baroreceptor and chemoreceptor influences on sympathetic ... · electroneurogram record speed = 70...

Baroreceptor and chemoreceptor

influences on sympathetic discharge to the heart

S. EVANS DOWNING1 AND JOHN H. SIEGEL2 Laboratory of Cardiovascular Physiology, National Heart Institute, Bethesda, Maryland

DOWNING, S. EVANS, AND JOHN H. SIEGEL. Baroreceptor and chemoreceptor in.uences on sympathetic discharge to the heart. Am. J. Physiol. 2o&) : 47 I -479. I g63.--Baroreceptor and chemoreceptor influences in the regulation of sympathetic discharge to the heart were investigated, utilizing electroneurographic recordings from the left inferior cardiac nerve in the cat. Spon- taneous discharge patterns exhibited phasic inhibition with the heartbeat and with inflation of the lungs. This was shown to be the consequence of baroreceptor and afferent vagal activity, respectively. Increasing blood pressure with epinephrine or angiotensin II caused marked inhibition of discharge which was abolished by baroreceptor deafferentation. No increase of cardiac sympathetic discharge occurred after the introduction of hypoxic blood into the isolated carotid sinus. Systemic hypoxia caused a marked increase in sympathetic discharge to the heart despite a large increase of systemic blood pressure. This response persisted after denervation of the peripheral chemoreceptors. A similar but less pronounced response to systemic hypercapnia was found. Systemic hypoxia frequently produced bradycardia which could be converted to tachycardia by atropine. This was associated with a large and continuous increase of cardiac sympathetic discharge to the heart. It is concluded that in systemic hypoxia both sympathetic and parasympathetic discharge to the heart is enhanced.

T HE EARLY STUDIES of Bronk et al. (I) demonstrated that cardiac sympathetic discharge is frequently rhythmic with the heartbeat, and concluded that this impulse grouping was the result of afferent activity from the baroreceptors causing central inhibition with each systole. They also observed that cardiac sympathetic discharge was increased by asphyxia and decreased by hyperventilation. Alexander (2) examined the response of the spinal sympathetic cardiovascular centers to hypoxia and hypercapnia using techniques similar to those of Bronk et al. (I). In contrast with these investi- gators Alexander reported that many of his preparations manifested a rhythmic, pulsatile discharge synchronous with the heartbeat after careful elimination of all affer-

Received for publication 7 September I 962. 1 Present address: Dept. of Pathology, Yale University School

of Medicine, New Haven, Conn. 2 Present address: Dept. of Surgery, University of Michigan

School of Medicine, Ann Arbor, Mich.

ents. He concluded that the pulsatility under these circumstances was due to the increased flow of blood to the spinal cord consequent upon the rise in blood pressure with each heartbeat. Thus, each ventricular systole inhibited sympathetic discharge by briefly increasing the oxygen supply to the spinal cardiovascular centers. Whereas hypoxia increased the impulse traffic in the inferior cardiac nerve, hypercapnia did not alter the discharge pattern in these preparations.

Recent hemodynamic investigations have shown that, whereas total body hypoxia produces an increase of ventricular contractility (3, 4), hypoxic stimulation of the separately perfused carotid bodies failed to increase ventricular contractility (4). These studies also confirmed the earlier observations (5, 6) that bradycardia, not tachycardia, is the primary response to carotid-body hypoxia, and indicated that the peripheral chemoreceptors may not participate in producing the increased cardiac sympathetic response in systemic hypoxia.

The investigations to be described were designed to examine with electrophysiological techniques those mechanisms responsible for the observed alterations of sympathetic discharge to the heart consequent to changes of systemic arterial pressure and to variations of arterial oxygen and carbon dioxide content. An evaluation of the influence of baroreceptor and chemoreceptor reflexes was made and compared with responses presumably originating in the central nervous system. A preliminary report on these experiments has been given (7).

