelimb, renal and coronary

vascular resistances during KCl infusion previously observed was not

l7

evident until the blood K+ concentration reached levels of more than 8 mEq/l
(20, 68, 81).

Dabney 23.21;.1" 1967 (11) studied the effects of local intra-
arterial infusions of isotonic solutions of KCl and MgC12 on both intest-
inal vascular resistance and intestinal wall compliance. These studies
were done in isolated, constant and natural flow perfused segments of
dog ileum. In the constant flow studies directional changes in ileal
venous blood outflow were inversely related to ileal vascular resistance.
Infusion of isotonic MgClz caused an increase in ileal segment venous
outflow reflecting a decrease in ileal vascular resistance. This occurred
progressively over the infusion rates of 0.05 to 2.1 mllmin. At the
0.5 ml/min infusion rate, ileal compliance was increased. These findings
suggest that magnesium may have a duel role in decreasing intestinal
vascular resistance. That is, a direct vasodilatory action on the intest-
inal vascular smooth muscle coupled with a relaxation of intestinal smooth
muscle resulting in an increased transmural pressure. The latter effect
of magnesium is evidenced by the observed increase in ileal compliance.
Furthermore, it has been suggested that the magnesium ion produces a much
greater decrease in vascular resistance through the superior mesenteric
bed relative to the decreases seen in the forelimb, kidney and coronary
vascular beds (9, 39). Intra-arterial infusion of isotonic KCl at
0.05-2.1 m1/min first elevated and then decreased blood flow, indicating
. an initial decrease and then increase in intestinal vascular resistance.
Ileal compliance was first increased and then decreased. Comparison of
constant and natural flow experiments, disclosed initially potassium
caused a vascular vasodilation and a decrease in intestinal muscle

compression on the blood vessels (producing an increased transmural pres-

18
sure). The subsequent decrease in ileal blood flow at the higher
infusion rates most likely resulted from active vasoconstriction of
the blood vessels and also intestinal smooth muscle contraction.
Similar intestinal vascular effects were observed by locally increasing
ileal segment potassium concentration by intraluminally placed KCl
or hydrochlorothiazide-KCl tablets (7). Canine hepatic artery vascular
resistance was not affected by KCl infusion until rather high rates
of KCl infusion (1.44 mEq/min) were produced in the hepatic artery and
then it increased. Isotonic KCl infusion has no effect on the portal
system vasculature (8). Isotonic MgClz infusion into the hepatic artery
or portal vein decreased canine hepatic vascular resistance at infusion

rates from 0.4-7.7 ml/min (8).

Skeletal Muscle Vasculature

Dawes in 1941 (12) studied the effects of injected KCl in contracting
skeletal muscles of the dog. He observed that KCl caused a greater
vasodilation when resting skeletal muscle vascular resistance was high.
It was postulated that the working muscle releases potassium ions that
causes a direct vasodilation of the skeletal muscle vasculature. Kjellmer
(53) demonstrated a vasodilator action of potassium infusion into the
isolated, constant flow perfused calf muscles of the cat. Indeed, intra-
arterial potassium salt infusions were shown to produce the same vascular
results as exercise. Skinner and Powell (86) also demonstrated a vaso-
dilator action of this ion on skeletal muscle. These investigators per-
fused the isolated dog gracilis muscle with blood containing varying
concentrations of oxygen and potassium. Interestingly, a minimal to
moderate vasodilation was produced by perfusion of blood with elevated

potassium (greater than 8 mEq/l) and normal oxygen tension. However, when

19

oxygen deficient and hyperkalemic (less than 8 mEq/l) blood was used as
the perfusate, a much greater and more rapid decrease in gracilis muscle
vascular resistance was observed. Furthermore, perfusion of hypokalemic
blood with a normal oxygen content caused vasoconstriction (86).

Producing local hypokalemia by means of hemodialysis, raises resis-
tance to blood flow through the canine gracilis muscle vascular bed(l, 75).
In these studies, the relationship between percent change in potassium
ion concentration and percent change in perfusion pressure appeared to
be linear. Perfusion pressure increased 12% when potassium ion concen-
tration was decreased 50%. Prolonged hypokalemia produced an irreversible
increase in perfusion pressure and a decreased responsiveness to close
arterial injection of levarterenol (75). In a similar preparation,
Anderson £2.21; (1) demonstrated that removal of up to 84% of the plasma
magnesium produced no effect, either alone or in conjunction with hypo-
kalemia on gracilis muscle vascular resistance.

Chen §t_§l;_(6) studied the effects of hyperkalemia and hypokalemia‘
on canine gracilis muscle and forelimb vascular resistances, both before
and after close intra-arterial infusion of ouabain (10 ug/ml at rate of
0.25 ml/min for 20-40 minutes). Again hemodialysis was utilized to
alter potassium concentration of the blood. Ouabain blocked or reversed
hypokalemic constriction and suppressed, blocked or reversed hyperkalemic
dilation in these isolated vascular beds. The results of this study support
the hypothesis that elevated plasma potassium stimulates an electrogenic
NaT-K+ pump located in the smooth muscle membrane. This increased activity
of the pump results in hyperpolarization of the smooth muscle cells and
dilation of the vessels (56).

Stainsby and Fregly (89) studied the effects of increasing plasma

20

osmolarity on gastrocnemius-plantaris muscle vascular resistance in the
dog. Increasing plasma osmolarity by addition of sodium chloride, sucrose,
glucose, mannitol, dextran or urea to the blood perfusate decreased muscle
vascular resistance. Furthermore, muscle vascular resistance increased
following perfusion of the muscle with hypo-osmolar blood. Similar results
were obtained in the lower leg skeletal muscles of cats (63). In this
study, intra-arterial infusion of hypertonic glucose or xylose into

resting skeletal muscles produced a vasodilation and decreased muscle
vascular resistance. The resistance changes were of the same magnitude
produced by muscular exercise (63). Lundvall and Mellander in 1969 des-
cribed skeletal muscle vasodilation in man during infusion of hypertonic
solutions (59).

Marshall and Shepherd (60) studied the effects of rapid single in-
jections of hypertonic solutions into the femoral artery of the dog. A
transient decrease followed by a prolonged two fold to three fold increase
in flow was observed after 20% sodium chloride, 20% sodium lactate, 20%
sodium bicarbonate, and acid and alkaline solutions of sodium phoSphate
injection. Also, 25%-50% solutions of dextrose caused similar effects.
Furthermore, continuous infusion of 10% and 20% NaCl and 50% dextrose
and urea solutions at 2.3 mllmin produced two to three fold increases
in flow which continued throughout the infusion period. The authors
concluded that direct vasodilation was induced by hypertonic solutions
irrespective of the sodium content of the solutions (60).

Skinner and Costin (72) showed that infusion of hyperosmolar solutions
of glucose into the isolated, innervated, constant-flow perfused dog
gracilis muscle caused a decrease in gracilis muscle vascular resistance.

