Regulation of Ventricular Contraction - Circulation...

Regulation of Ventricular ContractionInfluence of Cardiac Sympathetic and Vagal Nerve Stimulation

on Atrial and Ventricular Dynamics

By S. J. SARNOFF, M.D., S. K. BROCKMAN, M.D., J. P. GILMORE, M.S.,

E. J. LINDEN, M.D., CH.B., PH.D., AND J. H. MITCHELL, M.D.

THE vigor with which the ventricle con-tracts and propels blood through the tis-

sues of the organism is central to the problemof circulatory regulation. It is to be supposedthat a clearer understanding of those influ-ences which modify the ventricle's contractionand a systemization of the observed phenom-ena will have some integrative value andconfer a greater degree of predictability inthe analysis of circulatory adaptation tochanging states.

The effect of stimulating the cai'diac sympa-thetic and vagus nerves on the performancecharacteristics of the heart will be the subjectof this communication. Preliminary reportsof this work have appeared elsewhere.1"4

MethodsMongrel dogs of both sexes, weighing an aver-

age of 18 Kg., were used; they were premedi-cated with morphine sulfate intramuscularly andgiven R mixture of ehlornlose and urethane intra-venously.5 Pressures were measured in the rightand left atria, pulmonary artery, left ventricleand aorta with Statham strain gages; heart ratewas measured either with a Waters or Gilfordeardiotaehometer. Total aortic blood flow wasmetered with the Potter clectroturbinometer.6

All values were simultaneously recorded on an8-ehannel Sanborn direct writing oscillograph.An initial dose of 75 mg. heparin was injectedintravenously followed by 10 mg. each hour there-after. Intermittent positive pressure breathingwas maintained by a Starling pump after trache-otomy and tracheal intubation. An end-expiratorypressure of about 4 cm. H2O was usually main-tained by inserting the expiratory line an appro-priate depth into a water bottle, so as to preventthe tendency to arterial desaturation when thelungs are allowed to collapse completely duringexpiration.

From the Laboratory of Cardiovascular Physiology,National Heart Institute, National Institutes ofHealth, Bethesda, Md.

Received for publication June 13, 1960.

When either right-sided stellectomy, crushingof the sino-atrial node or surgically inducedatrioventricular block was required, these pro-cedures were done through a right thoractomyas the initial step in the preparation; the tho-ractomy was then closed. High cervical vagotomywas done in some experiments.

A left thoractomy in the fourth or fifth inter-space was then performed. Cnnnulne and tygontubing were placed so as to permit the recordingof aortic flow" with a side arm from the aortictubing supplying the head, either through thebraehioeephalic or the common carotid arteries.The braehioeephalic and left subelavian arterieswere ligated at their point of origin from theaortic arch. In this manner, aortic flow, i.e.,the output of the left ventricle minus coronaryflow, was continuously recorded. Care was takento avoid injury to nerves during the dissection.

In those experiments in which left stellateganglion stimulation was to be employed, allrami to this ganglion were sectioned and theganglion placed in a bipolar electrode. Less fre-quently, a unipolar Kubicek electrode8 was ap-plied to the common ansa subclavia. Vagal stimu-lation, when used, was applied to the distal cutend of either vagus nerve by means of a bipolarelectrode. The impulse duration used in stimu-lating the stellate, ansa, or vagus, was 3 to 10msec. The voltage and frequency were deter-mined by the particular experimental objectives.A Grass impulse generator was used.

Heart rate was controlled in all the experi-ments, except where otherwise specified, by bi-polar stimulation of either the right or leftatrium with a Grass impulse generator. The ratewas chosen by preliminary observations with theanticipated experimental intervention, such asstellate stimulation. The atrium was then pacedthroughout the course of the experiment justabove the highest rate thereby induced.

The term "ventricular function curve" will beindicated by the abbreviation V.F.C. In eachinstance, this abbreviation will be accompaniedby a subscript to indicate whether the curve isthe plot of mean left atrial pressure against leftventricular stroke work (V.F.C.LA) or left ven-tricular end-diastolie pressure against left ven-tricular stroke work (V.F.C.LV). Stroke work

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EFFECT OF AUTONOMIC STIMULATION ON THE HEART 1109

was calculated as previously described.0 Theactual changes in stroke work induced by anygiven experimental intervention were at least asgreat as those shown in the data presented below.Had the stroke work been calculated using strokevolume X mean systolic aortic pressure (insteadof moan aortic pressure) or as advocated byChapman ot al.10 the changes induced would ineach instance have been greater than those shownbelow. Similarly, the absence of coronary flowfrom the cardiac output measurement diminishesthe extent of the observed changes.11 The ven-tricular function curves were obtained by step-wise infusion of previous mixed blood (fromdonor dogs) from a reservoir connected to afemoral vein.0 In some experiments, changes inthe length of a segment of left ventricular myo-cardium"' were also recorded simultaneously withventricular diastolic pressure.

