AMERICAN JOURNAL OF PHYSIOLOGY Vol. 215, No. 3, September 1968. Printed in U.S.A.

Potassium-induced cardiovascular and ventilatory

reflexes from the dog hindlimb

KERN WILDENTHAL, DONALD S. MIERZWIAK, N. SHELDON SKINNER, JR., AN‘D JERE H. MITCHELL Pauline and Ado&h Weinberger La borator): for Cardiovascular Research, Department of Internal Medicine, and Department of PhI)siology, The Universig: of Texas Southwestern Medical School, Dallas, Texas

WILDENTHAL, KERN, DONALD S. MIERZWIAK, N. SHELDON SKINNER, JR., AND JERE H. MITCHELL. Potassium-induced cardio- vascular and ventilatory reflexes from the dog hindlimb. Am. J. Physiol. 215(3) : 542-548. 1968.-Although electrical stimulation of afferent nerve fibers from the limbs is known to induce reflex cardiovascular and ventilatory changes similar to the changes seen in muscular exercise, previous studies have not established a specific chemical or mechanical factor capable of initiating the reflexes. Since potassium is released from muscle during exercise, we investigated the effects of close arterial infusions of small amounts of KC1 (0.3-1.0 mmole) into the vascularly isolated, innervated dog hindleg. Arterial pressure, heart rate, cardiac output, left ventricular contractility, and ventilatory volume increased significantly during potassium infusions. The cardiovascular changes were seen both during spontaneous breathing with light anesthesia (chloralose) and during con- trolled ventilation with anesthesia sufficient to cause apnea. Both open-chest and closed-chest dogs showed the responses. Vagotomy did not alter the effects of KCl. Beta adrenergic blockade reduced the heart rate and cardiac outpu t changes and elim nated th .e inotropic changes , but did not block the blood pressure rise. Cutting the femoral and sciatic nerves abolished all changes. These data suggest the possibility that potassium can induce reflexes from the leg which may be functional during muscular exercise.

exercise; left ventricular function; contractility; heart rate; blood pressure; pain; isolated gracilis muscle; cardiac output; peripheral resistance

E LECTRICAL STIMULATION of afferent nerve fibers from the limbs can cause reflex increases in ventilation (7, 15, 26), blood pressure (12, 16, Zl), heart rate (Zl), cardiac output (Zl), and left ventricular contractility (21). It has been suggested that reflexes from the limb causing such changes may be activated physiologically during muscu- lar exercise (1, 2, 5, 8-l 1, 13, 14), but specific chemical or mechanical factors capable of initiating all the changes have not been defined.

Although some of the reflex changes known to occur are clearly related to motion about the joints (8, 11),

chemical stimuli have also been implicated by other studies, particularly those tending to relate cardiovascu- lar changes to accumulation of metabolites from contrac- ting, relatively ischemic muscle (1, 2, 10). Nevertheless, attempts at reproducing the responses to muscular exercise by perfusion of the limbs with blood collected from veins draining contracting muscle have not suc- ceeded (8). Al so, perfusion of the leg with blood made acidotic with HCl has been found to stimulate ventila- tory changes consistently orlly when arterial pH is reduced below 6.3 (8). Limb hypoxia and brief periods of ischemia are ineffective (2, 8, 10, 13), although pro- longed occlusions of blood flow to muscle can cause tachycarclia and hyperventilation, especially if accom- panied by subjective pain (2, 28). Results obtained with hvpercarbia are contradictory. S tegemann and co- workers (29) reported reflex hyperpnea, hypertension, and tachycardia after CO2 was bubbled into the abdominal aorta of the dog. On the other hand, Kao (13) noted no ventilatory changes in cross-circulated dogs with femoral artery PCO~ levels of 90 mm Hg.

Since potassium is released from muscle during exer- cise, the present study was undertaken to investigate whether this ion can induce reflex cardiovascular and ventilatory changes from the leg.

METHODS

Mongrel dogs weighing 14-20 kg were anesthetized with intravenous alpha-chloralose (50- 100 mg/kg) dis- solved in polyethylene glycol. After tracheal intubation, the sciatic nerve and the femoral nerve, artery, and vein of the right hindleg were carefully dissected free of sur- rounding tissue at the level of the proximal femur. Two metal bands were placed around the remaining tissue and the fernur as shown in Fig. 1. The bands were then tightened to occlude as much as possible all blood flow except that through the femoral vessels (and that travers- ing bone). The artery and vein of the gracilis muscle were ligated and cannulated proximally with polyethy- lene tubing (PE-190).