Osmolality was increased to 40 mOSm/Kg. A greater decrease in vascular

21

resistance occurred when hyperosmolarity was produced in the presence
of oxygen deficient blood and with oxygen deficient blood and hyperkalemia
(72).

Scott §t_al;_(78) alternately perfused the jn_§jtg_canine gracilis
muscle at constant flow with normal and hypoosmolar blood or with
normal and hyponatremic blood (isoosmolar) while measuring perfusion
pressure. Osmolality was lowered by hemodialysis against a modified
Ringer's solution low in NaCl. To create isoosmolar hyponatremic blood,
mannitol was used to replace NaCl in the Ringer's dializate. Hypo-
osmolar blood produced a prompt rise in gracilis muscle vascular resis-
tance. Furthermore, the gracilis muscle vascular resistance responSe
appeared to have a linear relationship to the decrease in osmolality.

A 10% decrease in osmolality produced a 22% increase in gracilis muscle
vascular resistance. Isoosmolar hyponatremic blood produced a slight
increase in gracilis muscle vascular resistance, however, upon returning
sodium concentration to normal the response failed to disappear these
studies supportr the concept that changes in plasma water and not neces-
sarily the sodium ion pgr_§g_can cause striking alterations in the resis-
tance to blood flow through a vascular bed (37).

Of particular relevance to this thesis are the effects of multiple
plasma electrOlyte and osmolar abnormalities on parallel organ vascular
resistances. Few studies have been completed in this area. In 1963,
Haddy gt_al;.examined the effects of inducing the single and multiple
electrolyte abnormalities of hypokalemia, hypomagnesemia, alkalosis, and
hypercalcemia on resistance to blood flow through the dog forelimb, kidney
and coronary vasculatures. The forelimb and kidney vasculatures respond

to combinations of local hypokalemia, hypomagnesemia, alkalosis and

22
hypercalcemia with much more marked vasoconstriction than occurs with
any one of the abnormalities. Furthermore, the same multiple electrolyte
abnormalities increases myocardial contractile force much more than does
any single abnormality alone (47).

All the aforementioned studies have demonstrated that slight local
alterations in one or more blood electrolytes or osmolarity can affect
cardiac and vascular smooth muscle. All of this information suggests
that generalized blood electrolyte and osmolar abnormalities in an animal
would change systemic blood pressure by effects on both the heart and
peripheral blood vessels unless prevented by compensatory systems. A
review of the literature fails to reveal a systematic study of the effects
of single or combined electrolyte and water abnormalities on total peri-
pheral resistance, a direct determinant of arterial blood pressure.

Also, conclusive data relative to the effects of electrolyte abnormalities
on cardiac output and venous return to the heart are lacking.

Effects of single electrolyte abnormalities of hyperkalemia,
hypermagnesemia, hypercalcemia, hypocalcemia, alkalosis, acidosis,
and hyperosmolarity on arterial blood pressure has been examined by a
number of investigators (10, 49, 57, 61, 69, 71, 74, 76, 82, 87, 90, 93, 94]
The changes in pressure relative to the changes in electrolyte concent-
ration is not impressive, although pressor responses sometimes result
from hypercalcemia and depressor responses follow hypermagnesemia, hypo-
calcemia, or hyperosmolality. Apparently a change in the blood pressure
is effectively prevented by the various remote regulatory systems such
as the barostatic mechanisms (46). To explore the possibility of altered
blood pressure responses due to barostatic mechanisms, Haddy gt;gg;_

examined the effects of generalized single and multiple changes in plasma

23

cationic and osmolality levels on arterial blood pressure in dogs by
utilizing two basic experimental methods. In one procedure, a
potent diuretic (furosemide) was administered intravenously and the
urinary loss from the animal was replaced with various electrolyte
solutions either rapidly after 90 minutes of diuretic action or mil-
liliter for milliliter as it appeared. The electrolyte solutions
used for the volume replacement were prepared to produce the desired
plasma abnormalities. Another procedure utilized was a simple dil-
utional one which produced rapid electrolyte changes. However, the
changes induced by this latter method were transient and associated
with hypervolemia. With the first method, single or multiple induced
hypokalemia, hypomagnesemia, alkalosis, hypercalcemia and hypoosmolarity
caused an increase in systemic arterial blood pressure when compared
to a control infusion of NaCl-fortified Ringer's solution which did not
greatly change plasma pH, calcium and potassium concentrations.
Superimposing complete spinal anesthesia upon the aforementioned com-
bined plasma abnormalities had no effect on arterial blood pressure.
However, superimposing complete spinal anesthesia upon the combined plasma
abnormalities of hyperkalemia, hypermagnesemia, acidosis and hypo-
calcemia greatly reduced arterial blood pressure. It was therefore sug-
gested that the pressure decrease associated with hyperkalemia, hypermag-
nesemia, hypocalcemia and acidosis was attenuated due to interaction of
neural buffering mechanisms(46).

Emerson gt al;_(17) used the dilutional technique described by
Haddy gt_al;_(46) and extended the investigation into the effects of
generalized acute multiple changes in plasma electrolyte levels on canine

blood pressure. Since this method required infusion of considerable

24

volumes of electrolyte solutions, a control infusion of Ringer's

solution was also employed. This enabled analysis of arterial blood

pressure responses to hypervolemia and dilution. These studies

showed that infusion of the Ringer's solution elevated arterial blood

pressure slightly, whereas the combined abnormalities of hyper-

kalemia, hypermagnesemia, hyperosmolarity, hypocalcemia, and acidosis

caused a 14% decrease in arterial blood pressure. The opposite

electrolyte abnormalities produced a 30% increase in arterial blood

pressure. This study illustrated that small, multiple electrolyte and

water abnormalities can acutely affect arterial blood pressure in

anesthetized dogs. It also illustrated that the local action of the

ions and osmolarity dominated any evoked remote compensatory mechanisms (17
An extension of the studies by Emerson gt_gl;_was completed by

McKeag gt_gl;_(64). The same experimental procedure was used except

for the addition of rendering the animals neurological barostatic

compensatory mechanisms inoperable by complete spinal anesthesia. Infusion

of an electrolyte solution which induced hyperkalemia, hypermagnesemia,

acidosis, hypocalcemia and hyperosmolarity causes a much greater decrease

in arterial blood pressure (when compared to the isovolumic Ringer's

control infusion) than that observed in neurologically intact animals.

This study illustrated that the arterial blood pressure responses to

acute multiple alterations of plasma electrolyte and osmolar concentrations

that cause a depressor response in intact dogs is partially compensated

by the various neurological mechanisms that operate to maintain a fairly

constant arterial blood pressure (64).