METHODS

Cats were anesthetized with pentobarbital sodium, 30 “g/kg. Endotracheal intubation was performed and constant mechanical respiration maintained with a Har- vard respirator. Observations were made on five animals in which all baroreceptor and chemoreceptor systems were left intact. These will be subsequently referred to as 9ntact preparations.” In four animals the vagi were cut bilaterally but the carotid sinus nerves were left intact. In four additional animals Hering’s nerves were cut bilaterally and observations were made before and after subsequent bilateral cervical vagotomy (Fig. I ).

In 14 animals the right carotid sinus and body were

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472 DOWNING AND SIEGEL

FIG. I. Preparation for re- cording cardiac sympathetic nerve discharges during ventilation with various gas mixtures. C.A. = carotid artery. F.A. = femoral artery. C.S.N. = carotid sinus nerve. V.N. = vagus nerve. Tr = transducer. LLP-A = low

v level preamplifier. C.R.O. = cathode-ray oscilloscope. Re- cordings were made prior to and following C.S.N. and V.N. sec-

denervated and the vagi were transected bilaterally. The left carotid was then vascularly isolated and cannulated for perfusion from a donor animal or by means of a mechanical perfusion system. This was achieved by ligating all branches of the carotid artery distal to the carotid sinus and body, and cannulating the common carotid artery with an “inflow” cannula and the external carotid artery with an “outflow” cannula. Care was taken to maintain the vascular integrity of the carotid body. In preparations utilizing a heparinized donor animal, the carotid artery of the donor was connected to the inflow cannula of the recipient by a flexible metal (lead) tube. This prevented excessive damping of the pulse wave. The outflow cannula was connected by appropriate tubing to the external jugular vein of the donor to complete the circuit. Endosinus pressure was measured by inserting a short polyethylene cannula into the perfused segment of the carotid artery via the facial artery.

In other preparations a mechanical system was utilized to perfuse the isolated carotid region (Fig. 2). This was composed of two reservoirs of heparinized cat blood, one containing hypoxic blood and the other well-oxygenated blood. The pressure within the reservoirs was increased to the desired level by air pressure. By appropriate manipulation of stop cocks, blood from either reservoir could be introduced to the carotid sinus. A pulsatile pressure wave was generated by mechanical compression of a soft segment of tubing leading from the reservoir system to the inflow cannula (8).

tioning.

their electrical activity was picked up with stainless steel electrodes. The signals were filtered and amplified by a Textronix 122 low-level preamplifier, and were displayed by one beam of a Textronix 502 dual-beam oscilloscope. They were also monitored aurally by way of a simple audio system.

Continuous measurements of femoral arterial, left carotid, and endotracheal pressures were made utilizing Statham transducers and a Sanborn recorder. The out-

- Air pressure

The left stellate ganglion was exposed by removing the left forelimb and resecting the posterior segments of the first and second ribs overlying the left stellate ganglion. Care was taken to avoid puncturing the pleura. The inferior cardiac nerve was identified, freed from surround- lx

ing connective tissue, and transected as far distally as possible. The nerve was placed on a grounded stainless steel dissecting platform and the field flooded with mineral oil. The nerve dissection was carried out under

FIG. I. Isolated carotid sinus preparation. C.S.N. = carotid

mineral oil with the aid of a IO X binocular dissecting sinus nerves. IX = glossopharyngeal nerve. Tr = transducer.

microscope. Multifiber preparations were obtained and Pulser = pulse-wave generator. C.R.O. = cathode-ray oscilloscope.


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BARORECEPTOR AND CHEMORECEPTOR INFLUENCES 473

_-______... ___-

FIG. 3. In each record upper trace = endotracheal pressure, middle trace = femoral arterial pressure, lower trace = electroneurogram from inferior cardiac nerve. Carotid sinus nerves and vagi intact in A, sectioned in B. Record A: inhibition of discharge

with each heartbeat and with lung inflation. Record B: respiratory and cardiac inhibition absent after deafferentation. Record speed in this and subsequent records, 70 mm/set. Time marks, 0.1 sec.