542

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POTASSIUM-INDUCED REFLEXES FROM THE LEG 543

Femoral

Nefve Art,ery /Vein

SN

FIG. 1. Diagram of right hindleg showing positions of occlusive bands before tightening. Upper left: ventromedial view; lower right : cross -sectional view. SN = sciatic nerve; nerve; FA = femora 1 artery; F V= femoral vein.

FN = femoral

Six dogs breathed room air spontaneously. A Sanborn direct-writing oscillograph recorded arterial blood pres- sure from a Statham P23Db strain gauge connected to a cannula in the right common carotid artery. Pulse rate was recorded simultaneously through an Electronics for Medicine cardiotachometer. Ventilatory rate was ob- tained from a second strain gauge which responded to changes in air pressure in the intubation tube. Minute ventilatory volume was collected and measured in a Gaensler-Collins spirometer.

In four dogs, ventilation with 100 % 02 was controlled by a Harvard respirator. Following a midline sternotomy, the dogs were prepared for study in a manner described in detail previously (3 1). All aortic blood except coronary flow passed into an extracorporeal circuit which was primed with heparinized blood from chloralose-anesthe- tized donor dogs. The circuit included a bottle of adjust- able height, which controlled aortic pressure, and a rotor pump (Med-Science) which returned blood at a controlled rate through a heat-exchange unit to the descending aorta and the common carotid arteries. A strain gauge was used to measure the perfusion pressure of the blood returned to the dog. Cardiac output (minus coronary flow) was measured with a Statham electro- magnetic flow probe located in the proximal tubing of the extracorporeal circuit. Right atria1 pacing from a Grass impulse generator (model S4) controlled heart rate. Large-bore metal cannulas attached to Statham P23Db strain-gauge transducers were placed in the left ventricle through the apical dimple and in the aorta through a carotid artery. A Dallons-Telco catheter-tip manometer was also placed in the left ventricular cavity through an apical stab wound and an R-C circuit elec- tronically differentiated its signal continuously (dp/dt).

Pressure, flow, and heart rate measurements and the

differentiated left ventricular pressure were recorded continuously on a Sanborn oscillograph at paper speeds of .5 or 1 mm/set. Tracings (100 mm/set) were taken at intervals on an Electronics for Medicine photographic recorder during brief periods of imposed apnea before and during KC1 infusions. With heart rate, blood pres- sure, and flow held constant, the observed relations of left ventricular end-diastolic pressure to the maximal rate of left ventricular pressure rise and to calculated stroke work, stroke power, and mean rate of ejection were used as indices of left ventricular contractility (20, 22, 31).

The extracorporeal circuit was designed so that by adjustment of clamps on the tubing, the pressure-con- trol bottle and pump could be excluded from the system and blood returned directly to the arteries. In this situation, changes in uncontrolled cardiac output, heart rate, and blood pressure could be recorded.

In both open-chest and closed-chest dogs, infusions of KC1 (0.3-l .O mmole/ml in saline) were made into the femoral artery through the gracilis artery cannula. In each instance the following procedure was carried out: the femoral vein was occluded with a vascular clamp; immediately thereafter 1 ml of KC1 solution was infused over a 15-set period with a Harvard constant-infusion pump (model 600-900); the vein remained occluded throughout the infusion and for 45 set afterward. Infus- ions (1 ml) of normal saline, hypertonic saline, or sucrose (2.3 mmole/ml or greater), and of norepinephrine W-75 Ptd 1) m in normal saline were made intermittently under identical conditions.

Femoral vein blood was collected before KC1 infusion and at intervals beginning immediately after release of the venous occlusive clamp, for determination of K+ with an Instrumentation Laboratories flame photometer. Maximal levels were observed approximately 5-15 set after release.