25

Haddy and Scott (43) reported the effects on arterial blood
pressure of steady state changes in isovolemically singly and mult-
iply produced hypokalemia, hypomagnesemia and hypoosmolality. Furo-
semide was injected intravenously and the urinary loss from the animal
was replaced with modified Ringer's solutions which produced the desired
electrolyte and water abnormalities. Control animals received a replace-
ment solution which maintained plasma cationic concentrations normal.
Relative to control animals, hypokalemia, hypomagnesemia or hyponat-
remia (and therefore hypoosmolality) had no effect on arterial blood
pressure. The combinations of hypokalemia and hypomagnesemia, hypo-
kalemia and hypoosmolality and hypokalemia, hypomagnesemia and hypo-
osmolality raised arterial blood pressure. In the case of multiply
induced abnormalities of hypokalemia, hypomagnesemia and hypoosmolality,
cardiac output measured by thermal dilution was increased while total
peripheral resistance was not changed. It was postulated that hypo-
‘kalemia induced depression of the Na+/K+ - ATPase activity at the cardio-
vascular muscle membrane resulted in a decrease in intracellular pot-
assium concentration, decrease in membrane potential, increased in
free intracellular calcium ion and hence enhanced contraction of cardio-
vascular muscle. Hypoosmolality may have further decreased intra-
cellular potassium concentration by osmotic cellular dilution, as well
as producing mechanical effects subsequent to red cell, endothelial cell
and vessel wall swelling.

In another study (42) arterial blood pressure was measured in
anesthetized dogs during acute, selective sodium chloride depletion with-
out water depletion. The total osmotic pressure of extracellular fluid

was held constant thereby preventing osmotic shift of water into cells.

26
The blood pressure changes produced were not different from those in a
control series where sodium concentration remained constant. Therefore
acute sodium chloride depletion pg; sg did not affect arterial blood
pressure. It was strongly suggested by this study (42) that the changes
previously observed with acute manipulation of the total body sodium
chloride concentration (5, 19, 35, 71) may have resulted from associated
changes in extracellular osmolality.

A further extension of the studies involVing the effects of general-
ized hypokalemia, hypomagnesemia and hypoosmolality on arterial blood
pressure was recently completed by Haddy and Scott (44). The general-
ized electrolyte and water abnormalities were produced by either a
rapid intravenous infusion technique or the slower non-dilutional tech-
nique previously described (17, 46). In these newer studies, cardiac
output was measured and total peripheral resistance was calculated to
ascertain the effects of hypokalemia, hypomagnesemia and hypoosmolality
on these two direct determinants of arterial blood pressure. When
hypokalemia, hypomagnesemia and hypoosmolality were produced rapidly
(within five minutes) by the dilutional technique arterial blood pressure
rose because total peripheral resistance did not fall proportionately
to roughly the same increase in cardiac output produced by a control
infusion. It was suggested that the electrolyte abnormalities may
have limited the fall in total peripheral resistance by activation of
vascular smooth muscle contraction, increased red cell size and rigidity,
vessel wall hydration, or all three.

When hypokalemia, hypomagnesemia, and hypoosmolality were produced
by the slower non-dilutional technique, arterial blood pressure rose

due to increases in both cardiac putput and total peripheral resistance.

27

The increase in cardiac output resulted from an increase in heart rate
even in the face of an increased pressure at the arterial baroreceptors.
Furthermore, stroke volume was not lower than normal, despite the
reduction (in some cases) in right heart filling pressure and elevation
of arterial pressure. Therefore a direct chronotropic and ionotropic
effect produced by the electrolyte abnormalities was suggested. The -
electrolyte abnormalities, apparently, increased total peripheral
resistance by stimulating vascular smooth muscle, increasing red blood

cell size, and/or waterlogging of the blood vessel walls.

Summary
It may be helpful to the reader at this point to summarize the

salient points from this large amount of data that led to the present
study.

Many experiments have been completed showing the effects of single
or multiple electrolyte and water abnormalities on cardiac performance
and vascular resistance in isolated organs. A small local increase in
potassium concentration causes a fall of resistance in the human and
dog forelimb (10, 12, 14, 20, 26, 29, 58, 68), kidney (20, 80), mesen-
tery (9, 11, 33, 91), stomach (91), coronary (51, 65, 81), skeletal muscle
(12, 86), skin (12), and adipose (77) vasculatures. Local hypokalemia
causes a slight constriction of vessels in the dog forelimb (47), kidney
(47), coronary (4), and skeletal muscle (1, 6, 75, 86). A local,
moderate to high increase in plasma magnesium concentration produces a
fall in resistance in all the aforementioned isolated vascular beds
(2, 8, 9, ll, 20, 29, 33, 37, 40, 61, 66-68, 79, 81, 91, 94). Locally
increasing plasma osmolality causes a decrease in forelimb, cardiac and

renal vascular resistance; decreasing plasma osmolality causes vasocon-

28
striction (3, 23, 24, 48, 59, 60, 63, 71, 79, 84, 85, 89, 44, 45, 78).

Several studies by Haddy gt_al;_have examined the effect on
vascular resistance in several organs by making local, combined changes
in plasma electrolyte and osmolar concentrations. These investigators
demonstrated that simultaneously increasing plasma [K+] and [Mg++] and
decreasing [Ca++] and pH in the dog forelimb or kidney caused a greater
vasodilation than occurred with any one of the changes made singly.

The opposite multiple electrolyte abnormalities caused a greater vaso-
constriction than occurred with any one of the changes made singly.
Furthermore, simultaneously inducing hypokalemia, hypomagnesemia, hyper-
calcemia and acidosis in blood perfusing the coronaries in an intact,
working heart caused an increaseiin left ventricular contractile force,
and increased coronary vascular resistance; local hypomagnesemia, alone,
caused little change in either parameter (29-40, 47). Locally induced
hypokalemia caused an increase in coronary vascular resistance and
ventricular contractile force in the jg_§jtg_canine heart (4).

Recent studies describe the arterial blood pressure response to
acute, concomitant alterations in plasma [K+], [Mg++], [Ca++], osmolality
and pH. A small generalized increase in plasma [K+], [Mg++] and osmol-
ality combined with a decrease in [Ca++] and pH produces a striking
decrease in mean, systolic and diastolic blood pressures. The opposite
electrolyte alterations produce an increase in mean, systolic and
diastolic blood pressures (9, 46, 64). Generalized, acute hypokalemia,
hypomagnesemia, and hypoosmolality increases arterial glood pressure
by effects on primarily the total peripheral vascular resistance (44).

when hypokalemia, hypomagnesemia and hypoosmolality are produced

more slowly by a dilutional technique, arterial blood pressure rises

29

due to increased cardiac output (43) and increased total peripheral
resistance (44).

It is still unknown whether the effects of increased plasma electo-
‘lyte and osmolar abnormalities on blood pressure are predominantly a
result of their influence on cardiac output or total peripheral resistance,
but it is suggested both are involved. To establish the contributions
of the heart and blood vessels to the blood pressure changes observed
when hyperkalemia, hypermagnesemia and hyperosmolality are generalized
throughout all of the blood, total peripheral resistance and cardiac
output must be determined. Also the involvement of neurological compen-
satory systems which tend to maintain blood pressure constant must be
determined if the direct effects of various electrolyte and osmolar
abnormalities are to be ascertained.

