Cardiac Responses to SympatheticStimulation

By JORGE ANZOLA, M.D. AND ROBEKT F. RUSHMEK, M.D.

The cardiac res|x>nses to stimulation of sympathetic nerves to the heart were studied both in thora-cotomized and in intact unanesthetized dogs. The changes in heart rate, left ventricular pressure,right and left ventricular dimensions and systemic arterial pressures were recorded. The powerfuleffects of sympathetic stimulation resemble cardiac responses to exercise more than those follow-ing administration of catecholamines. It is inferred that neural mechanisms may be more im-portant for cardiac control during spontaneous activities than the circulating hormones.

CARDIAC function is influenced both byneural reflexes and by circulating hor-mones. Since the automonic nerves to

the heart exert their influence by releasingneurohormones and since the circulating hor-mones are released by nerve stimulation, thesetwo mechanisms are frequently treated as one.For example, it was formerly believed thatunder certain conditions, epinephrine was re-leased both by sympathetic nerves in the heartand by the adrenal glands. More recently, im-pressive evidence1-6 has shown that norepineph-rine (U.S.P. lcvarterenol) is the predominanttransmitter substance released at sympatheticendings, and that only chromaffin tissues, mostof which are concentrated in the adrenalglands, can release epinephrine. Today, levar-terenol is regarded as having a local action ator near nerve terminals. This local action oflevarterenol clearly cannot be duplicated byits intravenous administration. The functionaleffects of circulating levarterenol are very dif-ferent from the effects of stimulating sympa-thetic nerves to the heart. For example, stimu-lating the sympathetic nerves to the heartgenerally produces tachycardia; intravenouslyadministered levarterenol usually producesbradycardia. For these reasons, cardiac per-

From the Department of Physiology and Bio-physics, University of Washington, School of Medi-cine, Seattle, Wash.

This investigation was supported in part by a re-search grunt, H-716, from the National Heart Insti-tute of the National Institutes of Health, U. S. PublicHealth Service, and from the American Heart Asso-ciation.

Received for publication December 27, 1955.

formance after stimulation of sympatheticnerves was studied in acute experiments andin intact, unanesthetized dogs.

METHODS

Eighteen dogs, weighing between S and 12 Kg.,were anesthetized with intravenous sodium [jento-barbital (27 mg./Kg.) and placed on artificialrespiration. An incision was made through the fifthleft intercostal space. Variable resistance gages8 weresutured in the free walls of both right and left ven-tricles to record changes in their dimensions. Theleft ventricular dimensional gages were placedparallel to the mitral ring and midway ljetween thering and the apax; the gages on the right ventriclewere placed just below the pulmonary eonus andparallel to it. Effective left ventricular pressure wasrecorded from a differential transformer type ofpressure gage,7 mounted near the apex of the heartwith a short polyethylene tube extending into theventricular chambers. The heart rate was recordedcontinuously by means of a condensor dischargesystem triggered at the same phase of each succes-sive cardiac cycle. In 11 dogs, aortic pressure wasalso measured with either variable inductance orStatham strain-gage pressure transducers. The sig-nals from the gages were amplified with Sanlx>rncarrier wave amplifiers and recorded directly on aPolyviso.

In 12 acute experiments, the stellate ganglion, theansa subclavia, the caudal cervical ganglion* andthe cardiac nerves were enrefully dissected bilat-erally and stimulated electrically (20-50 V. andfrom 20-30 c.p.s.) for 12 to 15 seconds. In eightexperiments the aorta was completely occluded justdistal to the coronary arteries by means of a Potts'type arterial clamp for 20 to 30 seconds while sympa-thetic nerves were stimulated. This eliminated pe-ripheral vascular responses and caused the ventricleto contract nearly isometrically.

302

* The nomenclature used here conforms to thedescription by N. J. Mizeres.'

Circulation R-tsrarcli, Volume IV, Matt 1936

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ANZOLA AND RUSHMER 303

Vagus Stellate- qanqlion

LEFT VENT. CIRCUM.

LEFT VENT. PRESSUREMMHg

I2CH-

STIMULATE W 4 . 5 STIMULATE # 6

Fio. 1. Changes in left ventricular circumference, effective left ventricular pressure, and rightventricular wall dimensions recorded during stimulation of left stellate ganglion, anterior root ofthe ansa subclavia and caudal cervical ganglion. Drawings are schematic representations of ana-tomical distribution of left sympathetic nerves to the heart in this dog. Stimulation of cardiacnerves (4, 5, 6) distal to caudal cervical ganglion (3) did not reproduce effects obtained by stimu-lating stellate ganglion, ansa subclavia or caudal cervical ganglion.