ResultsFifty-two experiments were performed to

ascertain the hemodynamic consequences ofsympathetic or parasympathetic stimulationfor the heart.

Stellate Ganglion Stimulation

Effects on Cardiac Output and Atrial and ArterialPressures

Supramaximal stimulation of the isolatedleft stellate ganglion produced the type ofchanges shown in figures 1A and 2?. Heart ratewas held constant throughout by left atrialexcitation. The prompt elevation of systolic,mean and diastolic aortic pressures after theonset of stimulation was accompanied by afall in left and right atrial pressures. Pul-monary artery pressure was not consistentlyaffected, but usually changed little. Uni-formly, however, there was a widening of thePA-LA pressure difference with the observedincrease in flow in each of the experimentsin which such observations were made. Theresponse to stellate stimulation was inhibitedby ganglionic blockade with tetraethylammo-nium chloride. An observation of interest wasthat, as found by Shipley and Gregg,12 leftstellate ganglion stimulation sometimes didnot cause an appreciable change in heart rate.In such animals, observations on myocardialcontractility were made with and without acontrolled heart rate and the results werethe same. In some experiments, the elevation

Circulation llec-ar':'^, Volume V1I1, September I960

Figure 1A: L.A. — mean atrial pressure; Ao. = aorticpressure; Ji.A. = mean right atrial pressure;P.A. = mean pulmonary artery pressure; A.F.= total aortic flow. Line at bottom right =interval of 1 minute. Chart speed is 0.5 mm./sec.During the interval between the arrows at topof first channel, the isolated left stellate ganglionwas stimulated at 6 volts, 4/sec. with a 5 msec,impulse duration. Heart rate was maintained at150/min. throughout by atrial pacing. The ramito the right stellate ganglion were cut and bothvagi sectioned in the neck. B: P.R. = pulse rate.Other symbols as in figure 1A. Stimulation ofleft stellate ganglion at signal in first panel,3.5 volts, 5/sec. 5 msec. Stimulus stopped at endof first panel. Second panel is 2.4 minutes afterfirst panel. Third panel, 1.3 minutes after secondpanel, shotvs effect of the intravenous injection of5.0 gamma of norepinephrine base at signal inthird panel. Fourth panel is 2.6 minutes afterthird panel. Heart rate held constant by atrialpacing. Chart speed is 2.5 mm./sec. Dog weight= 21.0 Kg.



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1110 SARNOFF, BROCKMAN, GILMORE, LINDEN, MITCHELL

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Figure 2Symbols same us in fgure 1A. Heart rate pacedat 150/min. throughout by atrial pacing. Chartspeed 0.5 mm/sec. The rami to the right stel-late ganglion and both vagi were sectioned. Theisolated left stellate ganglion ivas stimulated at7 volt* u ith an impvlxe duration of .10 msec. Thenumber at the top of each segment of tracingshoivs the impulse frequency ttsed. At the end ofthe changes shown in (A), the stimulus xoasstopped for 6 minutes, and an infusion of WOml. of blood given. The same sequence of fre-quency graded stimuli icere then again applied(li). Approximately 1.5 minutes elapsed betweeneach strip of tracing in (A) and (B).

of arterial pressure was small during stellateganglion stimulation, the increased contrac-tility being evidenced primarily by the fallin atrial pressure (fig. IB, left). In suchinstances it was reasoned that the initial risein arterial pressure produced reflex vaso-dilation mediated through the baroceptors.Whether the response was of the type shownin figure 1A or 12? (left) it could be mimickedwith the intravenous administration of a se-lected dose of norepinephrine (fig. IB, right).

Effects of Graded Stellate Ganglion Stimulation onCardiac Output, External Stroke Work and the Posi-tion of the Ventricular Function Curve (V.F.C.LA)

An examination was made of the effectsof applying frequency-graded stimulation tothe left stellate ganglion on cardiac output,stroke volume and external stroke work.Prom these data, ventricular function curves(V.F.C.LA) were then constructed.