This investigation was undertaken to explore the effects of single
and multiple plasma abnormalities of hyperkalemia, hypermagnesemia, and
hyperosmolality on one direct determinant of arterial blood pressure,
total peripheral resistance. Heart rate, venous return, and systemic
arterial blood pressure were also measured. By blOcking the barostatic
mechanisms, the direct effect of the abnormalities on total peripheral
resistance without the secondary, indirect effects mediated via the
autonomic nervous system were also investigated. In addition to im-
proving the understanding of basic physiological mechanisms which in-
fluence arterial blood pressure, total peripheral resistance, venous
return, and heart rate, these studies might be relevant to the clinical

recognition and management of hypertension and hypotension.

METHODS

A total of 129 experiments were completed in 102 adult mongrel
dogs of both sexes weighing an average of 15 Kg (range 13-20 Kg). All
animals were anesthetized with 30 mg/Kg sodium pentobarbitol and anti-
coagulated with 5 mg/Kg sodium heparin. Depth of anesthesia was main-
tained by giving small, supplemental doses of sodium pentobarbitol when-
ever a conjunctival reflex appeared. No more than three experimental
procedures were carried out in any animal of this group.

Following establishment of artificial respiration With a Harvard
constant volume respirator (Model 607, Harvard Apparatus Co.), the
chest was opened in the fourth or fifth intercostal space on the left
side. The pericardium was incised and the azygos vein ligated. In
35 experiments, the superior and inferior vena cavae were cannulated
with large bore, low resistance Tygon tubing near their entrance to
the heart. Since small increases in central venous pressure can appre-
ciably affect venous return, the outflow tips of the venous cannulae
were adjusted to permit a slight flutter of the vena cavae near their
points of cannulation, thus assuring a mean pressure of near 0 mmHg
at all times. Total systemic venous return (VR) flowed by gravity into
a lowered 500 cc plastic reservoir (situated in a water bath maintained
at 38°C) and was returned to the cannulated right atrium with a pressure
independant Sigamotor pump (Zero-Max Co.). This extracorporeal system
was primed with approximately 500 cc fresh whole blood from a donor dog.

In another 94 experiments, the right atrium was cannulated so that
all the blood from the superior and inferior vena cavae and azygos vein
flowed by gravity into the previously described extracorporeal circuit.
The blood was returned to the ligated and cannulated pulmonary artery by

30

31
means of a pressure independant Harvard Apparatus Piston Pump
(Model #1421).

In all experiments, cardiac inflow was held constant with the inflow
pumps, hence, changes in arterial pressure directly reflected changes
in total peripheral resistance. Pulmonary artery and left atrial pres-
sures were monitored to allow calculation of pulmonary vascular resist-
ances during the experimental period. Also post-mortem examination
of the lungs was performed to ascertain presence of pulmonary edema.

The amount of blood in the reservoir was allowed to vary; an increase‘

in reservoir volume indicated the amount of blood translocated centrally
while a decrease reflected the amount pooled. When the reservoir was
neither rising or falling, a state of equilibrium existed between cardiac
output and venous return. Venous return was measured with a graduated
cylinder and stopwatch at appropriate times.

Mean systemic arterial blood pressure was recorded from a poly-
ethylene cannula (PE 240) advanced into the aorta through a femoral
artery. Pressures were recorded using Statham pressure transducers
(Statham Laboratories, Model P23Gb) connected to a Sanborn direct writing
recorder. Cardiac frequency was recorded with standard electrocardio-
graphic leads connected to a Sanborn Cardio-Tach preamplifier. Total
peripheral resistance was calculated by dividing the appropriate mean
arterial blood pressure by the respective steady-state venous return.

A femoral vein was cannulated (PE 240) for administration of sodium
pentobarbitol and heparin as required. Blood was withdrawn from the
cannulated femoral artery before, during and following the infusion

for laboratory analysis. Plasma electrolyte concentrations were deter—
mined by the following methods: Mg++ and Ca++ by atomic absorption

spectrophotometry (Perkin Elmer, Model 2908); K+ and Na+ by flame photometry

32
(Beckman, Model 105). Plasma osmolality was determined with an advanced
osmometer (freezing point depression). Arterial blood hematocrit and
pH were measured with a micro-hematocrit centrifuge and Astrup expanded
scale pH meter, respectively. The instruments and methods employed for
measuring the blood parameters have the following limits:

Mg++ -- tome mEq/l; Ca“ - 10.04 mEq/l; i<i = 10.1 mEq/l; Na“ = 1-1 mEq/l;

Osmolality = 10.5 mOSm/l; pH = 30.02 units; Hematocrit = 10.5%.

The desired single plasma electrolyte changes were induced by a
5 minute infusion of isotonic KCl (1.91 cc/min), MgClz (1.91 cc/min)
or hypertonic NaCl (7.64 cc/min) into the venous tubing behind the inflow
pump by utilizing a Harvard apparatus infusion pump (Infusion Nithdrawl
Pump, Model 901, Harvard Apparatus Co.). The infusion rates were suf-
ficient to increase plasma [K+], [Mg++], or osmolality an average of
0.64 mEQ/l, 1.83 mEq/l, and 20 Osm/l, respectively, by the end of the
infusion period. Simultaneous infusions of an isotonic solution of
MgC12 and KCl (3.82 cc/min) in combination with hypertonic NaCl (7.64
cc/min) increased plasma [K+], [MgTT] and osmolality the same degrees
as during the single electrolyte infusions.

Similar single and multiple electrolyte abnormalities as described
above were created in spinally blocked dogs (6-8 cc procaine hydrochloride
(Abbott Laboratories) intrathecally via the cisterna magna). An additional
8 experiments were carried out in spinally blocked dogs in which plasma
[KT] and [Mg++] were elevated simultaneously.w Infusion of equal volumes
of isotonic KCl and MgC12 at a total of 3.82 cc/min raised plasma [K+]
and [Mg++] to similar levels as occurred when hyperkalemia or hypermag-
nesemia were singly induced. Following all spinal blockade procedures,

a continuous infusion of approximately 10 v/min (range 2-20 Y/min) of

norepinephrine (levarterenol) was required to maintain an arterial blood

33
pressure corresponding to the "preblocked" arterial blood pressure.

Five minute saline control infusions at 1.91 cc/min and 11.46 cc/min
in both intact and spinally blocked dogs were employed to ascertain
the effects of hypervolemia and dilution on the measured parameters.
Table l is a summary of the experimental procedures utilized, showing
the various solutions employed, the osmolality of the infused solutions,
the volume infused per minute, the total volume infused, and the pre-
dicted plasma changes to be created.

All data were subjected to a Student's t_statistical procedure
modified for paired replicate analysis, thereby allowing each experi-
mental animal to serve as its own control. A "p" value of less than
0.05 was considered significant. Also, an in-groups paired analysis
of 2 variants was employed to determine significance values for the

resistance changes observed in the spinally blocked animal series.