FIG. 4. Continuous record of cardiac sympathetic discharge during rapid increase of pressure in isolated left carotid sinus. Rising line in electroneurogram record = carotid sinus pressure. Pressure records below: TP = endotracheal pressure; CSP = left carotid sinus pressure; FAP = femoral arterial pressure. A =

put of two of these channels was passed into a beam- switching device (designed by Dr. Peter Frommer) and displayed on the second beam of the oscilloscope face. In early experiments a DuMont camera with 35-mm film was employed.

Ventilation with various gas mixtures was achieved by filling a Douglas bag with the desired mixture and con- necting it to the inlet of the respirator. The outlet line from an arm of the endotracheal tube was made uni- directional by placing the end 5 mm below the surface of a cylinder of water. In many experiments deca- methonium (Syncurine), 0.5 mg, was used to prevent excessive spontaneous respiratory efforts. This drug had no detectable direct effect on the impulse traffic in the

inferior cardiac nerve. Where applicable, tests were made for completeness of baroreceptor deafferentation by the very rapid intravenous infusion of 5-1 o ml isotonic saline. When even a single baroreceptor nerve was intact, this infusion caused a temporary inhibition of discharge. If no alteration of sympathetic discharge occurred the deafferentation was assumed to be complete. At the end of the experiments hexamethonium Cl (Bistrium), 2-10

mg/kg was given. This caused rapid and complete cessa- tion of discharge, indicating the fibers to be postgangli- onic.

Although it is recognized that all the fibers of the inferior cardiac nerve may not innervate the myocardium, it is likely that this is the predominant distribution (I, 9).

pressure changes with lowering of carotid sinus pressure; I) = pressure changes at time of corresponding electroneurogram, above. Vagi and right carotid sinus nerve previously sectioned. Electroneurogram record speed = 70 mm/set. Pressure record speed = 0.25 mm/set.


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FIG. 5. A: FAP = femoral arterial pressure. First bar, start tensin 4 min. Carotid sinus nerves previously sectioned. Vagi continuous infusion of angiotensin II, I pg/kg min. Second bar, intact. Electroneurogram record speed = 70 mm/set. Pressure stop angiotensin infusion. Electroneurograms below correspond record speed = 0.5 mm/set. B: events after bilateral cervical to letters in pressure trace above. FAP and endotracheal pressure vagotomy (carotid-sinus nerves previously sectioned). W = con- recorded on each electroneurographic record. W = control; X = trol; X = on angiotensin II aoo set; Y = on angiotensin 6 min; on angiotensin go set; Y = on angiotensin 14 min; Z = off angio- Z = off angiotensin 4 min.


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BARORECEPTOR AND CHEMORECEPTOR INFLUENCES 475

FIG. 6. Pressure records. A and B below = hypoxic blood in isolated left carotid sinus indicated by black bars; C and D = well-oxygenated blood in sinus. Corresponding electroneurograms above, A = low sinus pressure with hypoxic blood in sinus; B = hi.gh sinus pressure with hypoxic blood; C = low sinus pressure with well-oxygenated blood in sinus; D = high sinus pressure with saturated blood. Right carotid sinus nerve and vagi previously sectioned. Respiratory efforts evident in femoral pressure trace while hypoxic blood is in sinus. Record speeds same as Fig. 5.

~--~ St tt A4 AB AB cb

CAROTID SINUS PRESSURE FEMORAL ARTERIAL PRESSURE

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Fro. 7. Intact preparation. Record A; animal respired with room air. In this and all subsequent records, from above, endotracheal pressure, femoral arterial pressure, electroneurogram of inferior cardiac nerve. &cord B: animal respired with 5ojo 02 for 80 sec. Record C. animal respired with room air. Below, slow trace of blood pressure response to 57c 02 ventilation. FAP = femoral arterial pressure. A, B, and C refer to times of obtaining corresponding electroneurograms above. Double arrow indicates onset and dura- tion of hypoxia. Pressure record speed = 0.25 mm/set.