In the six chronic axperiments, a stimulating elec-trode was placed around the anterior division of theansa subclavia with its connections left intact. Thechest wall was reconstructed, and the animals wereallowed to recover. One to six days after the gageswere installed, cardiac responses were recordedduring electrical stimulation and during variousspontaneous activities, including changes in posi-tion, startle, feeding and exercise.

RESULTS

Responses in anesthetized, open-chested dogs.Electrical stimulation of the intact left stellateganglion caused reproducible changes of thetype illustrated in figure 1. The changes in leftventricular circumference, left ventricular effec-tive pressure, and right ventricular wall dimen-sions occurred, simultaneously, 2 to 4 secondsafter stimulation was begun. The maximal re-

sponse was attained in 7 to 10 seconds, and itcontinued at about that level during the re-mainder of the stimulation. The decrease in leftventricular dimensions amounted to about 40per cent of the stroke amplitude. The effectivesystolic pressure in the left ventricle increased60 to 120 mm. Hg, but the diastolic pressureoften fluctuated in an unpredictable fashion.The decrease in right ventricular wall dimen-sions was about 30 per cent of the strokechange. The heart rate accelerated 1 to 3 sec-onds after the beginning of stimulation, andwas persistently fast (over 210 beats/min.)during stimulation. After cessation of stimula-tion, the diastolic dimensions of both the rightand left ventricles gradually increased and thenreturned to the control level after 90 to 120seconds. The effective ventricular pressure re-

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304 CARDIAC RESPONSES TO SYMPATHETIC STIMULATION

LEFT VENT. PRESSURE * 4 SEVERED

Fio. 2. Responses to stimulations of anterior root of ansa subclavia after successive transectionsof individual cardiac nerves distal to caudal cervical ganglion. Last remnants of response were com-pletely abolished only after left vagus was severed. Drawing depicts schematically the anatomicaldistribution of left sympathetic cardiac nerves in this dog.

niained at peak levels for 20 to 25 seconds andthen slowly regained control levels 65 to 95seconds later. The heart rate began to diminishwhen stimulation was discontinued and whilethe ventricular pressure still remained at peaklevels.

Severing all the connections of the stellateganglion except those to the ansa subclaviaproduced no change in the response to stimu-lation of this ganglion (fig. 1). Stimulation ofthe distal end of the severed thoracic chaincaused no significant change in ventricularpressure, dimensions, or heart rate. The effectof stimulating the anterior root of the ansasubclavia closely resembled the response tostellate ganglion stimulation, but the responseswere slightly smaller (fig. 1). Generally, stimu-lation of the posterior root of the ansa sub-clavia produced very slight responses, and

stimulation of the nerves connecting the caudalcervical ganglion to the heart had very littleeffect. The changes produced by stimulatingthe caudal sympathetic ganglion could not beduplicated by stimulating any combination ofthe sympathetic nerves beyond this point.This suggested that other nerves conduct theseimpulses to the heart. To test this possibility,the anterior root of the ansa subclavia wasstimulated after its connections were sectionedsequentially (fig. 2). The cardiac response wasprogressively diminished by this procedure,indicating that integrity of these nerves wasessential to the original response.

The striking increase in left ventricular sys-tolic pressure could result from greater cardiacoutput, increased peripheral resistance or both.There were no known neural connections be-tween the point of sympathetic stimulation and

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ANZOLA AND RUSHMER 305

AORTICPRESSURE

LEFTVENTRICULAR

PRESSURE

LEFTVENTRICULAR

CIRCUM.