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RESULTS

Table 2 presents the average results of each experimental procedure
utilized in this study. Average changes in the denoted hemodynamic and
measured blood parameters before (C) during (1) and after (PI) each
procedure are shown. Analysis of electrolyte data shows that the predicted
plasma changes were created in each instance. Note that the experimental
procedures completed in the intact dogs directly precede their identical
counterpart procedure carried out in spinally anesthetized (procainized)
dogs.

Five minute control infusions of isotonic NaCl at 1.91 cc/min and
11.46 cc/min delivered a total infusate volume of 9.55 cc and 57.3 cc,
respectively, to the animals. In the intact dogs, infusion of isotonic
NaCl at either rate did not alter any measured cardiovascular or blood
parameter except pH and [K+] which decreased 0.02 units and 0.3 mEq/l,
respectively, by the fifth minute of infusion at the 11.46 cc/min rate.
pH and [KT] remained depressed at five minutes post infusion.

Infusion of isotonic NaCl at 1.91 cc/min in spinally anesthetized
dogs did not significantly alter any measured cardiovascular parameter
except reservoir volume which fell 44 cc by the fifth minute of infusion
and remained below control level at the fifth minute post-infusion.

Also, blood pH fell 0.03 units by the fifth minute of infusion with a
further decrease to 0.06 units below control by the fifth minute post-
infusion. In the spinally anesthetized dogs, infusion of isotonic NaCl

at 11.46 cc/min produced a slight decrease in mean arterial blood pressure
and total peripheral resistance of 5 mmHg and 0.003 mmHg/mllmin, respect-
ively, by the fifth minute of infusion. The decreases in these cardio-

35

 

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37
vascular parameters occurred by the first minute of infusion and persisted
throughbut the infusion period. At five minutes post-infusion, mean arterial
blood pressure and total peripheral resistance returned to levels not
different from control. Reservoir volume progressively decreased during
the infusion to a level 48 cc below control level by the fifth minute,
and returned to a value not different than control by the fifth minute A
post-infusion. Heart rate was slightly decreased by the fourth and
fifth minutes of the infusion and remained depressed five minutes post-
infusion (-4 beats/minute). Hematocrit was not altered by NaCl infusion
at either rate in both intact and spinally anesthetized dogs.

In intact dogs, infusion of isotonic KCl at 1.91 cc/min did not alter
any measured cardiovascular parameter except heart rate which increased
slightly throughout the infusion period. By the fifth minute post-infusion
heart rate returned to a level not different from control. In the spinally
anesthetized dogs, KCl infusion at the same rate produced a progressive
fall in mean arterial blood pressure and total peripheral resistance of
13 mmHg and 0.011 mmHg/mllmin respectively, by the fifth minute. Five
minutes after infusion, mean arterial blood pressure and total peripheral
resistance remained significantly below control levels. Reservoir volume
was not significantly altered during the infusion period, however, by
the fifth minute post-infusion it was decreased to 33 cc below control
level. Heart rate was not altered. In both intact and spinally anesthe-
tized dogs, plasma potassium concentration was significantly increased
an average of 0.64 mEq/l and 0.7 mEq/l, respectively, by the fifth minute
of infusion. Plasma potassium concentration remained above control level
(+0.4 mEq/l) by the fifth minute post-infusion in the spinally anesthetized
dogs, but returned to a level not different than control value in the

intact dogs. Blood pH and hematocrit were not altered in either experimental

38
series.

In intact dogs, infusion of isotonic MgCl2 at 1.91 cc/min did not
alter any measured cardiovascular parameter except heart rate which
. decreased slightly by the fifth minute of the infusion period. By the
fifth minute post-infusion, heart rate remained depressed below control
level. In the spinally anesthetized dogs, MgCl2 infusion at this same
rate produced a progressive decrease in mean arterial blood pressure and
total peripheral resistance of 14 mmHg and 0.009 mmHg/ml/min, respectively.
These decreases began after thirty seconds of infusion and reached their
lowest level by the fifth minute of infusion. Following cessation of
the infusion, mean arterial blood pressure and total peripheral resistance
_ returned to levels not different from control within 5 minutes. Reservoir
volume was not significantly altered by MgClz infusion. Heart rate fell
below control during the second through fifth minutes of infusion (-7 beats/
minute) and remained depressed at five minutes post-infusion. The only
measured blood parameter to be altered in both the intact and spinally
- anesthetized dogs was plasma magnesium concentration which increased an
average of 1.81 mEq/l in the former and an average of 1.93 mEq/l in the
latter dogs by the fifth minute of the infusion. Plasma magnesium con-
centration returned to a level not different than cbntrol by the fifth
minute post-infusion in the intact dogs, but remained above control level
(+0.72 mEq/l) by the fifth minute post-infusion in the spinally anesthe-
tized dogs.

In intact dogs, infusion of hypertonic NaCl at 7.64 cc/min produced
significant changes of all denoted cardiovascular parameters. Mean arterial
blood pressure and total peripheral resistance decreased during the first
minute of the infusion 4 mmHg and 0.004 mmHg/mllmin. respectively. Both

parameters remained depressed throughout the infusion period and by the

39
fifth minute post-infusion returned to levels not different from control.
Reservoir volume increased progressively throughout the infusion period
to +70 ml and by the fifth minute post-infusion rose to +88 cc above
control level. Heart rate was slightly decreased (-3 beats/minute) by
the second minute of infusion and remained depressed throughout the re-
mainder of the infusion period. Heart rate was not different from control
by the fifth minute post-infusion. In spinally anesthetized dogs, infusion
of hypertonic NaCl at the same rate produced a rapid and progressive de-
crease in mean arterial blood pressure and total peripheral resistance
of 14 mmHg and 0.011 mmHg/mllmin, respectively. The decreases in both
parameters occurred by thirty seconds of the infusion and was maximum
'by the fifth minute of infusion. At the sixth minute post-infusion,
mean arterial blood pressure and total peripheral resistance were at '
levels not different from control. Heart rate was not significantly altered.
Reservoir volume was increased at the fourth and fifth minutes of the
infusion to a maximum value of +24 cc and by the sixth minute post-infusion
it was at a level not different from the control value. In both the intact
and spinally anesthetized animals, plasma osmolality, blood pH and hema-
tocrit were significantly altered. Plasma osmolality was increased an
average of 20 mOSm/l in the intact dogs and 21 mOsm/l in the spinally
anesthetized dogs. Furthermore, plasma osmolality remained above control
by the fifth minute post-infusion in both experimental series. In the
intact dogs, blood pH and hematocrit were decreased on the average from
7.34 to 7.32 and 40% to 36%, respectively, by the fifth minute of infusion
and remained depressed at the fifth minute post-infusion. In the spinally
anesthetized dogs, blood pH and hematocrit were decreased on the average
from 7.34 to 7.31 and from 38% to 36%, respectively. By the fifth minute

post-infusion these parameters were not different from control values.