The discharge activity of this nerve will be referred tc _- 1 RS

the cardiac sympathetic discharge.

RESULTS

Spontaneous cardiac sympathetic discharge patterns. In the five intact animal preparations the discharge patterns demonstrated rhythmicity both with the heartbeat and with respiration (Fig. 3A). After each heartbeat the discharge intensity decreased and was usually followed by

a brief period of complete inhibition. After bilateral carotid sinus denervation and vagotomy the discharge pattern was altered such that the grouping of impulses was random and occurred with no temporal relation to the heartbeat (Fig. 3B). Before denervation, superim- posed on the cardiac rhythm there was a secondary resporatory rhythm which showed maximal inhibition during the inspiratory phase (Fig. 3A). The inhibition occurring during lung inflation was usually not complete


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and the cardiac rhythmicity continued throughout the respiratory cycle; the extent of inhibition was dependent on the degree of lung inflation. The respiratory inhibi- tory rhythm was also abolished by bilateral vagotomy and carotid sinus denervation (Fig. gB), or by bilateral vagotomy alone. In experiments in which the vagi were cut but the carotid innervation left intact only severe overinflation accompanied by wide swings in arterial pressure could still produce a respiratory rhythm.

Baroreceptor inJ’uence on cardiac sympathetic discharge. After section of the vagi and right carotid sinus nerve, in preparations in which the vascularly isolated left carotid sinus was perfused from a donor cat, it was possible to estab- lish a vascular rhythm of discharge in the sympathetics of the recipient. This rhythmic inhibition was in phase with the cardiac pulse of the donor but not with the heartbeat of the recipient. The rhythmic inhibition was best accomplished by using a high pressure in the isolated sinus, presumably because only one intact baro- sensory system was being utilized. Lowering the pressure in the perfused sinus caused an increase of discharge activity. Raising the endosinus pressure rapidly caused complete inhibition in all preparations (Fig. 4).

In preparations with carotid sinus denervation but with the vagi intact, raising the systemic blood pressure rapidly by the intravenous infusion of 5 ml normal saline, IO pg epinephrine, or I /*g angiotensin II caused temporary complete inhibition of all discharge activity. This was abolished by vagotomy. With the vagi intact, if the blood pressure was maintained at a higher level, as after blood infusion or continuous angiotensin II infusion, the discharge was reduced as long as the arterial pressure

DOWNING AND SIEGEL

FIG. 8. Cardiac sympathetic discharge response to systemic hypoxia before and after sectioning vagi. Carotid sinuses previously denervated. A: vagi intact, room air in respirator, mean BP 130 mm Hg; B: vagi intact, 5% 02 in respirator for CJO set, mean BP 170 mm Hg; C: vagi sectioned, room air in respirator, mean BP 113 mm Hg; D: vagi sectioned, 5% 02 in respirator for 130 set, mean BP I 14 mm Hg. Time marks 0.1 sec.

remained elevated (Fig. 5A). No alteration of discharge was observed with continuous angiotensin II infusion after vagotomy (Fig. 5B).

Influence of chemoreceptors in regulation of cardiac sympathetic discharge. In three reactive preparations hypoxic blood was introduced into the isolated left carotid sinus after denervation of the contralateral sinus and bilateral cervical vagotomy. The carotid-body reflex was active in these preparations as manifested by an increased respiratory effort with the introduction of the hypoxic blood into the sinus. Little alteration of cardiac sympathetic discharge was discernible when hypoxic blood was introduced into the sinus in these preparations. As shown in Fig. 6, raising the pressure in the sinus from 35 to 130 mm Hg reduced the cardiac sympathetic discharge, but the discharge intensity showed little difference with either hypoxic or saturated blood in the sinus at either pressure level.