Figure 2A (left) demonstrates the type ofresponse obtained. Each time the stimulusfrequency (with supramaximal voltage) wasincreased from zero up through 4 per second,

the fall in left and right atrial pressures andthe rise in aortic pressure was accompaniedby an increased cardiac output and, sinceheart rate was held constant, by a propor-tional increase in stroke volume. The cal-culated external ventricular stroke work thusrose with each increase in stimulus frequencywhile atrial pressure fell. The same type ofresult was also obtained when the stimulusvoltage was varied from zero to the level ofmaximal response while the stimulation fre-quency was held constant.

At the end of the series of observationsshown in the left panel of figure 2, stellatestimulation was stopped and an interval of6 minutes allowed to pass during which periodeach of the hemodynamic values returned tocontrol levels. An infusion of approximately100 ml. of blood was then made. This re-sulted in a modest eleA'ation of atrial andarterial pressures, cardiac output, stroke vol-ume and stroke work, as can be seen by com-paring the first segment of the left panel offigure 2 (before infusion) with the first seg-ment of the right panel (after 1 infusion).The same series of frequency graded stimuliwere then once again applied with the re-sults seen in the right panel of figure 2. Thissequence of interventions was repeated until6 sets of 6 points each were obtained. Heartrate was held constant throughout.

The plot of mean left atrial pressure versusleft ventricular stroke work (V.F.C.LA) re-sulting from these data is shown in figure 3(left). The number adjacent to each curveindicates the stimulus frequency. Worthy ofnote was the magnitude of change in the ven-tricular work produced at a given mean leftatrial pressure under the influence of leftstellate stimulation, especially since only aportion of the cardiac sympathetic nerveswere stimulated. The effects of left stellateganglion stimulation on right ventricularfunction (V.F.C.RA) were similar to the ef-fects observed on the left. One hour and fif-teen minutes after the completion of theexperiment shown in figure 3 (left), the en-tire experiment was repeated with similarresults (fig. 3, right).

The V.F.C.LA was shifted to the left by

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5 !O 15

L.A.MEANCM H 2 O20 25 5 10 15 20

L.A.MEAN CM H 2 015

Figure 3In the left panel are curves showing the relation between mean left atrial pressure andleft ventricular stroke work during control period (0) and during stimulation of isolatedleft stellate ganglion at 0.2, 0.5, 1.0, 2D and 4.0 per second, using 7 volts and an impulseduration 10 msec. Kami to right stellate ganglion and both vagi sectioned. Heart rate heldconstant at 150/min. by atrial pacing. One hour and 15 minutes later the experimenttuas repeated; the resulting curves are shown in the right panel.

stellate ganglion stimulation in each of the19 such experiments. In each of these suffi-cient data were obtained to construct curveswith 5 or more points on each curve. In 5additional experiments, the same results wereobtained by the continuous infusion of nore-pinephrine (see below).

Effect of Stellate Ganglion Stimulation or the Con-tinuous Infusion of Norepinephrine on the VentricularFunction Curve (V.F.C.Li.)

In the course of these and other experi-ments,13 high speed tracings of undampedpulse contours were obtained several hundredtimes in 59 experiments in which left stellateganglion stimulation was done while the heartwas held at the same rate by atrial stimula-tion. The fall in left atrial pressure duringstellate stimulation was consistently accom-panied by a lowering of left ventricular end-diastolic pressure. The more rapid develop-ment of tension, the more rapid myocardialshortening, the augmented aortic pressure,

Circulation Research, Volume Vlll, September 1900

the shorter duration of ejection and the morerapid relaxation were consistent and note-worthy. Changes of the type observed canbe seen in figure 6 (lower).