In two closed-chest dogs KC1 infusions were repeated after vagal effects were blocked (with atropinization in one, with bilateral vagotomy in the other). In two others infusions were repeated after additional large doses of chloralose (100-300 mg/kg) had abolished spontaneous breathing, and while ventilation was controlled by a pump. Similarly, infusions were repeated in two open- chest dogs after bilateral vagotomy. KC1 infusions were also repeated after administration of propranolol (1 .O- 1.5 mg/kg) in two open-chest dogs. In all dogs KC1 infusions were repeated after sectioning sciatic and femoral nerves.

Both open-chest and closed-chest dogs were submitted to various pain-provoking stimuli, including pinching of the skin, testicular crushing, and injection of 0.3-2.0 mmole KC1 intracutaneously and subcutaneously. Intra- muscular injections of similar amounts of KC1 were also given.

Four additional dogs were prepared for study using an isolated perfused gracilis muscle preparation. A detailed description of the basic method has been published pre- viously (27). Briefly, it consisted of cannulation of the major artery and vein to the gracilis muscle, ligation of

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544 WILDENTHAL, MIERZWIAK, SKINNER, AND MITCHELL

all minor vessels, and arterial perfusion of blood of varying K+ composition at constant flow rates through the muscle. The nerve to the gracilis was left intact, and reflex changes in heart rate and blood pressure were recorded from a carotid artery cannula as described above.

RESULTS

Effects of KC1 Infusions into the Isolated Leg

Arterial pressure and heart rate. All dogs showed increases in heart rate and arterial pressure during intra-arterial infusion of KC1 into the isolated leg. A typical tracing from an open-chest, uncontrolled preparation is shown in Fig. 2. In this experiment blood pressure increased 20 mm Hg and heart rate rose 15 beats/min following infus-

200

ABP

mm Hg E

100

0

200

LVP mm Hg 100

E 0’

30

cm l-i20

LVDP 20 1 1o

0

Lv dp/dt +4000

mm Hg /set 0

$4000 E

275

beatHsR/min. 175

T r.-

FIG. 2. Response to intra-arterial infusion of 0.9 mm& KC1 into the isolated leg of an open-chest dog (dog 8); heart rate (HR), aortic flow, and ar &al blood pressure (ABP) not controlled. LVP = left ventricular pressure; LVDP = left ventricular pres- sure amplified to emphasize diastolic pressures; LV dp/dt = rate of left ventricular pressure change. At the first arrow, the femoral vein was clamped; 0.9 mEq KC1 was infused during the period marked by the black bar. The femoral vein was released at the

second arrow.

TABLE I. Effects of intra-arterial KCl infusions (0.3-1.0 mmole) in 10 dogs*

Heart rate, beats/min 36 of 40 +13.2f8.0

Blood pressure, mm Hg

Ventilatory volume, ml/min

Ventilatory rate, breaths/min

Tidal volume, ml

(0 to 30) 36 of 40 +14.0*9.3

(0 to 45) 28 of 31 +781 f440

(0 to 1450) 15 of 31 +1.8f2.8

(-2 to +9) 25 of 31 t-45*41

(0 to 150)

P<

0.001

0.001

0.001

0.005

0.005

* Femoral venous potassium concentrations were 3.94k.55

(SD) control; 7.63 f 3.69 after KCl.

ion of 0.9 mmole KCl. Mean data for 40 infusions in 10 dogs are given in Table 1. No differences were observed between closed and open-chest dogs, nor between condi- tions of relatively light anesthesia and heavy anesthesia sufficient to cause apnea.

Vagotomy or atropinization caused no changes in blood pressure and heart rate responses. Propranolol, however, in doses sufficient to reduce substantially but not completely the response to exogenous isoproterenol, markedly reduced or abolished the heart rate changes. This effect was reversible with time (and with return of sensitivity to isoproterenol) and suggested that beta sympathetic activity was the primary efferent route for the heart rate response. In contrast to its effect on heart rate, beta adrenergic blockade had no observable effect on the blood pressure changes.

Cardiac output andperipheral resistance. The dogs in which uncontrolled cardiac output was measured responded to KC1 infusions with increases in cardiac output (range 50-150 ml/min increase; see Fig. 2). Changes in stroke volume (range O-13 % above control), as well as in heart rate, contributed to the increased output. Vagotomy did not alter significantly the responses in cardiac output and stroke volume, and propranolol (alone or combined with vagotomy) reduced them only moderately.