RIGHTVENTRICULAR

WALL

SYMPATHETICM M STIMULATION

ft!'1 - ^ ^' 2O~ w w W »/

100- ^8 0'^^^^^^^M^^^H^

MM ,Hg !180- _

STIMULATION

AORTACLAMPED

t*wwv*̂

AORTA CLAMPED ANDSYMR4THETIC STIMULATION

STIMULATION

Fin. 3. Records taken during stimulation of anterior root of ansa subclaviti, complete clamping of;iorta, and these combined effects (same dog as in fig. 2). Sympathetic stimulation during clampingof aorta shows powerful elTecIs of cardiac sympathetic nerves on pressure and dimensions of thovontriclos.

the principal sites of peripheral resistance (e.g.,the splanchnic bed). To eliminate the possi-bility that the great increase in ventricularsystolic pressure might have resulted from therelease of neurohormones from the heart intothe circulating blood, sympathetic stimulationwas performed while the aorta was completelyoccluded just above the coronary arteries witha Potts' type clamp. After the aorta wasabruptly occluded, ventricular pressurepromptly increased about 50 mm. Hg andreached a plateau in about 10 seconds (fig. 3).The ventricular chambers were progressivelydistended, reaching a plateau in about thesame time. The excursions during each cycledecreased 30 per cent from the right ventriculargage and 80 per cent from the left. These deflec-tions probably resulted primarily from a changein shape rather than in volume. Blood couldleave the left ventricle only through the coro-nary arteries or, possibly, through the mitralvalves if they became incompetent because ofmassive ventricular distention.

J-EFT VENTRICULAR CIRCUMFERENCE

LEFT VENTRICULAR PRESSURE

•ff., TfiPWfy, f̂rWW180ISO12090-'

FIG. 4. Records taken during electrical stimula-tion of the anterior root of the ansa subclavia in anunanesthetized, intact dog four days after operation.The response is similar to those obtained duringsympathetic stimulation in anesthetized open chesteddogs (fig. J).

Stimulation of the anterior branch of theansa subclavia while the aorta was clampedgreatly increased the ventricular pressure above

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30(5 CARDTAC RESPONSES TO SYMPATHETIC STIMULATION

the levels attained after clamping of the aortaalone (fig. 3). The excursions during each strokewere greatly accentuated (fig. 3). About fiveseconds after stimulation was begun, the ven-tricular pressure reached a plateau and re-mained at that level throughout the stimula-tion period. Soon after the clamp was removedfrom the aorta, the ventricular pressure nearedcontrol values, as did the ventricular dimen-sions. The aortic pressure records displayedvery large pulse pressures.

Responses in unanesthetized, intact dogs.Figure 4 shows the typical response to electricalstimulation of the anterior branch of the ansasubclavia several days after operation. Theresponse in the unanesthetized dogs was onlyslightly smaller than that in the thoracotomizedanimals. The responses to certain types ofspontaneous activity (e.g., exercise, eating)resembled those produced by electrical stimu-lation of the sympathetic cardiac nerves.

DISCUSSION

Electrical stimulation of sympathetic nervesto the heart produced consistent effects oneffective ventricular pressure, heart rate, aorticpressure, and heart dimensions in 18 dogs. Thesystolic pressures in the left ventricle and aortawere greatly elevated. Systemic hypertensionis usually attributed to increased peripheralresistance or increased cardiac output; in-creased rate of ventricular ejection and arterialdistensibility may also have roles. However,stimulation of the stellate ganglion elevatedsystolic pressure in thoracotomized dogs afterall known connections to the peripheral vascu-lature had been severed. Sympathetic stimula-tion could cause a rise in systolic arterial pres-sure because of increased cardiac output andmore rapid ventricular ejection. Peripheralvasoconstriction might result from a release ofneurohormones from the heart into the circu-lating blood. Arterial distensibility might bereduced by circulating catecholamines or fromthe neural stimulation.

The reduction in the systolic and diastolicdimensions of both ventricles during and im-mediately after electrical stimulation couldresult from an increase in heart rate, an in-crease in the contractility of the cardiac muscle

fibers or a combination of the two (fig. 1).The tachycardia and changes in ventriculardimensions occurred when either the right orthe left stellate gangljon were stimulated, de-noting a very wide distribution of nervefibers.8"10 In spite of the elevated systolic pres-sure, the tachycardia persisted. It is worth-while to note here that a similar pressure risefrom epinephrine injection produces brady-cardia.

The effects of stimulating the stellate gan-glion, ansa subclavia and caudal cervical gan-glion were never duplicated by stimulatingcardiac nerves beyond this point, either indi-vidually or in any combination. The explana-tion for this observation is not clear. Perhapsthe high threshold of the post ganglionic fiberswas involved, at least in part. Also, there mayhave been sympathetic nerves passing to theheart which were not stimulated; perhaps somesympathetic fibers to the heart travel along thevagus nerve,9 or along some presently unknownroute.