In 8 of the 19 function curve experimentsdescribed above (under stellate stimulation),left ventricular end diastolic pressure, as wellas mean left atrial pressure, were recordedbefore and during left stellate ganglion stimu-lation. Resolution of the diastolic ventricularpressure was increased by recording ventricu-lar pressure only from zero to 40 cm.H20.The type of tracings obtained is shown infigure 6. In all 8 such experiments (fig. 4,left), a shift of the ventricular function curveto the left was observed when either meanleft atrial pressure (V.F.C.LA) or left ven-tricular end-diastolic pressure (V.F.CLV)was plotted against stroke work; the meanleft atrial pressure fell more than the end-diastolic value at any given level of strokework. The extent of the difference between



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0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 40PRESSURE: CENTIMETERS H20

Figure 4Left panel: dashed lines show relation betweenmean left at rial pressure and left ventricularstroke ivork during control period (C) and dur-ing stellate stimulation (SS). Solid lines shotorelation between left ventricular end diastolicpressure and stroke work during control period(C) mid (hiring stellate stimulation (SS). Bi-lateral cerviral vagotomyj right stellate intact.Heart rate constant at 171/min. Bog weight =17.0 Kg. Eight panel: Symbols same as at leftexcept that a continuous infusion of 0.36 gammaper minute of norepinephrine base was admin-istered during curve marked (NE) after controlcurve (C) was obtained. Bilateral cervical vagot-omj; right stellate intact. Heart rate constant at1 iO/min. Bog weight = 16.0 Kg.

the fall in mean atrial and end-diastolic pres-sures depended upon whether the ventriclewas on a relatively steep or relatively flatportion of the function curve.

Five additional experiments were done inwhich the effect of norepinephrine on ven-tricular function (V.F.C.LV and V.F.C.LA)was examined. The results were directly com-parable to those obtained with stellate stimu-lation (fig. 4, right).

Influence of Stellate Ganglion Stimulation on theRelation between Ventricular Myocardial SegmentLength and StroTce Work

The lack of a change in the relation betweenventricular end-diastolic pressure and myo-cardial segment length during stellate stimu-lation as previously described indicated that,under such stimulation, the ventricle con-tracts more forcefully from any given fiber

length as well as from any given ventricularend-diastolic pressure.13 Figure 5 shows (left)the relation between left ventricular end-dias-tolic pressure and stroke work, (middle) therelation between left ventricular end-diastolicpressure and myocardial segment length, and(right) the work produced from any givenmyocardial segment length before and duringsympathetic stimulation. In 8 such experi-ments, it was observed that the ventricle con-tracts more forcefully from any given myo-cardial segment length as well as from anygiven end-diastolic pressure during stellatestimulation. An example of a more vigorousventricular contraction from a shorter end-diastolic fiber length as well as from a lowerpressure can be seen in figure 6 (lower).

More complete systolic emptying from anygiven end-diastolic pressure or length duringstellate ganglion stimulation is implicit in theresults described above; i.e., stellate stimula-tion induced the delivery of a substantiallygreater stroke volume as well as stroke workfrom any given left A'entricular end-diastolicsegment length or pressure.

Effect of Stellate Stimulation on the VentricularStroke Work Produced per Systolic Second (Ventric-ular Power)

The shortening of systole (fig. 6) observedduring stellate stimulation while the ven-tricle produced an increased work from anygiven end-diastolic pressure (fig. 4, left)indicated a greater increase in stroke powerthan in stroke work. In that experiment,during stellate stimulation the shortenedduration of ventricular systole from anygiven end-diastolic pressure was such thatthe increase in power was an average of 25per cent greater than the increase in work.A similar effect was produced by the admin-istration of norepinephrine (fig. 4, right).In that experiment, during norepinephrineinfusion the shortened duration of ventricu-lar systole from any given end-diastolic pres-sure was such that the increase in power wasan average of 33 per cent greater than theincrease in work. The increase in strokework produced during stellate stimulation ornorepinephrine infusion was consistently ac-

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EFFECT OF AUTONOM.IC STIMULATION ON THE HEART 1113

L.V. END.-CNASTOLIC PRESSURE-CM. H,0 MM CHANGE IN M T O C A I SEGMENT LENGTH

Figure 5Data for the curves shown in first, second and third 'panels were obtained simultaneously.First panel shows the relation between left ventricular end-diastolic pressure and strokework before (solid circles) and during (open circles) stellate ganglion stimulation. Secondpanel shows relation betiveen left ventricular end-diastolic pressure and change in end-diastolic myocardial segment length before (solid circles) and during (open circles)stellate stimulation. Third panel shows relation between changes in end-diastolic myo-cairdial segment length and left ventricular stroke work before (solid circles) and during(open circles) stellate stimulation. Heart rate held constant at 171/min. by atrial pacing.Bilateral cervical vagotomy; right stellate ganglion intact.

companied by a shortening of systole in allsuch experiments.Atrial Contractility during Stellate Ganglion Stimu-lation