4O

Simultaneous infusion of isotonic KCl at 1.91 cc/min and MgClz at
1.91 cc/min produced a progressive decrease in mean arterial blood
pressure, and total peripheral resistance of 13 mmHg and 0.009 mmHg/mllmin
respectively, by the fifth minute of infusion. The decreases in these
two parameters were evident by thirty seconds of the infusion. By the
fourth minute post-infusion, mean arterial blood pressure and total peri-
pheral resistance were at a level not different than control values.
Reservoir volume fell significantly at the fifth minute of infusion (-28 cc)
and at four minutes post-infusion remained below control level. Heart
rate was not significantly altered. Plasma potassium and magnesium con-
centrations increased 0.73 mEq/l and 1.94 mEq/l, respectively, by the
fifth minute of the infusion. Both ions remained above control concent-
rations in the plasma at the fourth minute post-infusion ([K+] = +0.19 mEq/l;
[Mg++] = +0.97 mEq/l). Blood pH and hematocrit were not altered.

The average effects of a five minute simultaneous infusion of KCl
and MgClz (3.82 cc/min) and hypertonic NaCl (1710 mOSm/l) at 7.64 cc/min
on the denoted cardiovascular and blood parameters are shown on the last
two columns in table 2. The total volume rate of infusion was 11.46 cc/min
and the total volume infused was 57.3 cc. In the intact dogs, significant
changes in all denoted cardiovascular parameters except heart rate occurred.
Mean arterial blood pressure and total peripheral resistance decreased
during the first minute of infusion and progressively fell 9 mmHg and
0.007 mmHg/mllmin. respectively, by the end of the infusion. These two
parameters tended to return toward control levels but still remained de-
pressed by the sixth minute post-infusion. In spinally anesthetized dogs,
mean arterial blood pressure and total peripheral resistance progressively
decreased 23 mmHg and 0.021 mmHg/ml/min respectively, during the infusion

period. At six minutes post-infusion these parameters remained below

41

control values although there was a tendency to return toward control
levels. In the intact dogs, reservoir volume increased by the first
minute of infusion and reached its peak value by five minutes (+105 cc).

By the-sixth minute post-infusion, reservoir volume was still above control
value (+119 cc). In the spinally anesthetized dogs, reservoir volume
exhibited a similar change in direction and magnitude. In the spinally
anesthetized dogs, heart rate was slightly but significantly decreased
during the infusion period and returned to a value not different from
control by the sixth minute post-infusion. Similar changes in plasma [KT],

[Mg++], and osmolality Occurred in both experimental series. Furthermore,
Vsimilar changes occurred in blood pH and hematocrit. In the intact dogs,
plasma [K+] and [Mg++] were increased 0.4 mEq/l and 1.94 mEq/l, respectively,
by the fifth minute of infusion. By the sixth minute post-infusion, plasma
[K+] fell to a value not different from control while plasma [Mg++] remained
above control level (+0.91 mEq/l). Plasma osmolality increased 22 mOsm/l
by the fifth minute of infusion and remained above control at the sixth
minute post—infusion. Blood pH and hematocrit decreased 0.03 units and

3% (from 41% to 38%), respectively, by the fifth minute of infusion and
remained below control at the sixth minute post-infusion. In the spinally
anesthetized dogs, plasma [K+], [Mg++] and osmolality increased 0.04 mEq/l,
1.8 mEq/l and 23 mOsmll, respectively, by the fifth minute of the infusion.
Plasma [Mg++] and osmolality remained above control levels at the sixth
minute post-infusion, however, plasma [K+] returned to a level not different
from control value. Blood pH decreased 0.04 units during the infusion
and remained depressed at the sixth minute post-infusion. Hematocrit

fell 5% (from 43% to 38%) during the infusion period and remained depressed

at six minutes post-infusion.

42

Figure 1 shows a representative tracing of one experiment which
employed simultaneous infusions of isotonic KCl (1.91 cc/min), isotonic
MgCl2 (1.91 cc/min) and hypertonic NaCl (7.64 cc/min) in intact dogs.

The abnormalities created were hyperkalemia (+0.5 mEq/l), hypermagnesemia
(+1.66 mEq/l), hyperosmolality (+20 mOSm/l) and decreased pH (-0.04 units).
Hematocrit fell from 39% to 37% and plasma sodium concentration rose 12 mEq/l.
Associated with these abnormalities was a decrease in mean arterial blood
pressure of 10 mmHg by the fifth minute of infusion. Calculated total
peripheral resistance decreased 0.008 mmHg/mllmin by the second minute

of infusion and remained depressed until the end of infusion. Mean arterial
blood pressure and total peripheral resistance returned to control level

by the sixth minute post-infusion. Also, at the sixth minute post-infusion
plasma [Mg++] and osmolality remained above control while blood pH and
hematocrit remained below control. Plasma [K+] returned to levels not
different than pre-infusion control values by the sixth minute post-
infusion. Heart rate remained unaffected.

Figure 2 shows a representative tracing of one experiment which
employed simultaneous infusions of isotonic KCl (1.91 cc/min), isotonic
MgClz (1.91 cc/min) and hypertonic NaCl (7.64 cc/min) in a spinally anesthe-
tized dog. The abnormalities created were hyperkalemia (+0.35 mEq/l),
hypermagnesemia (+1.37 mEq/l), hypernatremia (+13 mEq/l) and hyperosmolality
(+18 mOSm/l). Blood pH and hematocrit decreased 0.05 units and 4% (from
49% to 45%), respectively, during the infusion. Associated with these
abnormalities was a progressive decrease in mean arterial blood pressure
of 25 mmHg by the end of the infusion. In this experiment, calculated
total peripheral resistance progressively decreased to a maximum of 0.022

mmHg/mllmin during the infusion.

43

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47

Figure 3 shows the average total peripheral resistance results of
all experiments completed in this study. 'Graph A, on the left, shows data
from the intact dogs and Graph B, on the right, shows data from spinally”
anesthetized (procainized) dogs. The absolute level of starting resistance
was not statistically different in the two series, therefore, it was
considered appropriate to express these results as a percentage change
in calculated total peripheral resistance (TPR), which is depicted on the
ordinates. The abscissae are time coordinated in minutes. The asterisks
denote significance at the p §_0.05 level.

In the intact dogs, Graph A, a five minute infusion of isotonic
NaCl at 1.91 cc/min or 11.46 cc/min produced no significant change in
calculated TPR. Also when plasma [K+] or (Mg++] was elevated there was
no significant change in TPR. However, hyperosmolality and the-combination
of hyperkalemia, hypermagnesemia and hyperosmolality both caused significant
decreased in TPR of 6% and 11%, respectively. The decrease in TPR
caused by the multiple electrolyte abnormalities was significantly greater
than the Change caused by hyperosmolality alone.