Peripheral resistance, calculated from the pressure measured in the extracorporeal tubing and the flow, increased after Kf infusion, whether or not cardiac out- put was controlled. The mean rise in resistance was 550 dynes-set cm-j (9 % above control), with a range of O- 1,200 in 18 infusions. Neither vagotomy nor propranolol altered the response, indicating that, as in the cardiac output response, factors other than cholinergic and beta adrenergic activity caused the changes, at least in part.

Contractility of the left ventricle. Changes in the contrac- tile state of the left ventricle following KC1 infusions into the limb were evaluated in open-chest dogs. In order to eliminate the influence of changes in heart rate, arterial pressure, and flow on contractility, KC1 was infused while these factors were held constant. The results of one such infusion into the isolated leg of a dog are

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POTASSIUM-INDUCED REFLEXES FROM THE LEG

I -1 Set - I I -1 Set M I

+4800

LV dp/dt t 2400

mm Hg / set 0

-2400

-4800 I

32 r 125 r I-

24 t

cm Hz0 t-

8

Control

TABLE 2. E$ects of intra-arterial KCl infusions (0.5 and 0.9 mmole) in four open-chest dogs with controlled aortic pressure, heart rate, and cardiac output (8 trials)

Changes follow- -0.8 +0.1 +3.2 / +1.9 +375 ing KC1 in- fusion

I .5 . .

p< / .Ol / It1 ‘tli ial 1 3h0.01

LVEDP-left ventricular end-diastolic pressure; SW- stroke work; SP-stroke power; MIRE-mean rate of ejection; Max dp/dt-- maximal rate of left ventricular pressure rise.

shown in Fig. 3. It is apparent that while left ventricu- lar end-diastolic pressure declined slightly, the maxi- mal rate of left ventricular pressure rise increased, and the duration of systole decreased, indicating an increase in left ventricular contractility. Similar directional changes were obtained in all dogs. Results are sum- marized in Table 2. In he two dogs in which both vagi were cut, there was no change in the inotropic response to KC1 infusion. Increases in contractility were elim- inated in the two dogs which received propranolol.

Ventilation. All six spontaneously breathing clogs in- creased minute ventilation after KC1 infusion Tidal volume increased in all, but rate changes were not con- sistent: in one dog the rate increase was marked; in four, occasional moderate increases were seen; no rate change

0.9 m Eq K+

545

FIG. 3. Responses to intra- arterial KC1 infusion into the isolated leg in an open-chest dog with controlled hemodynamic conditions. Fast speed tracing; symbols as in Fig. 2. The left panel was recorded just before infusion ; the right panel 25 set after the infusion was completed, while the femoral vein was still clamped.

was observed in the sixth dog. Figure 4 shows two examples of ventilatory responses to KC1 infusion into the leg, one in which ventilation increased solely through tidal volume changes and one in which rises in both rate and tidal volume were significant. Mean values for the six dogs are given in Table 1. The increase in minute ven- tilation of 786 ml was 28 % above control values.

Changes associated with multifile KCI infusions. It seemed desirable to establish the existence . of a correlation between the amount of potassium given with each infusion and the magnitude of response seen. Most dogs, however, tended to have a diminished responsiveness to K+ after rnultiple frequent infusions (Fig 5) This factor of adaptation made dose-response characteristics dish- cult to quantify. Nevertheless, there did appear to be a rough correlation between the amount of Kc+ infused and the degree of change observed. For example, each dog with controlled heart rate, pressure, and flow received 0.5 and 0.9 mEq of K+ infused in random order; the increases in stroke power and mean rate of ejection were 30-50 % greater after the larger dose than after the smaller, from the same end-diastolic pressure.

E$ects of KCI in isolated muscle. Both injection of KC1 solution intramuscularly and infusion of KC1 in tra- arterially into an isolated muscle caused reflex changes similar to those seen with KC1 infusions into the entire leg. The magnitude and duration of the reflexes were of the same order of magnitude as those inclucecl from the whole leg, but with the small mass of tissue involved in the isolated muscle experiments, relatively larger amounts of KC1 were required to induce the reflex responses (e.g., 1 ml of 0.3 niniole/ml solution intramuscularly, or >40 mEq/liter Kf solution infused slowly intra-arterially).