Evidence indicating that the atrium as wellas the ventricle contracts with more vigorduring sympathetic stimulation is shown infigure 6. In the upper panel of figure 6 areleft atrial, left ventricular diastolic and aorticpressure tracings from a dog in which atrio-ventricular block had been surgically induced.The atrium was paced at a constant rate. Anincreased amplitude of the atrial a wave con-tour was observed during stellate stimulation.It was also observed that the duration of atrialsystole is shortened during stellate stimula-tion, suggesting that atrial as well as ven-tricular power is augmented by sympatheticstimulation. The same results were obtainedafter the intravenous administration of nor-epinephrine (fig. 6, middle). These findingsindicate that sympathetic stimulation aug-ments the vigor of atrial contraction.

Circulation Research, Volume VIII, September 1960

The study of the atrial a wave in the heartblock dog as above has the advantage of per-mitting observations on the consequences ofatrial activity to be made without contiguousventricular disturbances. "With this back-ground at hand, however, experiments on theheart with normally conducted impulses wereundertaken. In addition to pressure measure-ments, recordings were also made of changesin myocardial segment length. Figure 6 (low-er) shows one such record before and duringstellate stimulation. Mild efferent vagal nervestimulation was used so as to slow the heartto a rate of approximately that in the un-anesthetized resting dog. This mild vagalactivity was held as a constant backgroundthroughout the course of the experiment. Thecontrol tracing is at the left; that duringstellate stimulation is at the right. Table 1shows the values for each of the componentsanalyzed. It is clear from these tracings thatduring stellate stimulation the atrial contrac-tion produced a larger end-diastolic increment



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Figure 6Upper: Chart speed = 50 mm./sec. Surgicallyinduced heart block, bilateral cervical vagotomy.Atrial rate held constant at 116/min. by pacing.A.P = aortic pressure; L.A. = left atrial pres-sure; L.V.D. = left ventricular diastolic pressure.Control tracing at left. Tracing at right takenduring left stellate stimulation. Arrows indicateleft .atrial a waves during diastole. Middle: Sameexperiment, atrial rate and chart speed as in upperpanel. Control tracing at left. Tracing at righttaken during peak of reaction after the intra-venous administration of 10 gamma of norepi-nephrine base. Lower: Chart speed = 100 mm./sec. Heart rate held constant at 116/min. by atrialpacing. Bilateral cervical vagotomy. Continuousstimulation of distal cut end of vagus nervethroughout experiment. Control tracing at left.Tracing at right taken during stimulation of theisolated, left stellate ganglion. In each tracing, thearrows indicate the left atrial (L.A.) a wave, theatrially induced increase in left ventricular end-diastolic pressure (L.V.D.) and myocardial seg-ment length (M.S.L.) + = elongation of segment;- == shortening of segment.

of both ventricular pressure and segmentlength. The greater rise in end-diastolic ven-tricular pressure can only be attributed tothe more vigorous atrial contraction; thegreater elongation of the myocardial segmentis attributed not only to the more forcefulatrial contraction but also to the lower posi-tion on the ventricle's pressure-length curve,5

brought about by the more complete systolicemptying in the previous beat. In some ex-periments, the increased atrial contraction wasnot apparent during sympathetic stimulationwhen the drop in ventricular and atrial pres-sure is pronounced. Under such circumstances,restoring the level of atrial and ventricularpressure by infusion revealed the strongeratrial contraction.

Vagal Stimulation

Effect of Vagal Stimulation on the Relation betweenMean, Left Atrial Pressure and Left VentricularStrolce WorTc (V.F.C.LA)

Some of the hemodynamic consequences ofvagal stimulation, while the heart rate is main-tained constant by atrial pacing, are shownin figure 7 (left). Mean right and left atrialpressures rose while aortic pressure, cardiacoutput and stroke work fell. That the magni-tude of the response was a function of thevagal impulse frequency used is shown inthe data at the right in figure 7; the observedresponses increased in a stepwise manner asthe stimulation frequency was increased from0 to 6 per second. It should be noted that thecarotid sinus pressure was maintained con-stant throughout the course of this experi-ment in order to control the reflex sympa-thetic influences emanating from this area.14

More complete experiments were then car-ried out in which the effect of vagal stimula-tion on the relation between mean left atrialpressure and left ventricular stroke work wasexamined over wide ranges. The results of1 of the 9 such experiments performed areshown in figure 8. The curve describing therelation between mean left atrial pressure andstroke work (V.F.C.LA) is shifted to the rightas a result of vagal stimulation; the extentof the observed shift is a function of the vagal




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impulse frequency applied. The same effectwas observed on the right (V.F.C.RA).