In the spinally anesthetized (procainized) dogs, Graph B, infusion
of isotonic NaCl at 1.91 cc/min did not alter TPR. .However, infusion at
11.46 cc/min did produce a small but significant decrease in TPR. Increasing
plasma [Mg++] produced a significant fall in TPR of 14% when compared
to its isovolemic NaCl control infusion. Similarily, increasing plasma
[K+] and [Mg++] produced a 15% decrease in TPR when compared to the 1.91 cc/min
isotonic NaCl control infusion. The per cent change in TPR due to singly
increasing plasma [K+] or [Mg++], or due to simultaneous increases in [K+]

and [MgTT] were not significantly different from one another. Increasing

plasma osmolality caused a decrease in TPR of 15% when compared to the

48

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50
ll.46 cc/min isotonic NaCl control infusion. Increasing plasma [K+],
[Mg++], and osmolality simultaneously caused a significant decrease in
TPR of 22% when compared to the ll.46 cc/min saline control infusion.
This change was significantly different from the per cent change in TPR

caused by single electrolyte abnormalities of hyperkalemia, hypermagnesemia

and hyperosmolality or the combination of hyperkalemia and hypermagnesemia.

DISCUSSION

These studies show that acutely induced generalized hyperosmolality
and the combination of hyperkalemia, hypermagnesemia and hyperosmolality
in open chested dogs with cardiac output maintained constant produces a
fall in mean arterial blood pressure. The fall is due to increases in
vessel caliber resulting in a decrease in total peripheral resistance.
These studies also indicate that mean arterial blood pressure changes
in response to single and multiple electrolyte and osmolar abnormalities
are partially masked by neurological barostatic systems.

These findings are in agreement with the predicted arterial blood
pressure effects induced by generalized acute electrolyte and osmolar .
abnormalities derived from studies in isolated organs (1, 4, 6, 8,

ll, l2, l4, l7, 20, 24, 29, 33, 40, 42, 46, 47, 50, 60, 63, 64, 66, 68,
7l, 75, 78—8l, 86, 89, QT), and on myocardial contractile force (2, 3,
4, 21, 22, 27, 37, 45, 47, 49, 5l, 54, 56, 57, 61, 62, 69, 74, 76, 82,
90, 92-94). These results are also in general agreement with previous
studies on the effects of acute single and multiple increases in plasma
electrolyte and osmolar concentration on canine arterial blood pressure
(l7, 46, 64).

The experimental design of this study was developed to answer the
question: "are the blood pressure changes produced by electrolyte and
osmolar abnormalities due to differences in cardiac output, peripheral
resistance or both?" Previous studies suggest that both of these im-
mediate determinants of arterial blood pressure play a role. However,
this is the first study which demonstrates by direct means that various
ionic abnormalities can decrease total peripheral resistance. This
does not, however, rule out that in the intact animal cardiac output

5]

52
may also contribute to the fall in mean arterial blood pressure.
Systemic studies to measure changes in cardiac output during similar
plasma abnormalities are needed to define the role of this direct
determinant of arterial blood pressure.

Effects of single electrolyte abnormalities of hyperkalemia, hyper-
magnesemia, hypercalcemia, hypocalcemia, alkalosis, acidosis, and hyper-
osmolality on arterial blood pressure has been examined by a number of
investigators (37, 42-45, 49, 6l, 62, 69, 7l, 74, 76, 82, 90, 93).

While changes in pressure relative to changes in electrolyte concentra-
tion are not impressive, pressor responses sometimes result from acutely
induced hypercalcemia and depressor responses sometimes follow hyper-
magnesemia, hypocalcemia, or hyperosmolality. Apparently consistent
changes in the blood pressure are effectively prevented by the baro-
static systems (46). Haddy gt El; (46) examined the effects of general-
ized single and multiple changes in plasma cationic and osmolality
levels on arterial blood pressure in dogs by utilizing two basic exper-
imental methods. In one procedure, a potent diuretic (furosemide)

was administered intravenously and the urinary loss from the animal was
replaced with various electrolyte solutions either rapidly after 90
minutes of diuretic action or milliliter for milliliter as it appeared.
The electrolyte solutions used for the volume replacement were prepared
to produce the desired plasma abnormalities. Another procedure utilized
was a simple dilutional one which produced rapid electrolyte changes.
However, the changes induced by this latter method were transient and
associated with hypervolemia. With the first method, single or multiple
induced hypokalemia, hypomagnesemia, alkalosis, hypercalcemia, and hypo-

osmolality caused an increase in systemic arterial blood pressure. Super-

53
imposing complete spinal anesthesia upon the aforementioned combined
plasma abnormalities had no effect on arterial blood pressure. However,
superimposing complete spinal anesthesia upon the combined plasma abnor-
malities of hyperkalemia, hypermagnesemia, acidosis, and hypocalcemia
greatly reduced arterial blood pressure. It was therefore suggested
that the pressure decrease associated with hyperkalemia, hypermagnes-
emia, hypocalcemia and acidosis is attenuated due to interaction of
neural buffering mechanisms.

Emerson gt_al;_in l970 (17) used the previously mentioned dilutional
technique to extend the investigation into the effects of generalized
acute multiple changes in plasma electrolyte levels on canine blood
pressure. Since this method required infusion of considerable volumes
of electrolyte solutions, a control infusion of Ringer's solutions was
also employed. This enabled analysis of arterial blood pressure
responses to hypervolemia and dilution. Infusion of Ringer's solution
elevated arterial blood pressure slightly, but not significantly, whereas
the combination of hyperkalemia, hypermagnesemia, hyperosmolality, hypo-
calcemia, and acidosis caused a l4% decrease in arterial blood pressure
(l7). Furthermore, blood pressure decreased 35% when the same abnormal-
ities were created in dogs with their neural barostatic mechanisms
rendered inoperable (64). The opposite electrolyte abnormalities
produced a 30% increase in arterial blood pressure (l7). These studies
illustrate that small, multiple electrolyte and water abnormalities can
affect arterial blood pressure in dogs and that the neurological
compensatory systems are involved in the blood pressure responses..

In the present study, animals whose barostatic mechanisms were rend-

ered ineffective by cisterna magnal procaine anesthesia responded to

54
hyperkalemia and hypermagnesemia with a decrease in total peripheral
resistance. In neurologically intact animals the same electrolyte abnor-
malities produced no significant changes in peripheral resistance. Further-
more, in the spinally anesthetized animals hyperosmolality and the combination
of hyperkalemia, hypermagnesemia, and hyperosmolality decreased total
peripheral resistance more than when the same abnormalities were
created in neurologically intact animals. These decreases were signi-
ficant even though control isotonic NaCl infusion at ll.46 cc/min in
the spinally anesthetized dogs produced a small but significant de-
crease in total peripheral resistance. Thus, only a small portion of
the decrease in total peripheral resistance observed during the-elect-
rolyte and osmolar abnormalities can be attributed to changes created
by volume of infusate.

Acidosis may also have contributed to the decrease in total peripheral
resistance when hyperosmolality and the combination of hyperkalemia,
hypermagnesemia and hyperosmolarity were induced. Significant acidosis
occurred in both intact and procainized animals in which the afore-
mentioned abnormalities were created. It has been well documented that
acidosis also causes a decrease in peripheral resistance in isolated
organs and in the whole animal (l3, l5-l8, 25, 28, 30-32, 36, 37, 40,

46, 52, 55, 64, 79).