In contrast with the failure to demonstrate significant chemoreceptor influence on the heart, it was consistently observed that the systemic arterial pressure changes in response to alterations of carotid sinus pressure were greatly enhanced by the presence of hypoxic blood in the sinus. As illustrated in Fig. 6, the presence of hypoxic blood in the isolated sinus caused a greater rise of arterial pressure when the sinus pressure was lowered (A), and a greater fall of arterial pressure when the sinus pressure was returned (B) than did equivalent changes with saturated blood in the sinus (C and D).

E$ct of systemic hypoxia on cardiac sympathetic discharge. The administration of 5 % 02 to the intact preparation repeatedly caused a moderate to marked increase in dis-


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FIG. 9. Heart rate response to atropine during systemic hypoxia. A: room air in respirator, heart rate = 198; B: 5% 02 in respirator for I IO set, heart rate = 161, signal mark indicates

charge activity in each of the five animals in which this was done. This was nearly always accompanied by a large rise in blood pressure and a widening of the pulse pressure. In spite of the rise in arterial pressure the cardiac sympathetic discharge was increased (Fig. 7). After 1-2 min of 5% 0% the arterial pressure sometimes fell to initial levels or below, but the discharge continued at its increased level. With IO% 02, only a modest increase of discharge was evident and the blood pressure remained moderately elevated. Soon after the animal was changed from low 02 mixtures to breathing room air a consider- able reduction of discharge occurred. This was usually less than the initial intensity on room air with complete inhibition in some animals, but returned to control levels within 2 min or less.

In preparations in which bilateral carotid denervation had been done but the vagi were intact, systemic hypoxia with 5 % 02 produced an increased discharge and the pulratile inhibition was either diminished or abolished (Fig. 8A, B). After bilateral vagotomy there was an un- diminished increase of the sympathetic discharge with hypoxia (Fig. 8C, D). With less severe hypoxia (IO % 02) a modest increase in discharge was occasionally seen after vagotomy. A reduction of sympathetic discharge was never observed with either 5 or IO % 02 mixtures.

In three intact preparations the administration of 5 % 02 for several minutes repeatedly produced a substantial reduction in heart rate, whereas the cardiac sympathetic discharge remained greatly increased. In two of these preparations 0.4 mg atropine was given intravenously during such an episode of bradycardia. This was associated with a prompt increase of heart rate. For example, in one experiment (Fig. g) the heart rate was I g8/min on room air (A). After 3 min of being respired with 5 % 02, the rate had slowed to 161 (B), even though the discharge was increased. Atropine, 0.4 mg, was adminis- tered intravenously and after 30 set the rate increased to 218/min (C). Subsequent episodes of hypoxia produced

C: 5% 02 continued in heart rate = 218.

intravenous injection of 0.4 mg atropine; respirator, 30 set after atropine injection,

only tachycardia, during which time the cardiac symga- thetic discharge was also increased.

, *

Injuence of systemic hypercapnia on cardiac sympathetic discharge. The administration of IO % CO2 (in 20 % 02, 70 % Nz) produced a moderate or marked increase in discharge intensity in both the intact and deafferented preparations (Fig. IO) when respiration was controlled with deca- methonium and artificial ventilation. If the animal were permitted to respond with hyperpnea, inhibition during inspiration was enhanced in those with intact vagi. Five per cent CO2 (in 20 % OS, 75 % Nz) failed to significantly alter the discharge intensity in either preparation.

In order to investigate the possibility of response potentiation, a gas mixture containing 5 % 02 and 5% CO2 (in nitrogen) was compared with 5% 02 (in nitrogen), also with 5 % CO2 (in 20% 02, 75% Nz). The usual intense response was observed to 5% 02. No response to 5 % CO2 was seen. The combination of gases produced a response not readily differentiated from 5 % 02 alone.