Effect of AtropineIn 3 experiments, atropine was adminis-

tered at the height of the response to vagalstimulation in order to block the cholinergicmechanism involved in the observed changes.One such experiment is shown in figure 9.After 3 control responses to vagal stimula-tion were obtained (A, B and C), 8.0 mg. ofatropine sulfate were given intravenously dur-ing the plateau of the fourth response (at thearrow between D and D') while the stimuluswas maintained. The effects of the sustainedvagal stimulation were promptly abolished(D') and subsequent stimulation was withouteffect (E). Carotid sinus pressure was notcontrolled in this experiment and it is ofinterest to note the rebound from the initialdrop in arterial pressure and initial pressuresoon after the onset of each period of vagalstimulation. Such recoveries were not ob-served when the carotid pressure was heldconstant (fig. 7).

Difference Between V.F.C.LV and V.F.C.n DuringVagal Stimulation

At this point in the investigation, it wasconsidered that the observed phenomena couldbe explained in 3 different ways: (1) thatdespite the lack of available anatomic evi-dence for vagal innervation of the ventri-cle,15' 10 vagal stimulation can in some wayinfluence the force of ventricular contractionfrom any given e^d-diastolic pressure; (2)that changes in mean left atrial pressure donot, during vagal stimulation, indicate similardirectional changes in left ventricular end-diastolic pressure; (3) that changes in leftventricular myocardial extensibility duringvagal stimulation could account for the ob-served phenomena. The latter possibility wassatisfactorily eliminated in other experimentsdescribed elsewhere13 and the remaining ex-periments were therefore designed to differ-entiate between 1 and 2 above.

Four experiments were done in which datawere gathered in such a manner as to make itpossible to relate both mean left atrial pres-


Figure 7R.A. = right atrial, Ao = Aortic, L.A. = leftatrial, P.A. = pulmonary artery and C.S.P. =carotid artery pressures. The latter was main-tained constant by bilateral carotid artery per-fusion. A.F. = total aortic floiv; H.R. = heartrate. Bilateral vagotomy, stellates intact. Dogweight = 26.0 Kg. Heart rate held constant byatrial pacing. Left: Stimulation of the distal cutend of the left vagus nerve during period indi-cated by the signals at A and B. Stimulation was5.2 volts, 8/sec. and 5 msec. Chart speed 30 mm./min. Right: Results of varying the impulse fre-quency applied from 0 to 6/sec.

sure and left ventricular end-diastolic pres-sure to the stroke work of the left ventricle.The results of one such experiment are shownin figure 10. It was clear that no change in leftventricular contractility had taken place, i.e.,the left ventricle produced as much work fromany given end-diastolic pressure (V.F.C.LV)during vagal stimulation as without it (fig.10, left). Mean aortic pressure ranged from58 to 165 mm. Hg when the control valueswere obtained, from 54 to 158 mm. Hg whilethe vagus was stimulated. The relation be-tween mean left atrial pressure and strokework (V.F.CLA) was shifted to the right(fig. 10, right) as observed in the previousexperiments (fig. 8).

Effect of Vagal Stimulation on Atrial ContractilityIn view of the above, it appeared worth

while to make a direct and detailed re-



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11.16 SARNOFF, BROCKMAN, GILMORE, LINDEN, MITCHELL

Table 1Changes in Cardiac Cycle Due to Stellate Ganglion Stimulation*

ControlStellate

stimulationPer centchange

Duration of atrial systole, msec.tDuration of ventricular systole, msec.tDuration of ventricular diastole, msec.§A — TJ interval, msec.||Increment in Ii.V.E.D. (cm. H»O), produced by

atrial sy.stoleDuration of isometric contraction, msec.**Relaxation time, msec.t t