Another point that must be considered is that the affects observed
on total peripheral resistance following spinal blockade may have
resulted, in part, from an alteration in the responsiveness of blood
vessels to the constant infusion of levarterenol utilized. It has
been well documented in the isolated dog forelimb vascular bed that

hyperkalemia (l4), hypermagnesemia (29) and hyperosmolality induced by

55

hypertonic NaCl (29) or dextrose (20) can depress the vascular smooth
muscle response to close intra-arterial injection of levarterenol.
Furthermore, locally induced hyperkalemia (20) or hypermagnesemia (29)
attenuated the vascular smooth muscle response to locally administered
levarterenol in the renal vascular bed.

Recently, insight into the mechanisms of action of electrolyte
and water abnormalities have been provided by coronary and skeletal
muscle vascular bed studies. Perfusion of these vascular beds with
hypokalemic blood increases resistance to blood flow due to active
vasoconstriction (l, 4, 47, 75) possibly due to inhibition of the membrane
Na+-K+-ATPase and slowing of the electrogenic pump in the vascular
smooth muscle (6). Furthermore, perfusion of the coronary vascular bed
with hypokalemic blood increases myocardial contractile force (4).
The decrease in vascular smooth muscle tone and organ vascular resistance
during perfusion with hypokalemic blood (6, l2, l4, 53, 79-8l, 86,
9l) may be due to stimulation of the membrane Na+-Kf-ATPase in the vas-
cular smooth muscle.‘ This would lead to hyperpolarization of the smooth
muscle cells and thus active vasodilation. When vascular beds are per-
fused with low osmolality blood, resistance to blood flow increases
(23, 45, 68, 78). This may result from hypoosmolality causing smooth muscle
cell hydration, a reduction in the intracellular potassium concentration, a
decrease in the membrane potential and cellular contraction (42). The op-
posite mechanism may account for decreases in organ vascular resistances seen
with hyperosmolality (23, 24, 48, 59, 60, 63, 7l, 79, 84, 85, 89). Apparently
changes in extracellular osmolality redistribute water across cell membranes

such that intravascular blood volume and cell hydration are altered. When

56

osmolar changes are produced systemically, these alterations influence
cardiac output and total peripheral resistance (42). Thus it may be
postulated that acute hypernatremia raises osmolality resulting in
osmotic shift of cellular water into the extracellular compartment.
This, in turn, raises blood volume and dehydrates cells. The hypervolemia
would increase cardiac output via a starting mechanism and momentarily
decrease total peripheral resistance via the baroreceptor mechanism.
Cell dehydration could also decrease total peripheral resistance by
deactivation of the contractile machinery of the vascular smooth

muscle cells by altering intracellular/extracellular potassium
concentrations as described above(42), and by shrinkage of endothelial
and red blood cells. Hemodilution and resultant decreased viscosity may
also decrease total peripheral resistance. Apparently, when the
hypernatremia and consequently the hyperosmolality is very acute, the
total peripheral resistance falls proportionately greater than the

rise in cardiac output and blood pressure falls (5, l9, 7l).

As demonstrated by this study, various combinations of electrolyte
and water abnormalities such as hyperkalemia, hypermagnesemia, and hyper-
osmolarity are associated with a decrease in total peripheral resistance
which may cause a decrease in arterial blood pressure. Similar abnormal-
ities in plasma and electrolyte content are also associated with such
clinical conditions as dehydration, shock, diabetic acidosis, and other
metabolic disorders. Furthermore, some diseases which cause hypertension
are associated with opposite electrolyte and water abnormalities to those
which cause hypotension, e.g. Primary or secondary aldosteronism, Cushing's
disease, hyperparathyroidism, idiopathic hypercalcemia of infants,

Vitamin D intoxication, acromegaly, acute prophyria, and renal artery

57

stenosis. hild hypokalemia, hypomagnesemia and alkalosis have also been

found in essential hypertension (l8, 32, 36). Therefore, an implicatory

consideration of this study may be that subtle water and electrolyte

abnormalities for prolonged periods of time could set the stage and

also contribute to the development of hypotensive and hypertensive disorders.
This research supported in part by NIH grant HEl0899 and completed

during a traineeship of NIH cardiovascular Training Grant #HL05873.

SUMMARY AND CONCLUSIONS

To summarize the results of this study, the data support that part
of the fall in arterial blood pressure seen in intact dogs during
hyperosmolality and the combined abnormalities of hyperkalemia, hyper-
magnesemia and hyperosmolality is due to active changes in vessel
caliber resulting in the decrease in total peripheral resistance.

This does not, however, rule out that in the intact animal, cardiac
output may also contribute to the fall in arterial blood pressure.
These results also indicate that arterial blood pressure changes

in response to single and multiple electrolyte abnormalities may be
partially masked because of operable compensatory systems such as the

barostatic mechanisms.

58

APPENDIX

Tables l-7 show the average effects of electrolyte solution infusions
on mean arterial blood pressure, total peripheral resistance, change
in reservoir volume, heart rate and selected measured blood parameters
in 60 intact dogs and 69 spinally anesthetized (procainized) dogs.
All tables except Table 6 allows direct comparison of experimental pro-
cedures carried out in intact dogs with the identical procedures completed
in spinally anesthetized dogs. Spinal anesthesia was sufficient to
render neurological barostatic mechanisms inoperable. During spinal
anesthesia, a continuous infusion of approximately l01/min (range 2-20Y
/min) of norepinephrine (levarterenol) was required to maintain an arterial
blood pressure and total peripheral resistance corresponding to the
pre-spinal anesthesia level. Average steady state venous return which

equalled cardiac output is given at the bottom of each table..

59

60

 

 

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65

TABLE 6 . The average effects of increased 1C" and Mg'H' on arterial blood pressure,
total peripheral resistance, change in reservoir volume, heart rate,
plasma [K+], plasma IMg++], pH and hematocrit in 8 spinally anesthetized
(procainized) dogs.

 

 

Measured Time (minutes)
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Arterial
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Pressure
(an Hg) 92 92 85 * 84 * 83 * 81 * 80 * 79 * 88

Total

Peripheral

Resistance 7

(mm Hg/m1/;0.062 0.060 0.057 * 0.056* 0.055* 0.054* 0.053* 0.053* 0.059
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Change in

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(ml) 0 0 +2 —2 -7 -14 -21 -28* -31*

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Mg++
(mEq/l) 2.83 4.77* 3.8*

Units 7.38 7.37 7.36

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Maxwell, 6. M, R. 8. Elliot, and R. H. Burnell.
Effects of hypermagnesemia on general and coronary hemodynamics
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The effects of hyperosmolarity on intact and isolated vascular

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The Physiologist, 12: 343, 1969.

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Vascular effects of ions.
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89.

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75

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Effects of calcium and magnesium ions on the unipolar electrogram,
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Cardiovascular effects of prolonged induced severe hypercalcemia.
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Cardiovascular effect of potassium, calcium, magnesium and
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