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546

Ejects of Control Procedures

Since a number of changes other than just an increase in K+ concentration in the leg could result from the KC1 infusions given, it was necessary to evaluate the effects of various other factors. To test the effect of venous occlusion alone, the basic protocol was followed using normal saline. No effects were observed (Fig. 6). Since KC1 solu- tions used were hypertonic and hypertonic solutions are known to be reflexogenic (17), hypertonic sucrose or saline was infused. Effects were seen only when the toni- city of the sucrose or saline was at least 5-25 times that of the KC1 used. Since pain may be a cause of reflex changes of ventilation (19) and circulation (30), all ex- periments were conducted with sufficient anesthesia to prevent any objective sign of the dogs’ perceiving pain during KC1 infusion. Under these conditions, proce- dures designed to stimulate pain receptors, including subcutaneous and intracutaneous KC1 injections, caused neither ventilatory nor circulatory changes.

KC1 infusions were repeated after femoral and sciatic nerves were sectioned. All responses were abolished in 9 of 10 dogs. In the remaining dog, a small increase in tidal volume persisted. Because of the possibility of adaptation or extinction of responses after multiple infusions, the

t- + B.

t- t A. 0.8 mEq Kt 0.8 mEq K+

FIG. 4. Responses ofarterial blood pressure (ABP) and ventilation (Vent.) in 2 dogs, showing variability of ventilatory rate responses. Symbols for infusion times are identical to those in Fig. 2.

ABP 100

m m Hg 0

t-n t 0.6 mEq K+

WILDENTHAL, MIERZWIAK, SKINNER, AND MITCHELL

nerves were cut in each of two dogs following only two and four KC1 infusions, respectively. Responses were completely abolished in both.

In order to establish the adequacy of vascular isolation for the purposes of these experiments, saline containing norepinephrine was infused into the leg under the stand- ard conditions employed with KC1 infusions. No cardio- vascular changes were observed until the femoral vein was released and blood from the limb allowed to return centrally (Fig. 6), thus demonstrating that collateral circulation was not significant.

DISCUSSION

The present study demonstrates that intra-arterial infusions of potassium into an isolated leg can initiate cardiovascular and ventilatory responses similar to those seen during muscular exercise. Two interrelated ques- tions arise immediately when interpretation of the physio-

FIG. 6. Conmarison of effects of KC1 infusion with effects of I

(75 pg/:/ml in saline) in dop 3. Sym- saline and of norepinephrine bols as in preceding figures.

0.8 mEq K+

,i,.L i,i,i

t- c. t 0.4 mEq Kt

t D. t 0.6 mEq Kt

FIG. 5. Responses of blood pressure and ventilation to repeated KC1 infusions. From left to right are shown the 5th, 7th, 9th, and 11 th infusions in dog 3. Symbols as in Fig. 4. (The first and third

KC1 infusions in this dog are shown in Figs. 6 and 4A, respec- tively.)

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YOTASSIUM-INDUCED REFLEXES FROM THE LEG 547

logical significance of the data is attempted: first, is potassium the normal physiological stimulant of the observed reflexes, and second, are the reflexes physio- logicallv active during I exercise? Al though the data obtained in this study and those of others do not allow a definitive answer to these questions, some of the infor- mation available is pertinent to any consideration of them.

It is well established that potassium is released from contracting muscle. With heavy exercise in man, for example, arterial potassium commonly exceeds 5.5 mEq/liter (6, 18, 25). Venous blood draining exercising extremities can be as much as 1 mEq/liter higher than arterial (6, 25). I f it is legitimate to extrapolate findings from contracting heart muscle to contracting skeletal muscle, data of Areskog and co-workers (3) on interstitial fluid-venous K+ gradients make it reasonable to postu- late that interstitial K+ levels in excess of 8 mEq/liter may occur during heavy exercise. Such figures are not out of line with the K+ levels observed in our study, in which reflexes were sometimes induced by KC1 infusions which increased venous K+ to only 5.3 mEq/liter; interstitial K+ levels produced by arterial infusions should be, at most, not significantly higher than venous concentrations. It seems likely, therefore, that changes produced by intra-arterial KC1 infusion into the leg were accompli shed while interstitial and venous K+ concentrations were within physiological ranges. On the other hand, K+ levels in the arteries were probably, at least transiently, higher than occur physiologically.