When the heart was made to contract nearlyisometrically by clamping of the aorta (fig. 3),the ventricular pressure increased abruptly,but a further and much greater increase wasobtained with additional electrical stimulationof cardiac nerves. This increase in the ven-tricular pressure can only be explained by achange in contractility of the muscle fibers.These powerful sympathetic effects (fig. 3)very strongly suggest that neural controls playan important role in the regulation of cardiacfunction.

SUMMARY

Direct electrical stimulation of sympatheticcardiac nerves produced consistent changes incardiac function including tachycardia, morecomplete systolic ejection and systemic hyper-tension.

The changes occurring in ventricular dimen-sions during direct sympathetic stimulation arebelieved to result from changes in heart rateas well as from an increase in the contractilityof the heart muscle.

Clamping of the aorta increased left ven-tricular pressure by about 90 per cent. Sympa-thetic stimulation while the aorta was clamped

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ANZOLA AND RUSHMER 307

increased left ventricular pressure by an addi-tional 120 per cent (over 300 mm. Hg). Thegreatly increased tension exerted when theventricle was contracting almost isometricallyunquestionably represents a change in thecontractile characteristics of the heart musclefibers. These powerful sympathetic effects sug-gest that the neural factors may be far moreimportant than circulating hormones to thecontrol of the heart.

Spontaneous activity (e.g., feeding or exer-cise) produce effects which resemble the re-sponses to direct electrical stimulation of sym-pathetic nerves to the heart.

SUMMABIO IN INTERLINGUA

Le directe stimulation electric de sympathicnervos cardiac resultava regularmente inalterationes de function cardiac, includentetachycardia, un plus complete ejection systolic,e hypertension systemic.

Nos opina que le alterationes occurrente inle dimensiones ventricular durante le directestimulation sympathic resulta ab alterationesdel rapiditate del corde e ab un augmentatecontractilitate del musculo cardiac.

Clam page del aorta effectuava un augmentode circa 90 pro cento in le pression sinistro-ventricular. Stimulation sympathic duranteclampage del aorta augmentava le pressionsinistro-ventricular per ancora 120 pro cento(per plus que 300 mm. Hg). Le grande aug-mento de tension, que esseva exercite quandole ventriculo se contraheva quasi isometrica-mente, representa sin question un alteration

del characteristicas contractile in le fibras delmusculo cardiac. Iste marcate effectos delstimulation sympathic suggere le notion quefactores neural es possibilemente multo plusimportante in le regulation del corde quehormones circulante.

Activitates spontanee (p. ex. alimentation oexercitio) produce effectos simile al responsasproducite per le directe stimulation electric desympathic nervos cardiac.

REFERENCES1 VON EULER, U. S.: Hormones of the sympathetic

nervous system and the adrenal medulla. Brit.M. J. 1: 105, 1951.

1 —: Sympathetic neuro-effectors of the heart.Cardiologia 21: 252, 1952.

•WEST, G. B.: Adrenaline and noradrenaline. J.Pharm. & Pharmacol. 7: SI, 1955.

* GOODALL, M.: The presence of noradrenaline,adrenaline and an unknown sympathicolyticfactor in cattle heart. Acta physiol. Scnndinuv.20: 137, 1950.

6RAAB, W., AND GIOEE, W.: Norepinephrine andepinephrine content of normal and diseasedhuman hearts. Circulation 11: 593, 1955.

'RusmrER, R. F.: Length-circumference relationsof the left ventricle. Circulation Research 3:639, 1955.

7 — , CBYSTAL, D. K , WAGNER, C, ELLIS, R. M.,AND NASH, A. A.: Continuous measurements ofleft ventricular dimensions in intact, unanes-thetized dogs. Circulation Research 2: 14, 1954.

8 TCHENG, K. T.: Innervation of the dog's heart.

Am. Heart.!. 41:512, 1951.•MIZERES, N. J.: The anatomy of the autonomic

nervous system in the dog. Am. J. Anat. 96:285, 1955.

10 MITCHELL, S. A. G.: The innervation of the heart.

Brit. Heart J. 16: 159, 1953.

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JORGE ANZOLA and ROBERT F. RUSHMERCardiac Responses to Sympathetic Stimulation

Print ISSN: 0009-7330. Online ISSN: 1524-4571 Copyright © 1956 American Heart Association, Inc. All rights reserved.is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation Research

doi: 10.1161/01.RES.4.3.3021956;4:302-307Circ Res. 

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