120270250495

2.010593

87207313365

6.55575

— 28— 23+ 25— 26

+225— 48- 19

*Heart rate constant at 116/niin; (total cycle time = 520 msec); analysis of tracingshown in figure 6 (lower)

tFrom beginning of increase in atrial pressure until beginning of rise in ventricular pressure.{From beginning of rise in ventricular pressure until aortic incisura.§ From beginning of aortic incisura to the rise in ventricular pressure.|]A-B interval: from beginning of rise in atrial pressure to lowest point of ventricular

rli.istolie pressure ("relaxation Tjoint")-"From beginning of rise in ventricular pressure until beginning of rise in aortic pressure.ttFrom aortic incisura until lowest point of ventricular diastolic pressure.

examination17'18 of the extent to which vagalstimulation can alter atrial contractility. Thiswas done in hearts with and without heartblock. Figure 11 (upper) shows the changesinduced in the amplitude of the atrial pulseand the consequent changes in the contourof left ventricular diastolic pressure before,during and after distal vagal nerve stimula-tion. During stimulation, in late diastole,atrial pressure was higher and left ventricu-lar pressure lower. In figure 11 (middle) theleft panel (control) shows the individual atrialcontractions that occur between each ventricu-lar beat, the effect thereof on left ventriculardiastolic pressure and the increased myo-eardial segment length that is induced. Theright panel, a tracing taken during vagalstimulation, and with the atrium still beingpaced, shows the suppression of the atriala wave and the effect thereof on left ven-tricular diastolic pressure and segment lengthchanges. This response was also observed inthe dog without heart block and in which theheart rate was either maintained constant orallowed to decrease during vagal stimulation(fig. 11, lower). Vagal stimulation not onlyproduced bradycardia in the nnpaced heart;the atrial quieting during mild vagal stimu-lation also diminished the end-diastolic aug-

mentation of both the ventricular pressureand myocardial segment length.

DiscussionThe central nervous system has available

direct efferent pathways to the heart overwhich it can, at any given heart rate, sys-tematically regulate the ventricle's contrac-tion by either of 2 means. First, it can con-trol the atrial contraction over a wide range,augmenting the atrial contraction by sympa-thetic stimulation (fig. 6) and diminishingit with vagal stimulation (fig. 11). The ven-tricle is thereby presented with more orless blood at the end of diastole, its end-diastolic pressure and fiber length are modi-fied, and a consequent alteration is made inthe vigor of its contraction. This can transph'ein the absence of any change in the contrac-tile characteristics of the ventricle, i.e., withno change in V.F.CLV (fig. 10, left).

Secondly, the central nervous system, byway of cardiac sympathetic efferents, candirectly cause the ventricle to contract moreor less forcefully from whatever end-diastolicpressure and fiber length has been obtained.The magnitude of the observed changes isnoteworthy.

During sympathetic stimulation, the aug-Circulation Research, Volume VIII, September 1900



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GRADED VAGAL STIMULATION

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1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

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Figure 8Curves showing relation between mean left atrialpressure and left ventricular stroke work '10111stimulating the distal cut end of the vagus nerve(5.2 volts 5 msec.) at frequencies of 0, 2.0, 3.5 and6.0/sec.

mented ventricular contraction from anygiven end-diastolic pressure or fiber lengthresults in more complete systolic emptying,an observation in support of the early ex-periments of von Anrep,19 and of Patterson,20

the clearly stated position of Starling,21 theexperiments of Cotten and Mating,22 the seriesof studies by Eushmer and his colleagues,23"27

and the recent oncometer experiments ofKe'.so and Randall,28 as well as earlier experi-ments from the same laboratory.29'30

A more precise appreciation of the neteffect of sympathetic impulses on the heartbeating at any given rate is best appreciatedby an analysis of the tracings shown in figure6 (lower), the values in table 1 taken inconjunction with the experiments shown infigures 1, 2, 3, 4, and 5 and the data onventricular pressure-length curves shown else-where.5- 13 The more forceful ventricular con-traction resulting from sympathetic stimula-tion produces more complete systolic empty-ing and, consequently, a lower diastolic im-


a~ i o I ff E

Figure 9Symbols as in previous figures. Chart speed = 0.5mm./sec. Bilateral cervical vagotomy, stellates in-tact. Stimulation of distal cut end of right vagusnerve at 1.4 volts, 17/sec. and 5 msec, during 1-minute periods indicated by marker at A, B, andC. Stimulus begun again at D maintained throughend of D'; 8 mg. atropine sulfate given intra-venously at arroio between D and D'. Stimulusapplied again for 1 minute at E. Carotid sinuspressure not controlled, stellate ganglia intact.

pedance to ventricular inflow,Sl i.e., the morecomplete systolic emptying places the ven-tricle on a more sensitive portion of its ven-tricular pressure-length and pressure-volumecurve. Finally, it is in this circumstance, inwhich a smaller increase in pressure producesa larger fiber length increase, that the morevigorous atrial systole propels blood and ele-vates ventricular end-diastolic pressure.