DISCUSSION

These investigations indicate that the baroreceptor reflexes have a major role in the regulation of sympathetic discharge to the heart. The peripheral chemoreceptor reflexes, on the other hand, have little influence. This study and the prior observations of Alexander (2) show that the gas composition of the blood perfusing the central nervous system may greatly influence the level of cardiac sympathetic discharge. It is also apparent from these and other studies (4) that there is a functional dichotomy between those areas which influence the sympathetic discharge to the heart and that to the periphery. Whereas carotid-body hypoxia increases sympathetic activity to the periphery (IO, I I), there is either no effect or a decrease of svmDathetic dischame to the heart.

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FIG. IO. Cardiac sympathetic discharge response to systemic in respirator. Lower panel: carotid sinus nerves and vagi sectioned hypercapnia before and after sectioning carotid sinus nerves and X, room air, Y, 10% CO%, 20% OS; 2, room air. Time marks, vagi. Upper panel: carotid sinus nerves and vagi intact; A, room 0.1 sec. air in respirator; B, 10% CO*, 20% 02 in respirator; C, room air

In the present study, convincing evidence of cardiac with carotid-sinus stimulation. Of greater importance sympathetic withdrawal during carotid-body stimula- was the failure to demonstrate an increase of cardiac sym- tion was not obtained. This may be explained by the in- thetic discharge consequent to carotid-body stimulation, trinsic difficulty of discriminating small quantitative whereas systemic hypoxia produced a large increase, changes in the multifiber electroneurogram. In view of presumably originating within the central nervous sys- the small changes in heart rate (about I o %) attributable tern. to sympathetic withdrawal (4) correspondingly small In preparations with intact baroreceptor reflexes the alterations of discharge intensity would be expected. cardiac sympathetic discharge was momentarily in- Any reduction in the level of discharge in response to hibited by each pulse wave, resulting in a rhythmic dis- carotid-body stimulation was very small when compared charge with the heartbeat. After sectioning the carotid


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BARORECEPTOR AND CHEMORECEPTOR INFLUENCES

sinus nerves and the vagi, the discharge activity was no longer in synchrony with the pulse, although a rhythmic pattern was sometimes seen which was fortuitously in phase with the pulse for two or three beats. These findings agree with those of Bronk et al. (I) and Pitts, Larabee, and Bronk (I 2). In contrast with the findings of Alexander (2), raising the systemic blood pressure by transfusion or epinephrine failed to inhibit the sympathetic discharge after the buffer nerves had been sectioned. Possibly this was because the initial blood pressures in these preparations were generally over IOO

mm Hg, and the central nervous system was presumably continuously well oxygenated.

Potentiation of the carotid-sinus response by chemoreceptor stimulation has been described by Von Euler and Liljestrand (I 3) and may be explained by the observations of Gellhorn, Cortell, and Carlson (I 4). These workers demonstrated that hypoxia increases the excitability of certain autonomic centers of the hypothalomus, medulla, and spinal cord. They found that the blood pressure response to electrical stimulation of the medullary centers was enhanced by systemic hypoxia, and concluded that the increased excitability of the medullary sympathetic vasomotor centers during hypoxia was dependent on afferent stimuli from the peripheral chemoreceptors. After sectioning the carotid-sinus nerves and the vagi, the response was greatly diminished during hypoxia. Thus, chemoreceptor impulses may increase the excitability of the medullary centers such that the response to other stimuli, possibly including baroreceptor stimuli, is accentuated.