Thus, a key question revolves around the site of the receptors involved. The results of the present study suggest that they are located in muscle and that stimula- tion of sites in major arteries need not be invoked. With data available at the present time, however, definitive information on the precise microscopic location and nature of the receptors is unavailable. Comroe and Schmidt (8), who also observed ventilatory changes after arterial injection of KC1 into the leg, concluded that depolarization of pain receptors or fibers in or near the arterial wall is involved. Moore and co-workers (23), who demonstrated hyperventilation, vocalization, and motor withdrawal activity in very lightly anesthetized dogs after injection of several substances including potas- sium ion, also interpreted all the responses, including hyperventilation, as being pain reactions. Their data, however, indicate that the potassium ion must reach at

least the smallest arterioles or capillaries before effects are seen. If so, it would be equally plausible to suspect that receptors bathed by interstitial fluid rather than arterial blood are involved.

There can be no doubt that intra-arterial infusions of potassium can cause pain in unanesthetized subjects. The question remains whether the pain impulses pro- duced by K+ are an accompaniment or the cause of cardiovascular and ventilatory reflexes. The fact that many types of pain encountered clinically and experi- mentally are not accompanied by pressor reactions (30)

indicates that perception of pain, of itself, does not neces- sarily cause such changes inherently. Stimuli used as control procedures in the present study were “painful” enough to cause motor withdrawal reactions at times, yet caused no circulatory nor ventilatory changes, demon- strating further that pain reception, in an unmodified sense, is not necessarily reflexogenic.

Even if “pain” fibers carry the afferent limb of the reflexes, it would not be established that pain sensation must be present before the reflex could be initiated physiologically. Paintal (24) has presented convincing evidence that the same muscle receptors and afferent group III fibers which are stimulated by external pres- sure on the muscle or by contraction of the muscle are stimulated equally well by some painful stimuli. In this regard it may be pertinent that voltages required to initiate cardiovascular and ventilatory reflexes from muscle afferent fibers are compatible with stimulation criteria for group III fibers (21, 26), and that external pressure on muscle has been found to stimulate ventila- tion (14, 26). The possibility might be considered that, in exercise, activation of Paintal’s “pressure-pain” recep- tors by increased muscle tension could be facilitated by potentially painful increasing potassium concentrations, or vice versa.

Finally, it is worth noting that exercise itself may be painful at times. Prolonged isometric contractions are particularly apt to cause pain in the active muscles. The pain is presumably due to accumulation of metabolites in relatively ischemic contracting areas. Donald and co- workers (10) have demonstrated that intense sustained static exercise is accompanied by marked tachycardia and hypertension, and they have suggested that such a reaction would be teleologically useful in supplying additional blood to ischemic muscle. It is interesting that potassium efflux from the muscles correlates well with the time course of the cardiovascular changes seen in isometric exercise (10).

Although the reflex changes in ventilation, heart rate, blood pressure, cardiac output, and left ventricular contractility produced with intra-arterial infusion of KC1 into the isolated leg are consistent with a hypothesis that potassium may be important in physiological reflexes from the leg, it should be emphasized that with the data presently available one cannot determine whether potas- sium-induced changes are specific reflexes or nonspecific effects of a noxious stimulus. Even if it exerts a specific physiological effect, the potassium ion alone is unlikely to be the “work factor” often mentioned in discussions of exercise physiology (4). It seems more probable that multiple factors, chemical and mechanical, may be involved in the reflexes seen during exercise. Further- more, reflex stimuli may be different in one species than another, in static than in dynamic exercise, in intense than in light exercise, and in circulatory than in ventila-

tory changes. Our data suggest that potassium deserves consideration as one possible mediator in exercise-in- duced reflexes.

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548 WILDENTHAL, MIERZWIAK, SKINNER, AND MITCHELL

This work was supported by grants from the Public Health

Service (HE 06296, HE 0771 7, HE 106 1% t he A merican Heart

Associ ation, and the Dallas Heart 14ssociation.

K. Wildenthal is a Public T-Iealth Service

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Postdoctoral Re-

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search Fellow (HE 31,976). D. S. Mierzwiak is an Advanced Research Fellow, American Heart Association. J. H. Mitchell is an Established Investigator, American Heart Association.

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