The administration of low oxygen mixtures caused a large increase of cardiac sympathetic discharge. That the peripheral chemoreceptors are not responsible for the increased discharge was demonstrated by the failure of hypoxic stimulation of a separately perfused carotid body to increase the discharge, and by the fact that sectioning the chemoreceptor afferent nerves failed to decrease the response during systemic hypoxia. Also, the observations that carotid body hypoxia causes cardiac slowing and a reduction of myocardial contractility (4) is not consonant with increased sympathetic discharge to the heart. These data indicate that, although peripheral chemoreceptor stimulation during systemic hypoxia may enhance the activity of the sympathetic vasomotor centers, it is not responsible for an increased sympathetic discharge to the heart. Although other peripheral chemoreceptors may be found which act differ-

REFERENCES

I. BRONK, D. W., L. K. FERGUSON, R. MARGARIA, AND D. Y. SOLANDT. Am. J. Physiol. I I 7 : 237, 1936.

2. ALEXANDER, R. S. Am. J. Physiol. 143 : 698, 1945. 3. KAHLER, R. L., A. GOLDBLATT, AND E. BRAUNWALD. C&n.

Res. 8 : 366, 1960. 4. DOWNING, S. E., J. P. REMENSNYDER, AND J. H. MITCHELL.

Circulation Res. I 0: 676, 1962. 5. BERNTHAL, T. G., W. GREEN, AND A. M. REVZIN. Proc. Sot.

Exptl. Biol. M’ed. 76 : I 2 I, 1951. 6. DALY, M. deB., AND M. J. SCOTT. J. Physiol., London I 44:

148, 1958. 7. DOWNING, S. E., AND J. H. SIEGEL. Clin. Res. IO: 171, 1962.

439

ently on the cardiac sympathetic centers than those known at present, it seems most probable that direct stimulation of the central nervous system itself is responsible for increased cardiac sympathetic discharge resulting from systemic hypoxia.

The possibility remains that a circulating humoral factor such as potassium may appear in systemic hypoxia and stimulate the cardiac sympathetic centers directly. However, the very rapid onset of inhibition of discharge when the animal is returned to breathing room air (within 5 set) d iminishes the likelihood of this explana- tion.

When systemic hypoxia was maintained for several minutes, bradycardia commonly developed in the intact preparations. This was associated with no reduction in cardiac sympathetic discharge. The administration of atropine caused an abrupt increase of heart rate which continued until the hypoxia was relieved. These findings demonstrate that simultaneous activation of cardiac sympathetic and parasympathetic centers occurs during systemic hypoxia. The parasympathetic bradycardia may be largely the result of peripheral chemoreceptor stimulation (2, 5, 6, I 5). The increased cardiac sympathetic activity is probably in response to direct stimulation of centers within the central nervous system. Thus, in systemic hypoxia the usual reciprocal nature of the two divisions of the autonomic nervous system is abolished and both increase their activity simultaneously.

Systemic hypercapnia also elicits substantial increases of sympathetic discharge in either the intact or deafferented preparation. This requires the inhalation of IO 70 COZ, and is not seen with 5 % COZ. Alexander (2)

was unable to elicit this response in his spinal preparations. It is possible that the relatively depressed condition of the spinal preparations prevented this observation.

From the evidence presented it would seem reasonable to conclude that in systemic hypoxia the peripheral chemoreceptors reflexly stimulate the sympathetic vasomotor centers and the parasympathetic cardioin- hibitory centers but have little reflex effect on the cardiac sympathetic centers. The increased cardiac sympathetic discharge during systemic hypoxia or systemic hypercapnia appears to be the consequence of direct rather than reflex stimulation of centers within the central nervous system.

The authors express their gratitude to Dr. Stanley J. Sarnoff

for his advice and critical counsel in the execution of this study.

83

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BERNTHAL, T. G. Am. J. Physiol. I og : 8, 1934. COMROE, J. H., JR. Am. J. Physiol. I 27 : I 76, 1939.

PITTS, R. F., M. G. LARABEE, AND D. W. BRONK. Am. J.

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VON EULER, U. S., AND G. LILJESTRAND. Acta Physiol. Stand,

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Physiol. 135: 641, 1941. NEIL, R. Arch. Intern. Pharmacodyn. 10.5 : 477,


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