It remains to consider the altered timingof events which accompanies these phenom-ena. Reference is made to table 1, in whichit can be seen that sympathetic stimulationsubstantial!}' reduced the total period of theheart's active state (from the beginning ofatrial systole to the "relaxation" point, i.e.,lowest pressure in diastole). The shorteningof the duration of each of the components ofthe heart's activity during sympathetic stim-ulation resulted in a 25 per cent longer ven-tricular diastole. The cardiac sympatheticnerves may thus be construed, in an impor-tant sense, as the guardian of diastole, a viewimplicit in the experiments of Wiggers m1927.32

The shorter the diastotic interval, the moreimportant it is for blood to enter the ven-



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Figure 10Left: 'Relation of left ventricular end diastolicpressure and left ventricular stroke work before(solid circles) and during (open circles) stimula-tion of the distal cut end of the left vagus nerve(6.7 volts, 15/sec). Heart rate held constant at187/min. by left atrial pacing. Bilateral vagotomy.Right: Relation of mean left atrial pressure andleft ventricular stroke work. Data is from sameexperiment and taken in the same run as thatshown in left panel. Dog weight = 19.0 Kg.

tricle at an increased rate. Thus, not onlydoes the contribution of atrial systole becomemost important at high heart rates, but itmay, in addition, be expected that the extentto which the atrial systole becomes shorter andmore forceful will determine the extent ofventricular filling under these circumstances.

There can be little doubt that efferentsympathetic cardiac nerve stimulation pro-duces an increase in the myocardial levelsof catechol amines. Pertinent to this view arethe observations of Outschoorn and Vogt,33

who found marked elevations of norepineph-rine iu coronary sinus blood during stellateganglion stimulation, as well as similar ob-servations in this laboratory.34 Our experi-ments (figs. IB, 4 and 6), iu which each ofthe consequences of stellate ganglion stimula-tion could be mimicked with norepinephrinegiven intravenously, are in accord with thisposition.

The alteration of the mechanical events ofthe cardiac cycle consequent to sympatheticstimulation correlates well with observed elec-trical phenomena, such as the increased con-duction velocity observed in the atrium, at

the atrioventricular node and in the ven-tricle.35'36 There is also a shortening of thetotal refractory period and, with adminis-tered catechol amines, an increased excita-bility.35 With this in view, it is desirable toevaluate what contribution the altered elec-trical phenomena might be making to thehemodynamic phenomena observed. It is ob-vious that if the sequence of ventricular con-traction is so prolonged that each fiber orgroup of'fibers is contracting while the othersare relaxed, little or no external work will beproduced. Conversely, if each of these fiberscontract with the same vigor but simulta-neously, the external work and power pro-duced will be at its maximum. On this basis,the extent to which the contraction is asynchronous one will determine the externalwork and power produced when each of themyocardial fibers is contracting from anygiven initial length and with the same vigor.The suggestion that such changes in syn-chronicity are of sufficient importance to beoperative was postulated and later apparentlyabandoned by Wiggers.37 Recently, data havebeen obtained in which the synchronicity ofthe ventricle's contraction was varied bychanging the site of pacing and withoutchanging the norepinephrine background.When the ventricular contraction was made tobe less synchronous, as evidenced by the lowerrate of development of pressure, less exter-nal stroke work and power were producedfrom any given ventricular end-diastolic pres-sure. This mechanism has also been invokedto explain the changes under hypothermia.38

It would thus appear unwise to attribute theincreased ventricular work and power pro-duced under sympathetic stimulation solelyto a direct effect of the catechol amines onthe myoeardial fibers without making allow-ance for the obvious increase in the synchro-nicity with which they contract. This aspectof ventricular performance is construed to bea matter of importance.

The net effect of efferent vagal impulses,at least with the intensities of vagal stimula-tion used in these experiments, was to dimin-ish the vigor of atrial contraction; they did




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not directly modify ventricular contractility.These observations are in accord with theapparent lack of vagal fiber distribution tothe ventricular myocardium.15'1(i Schreiner,Berglund, Borst and Monroe39 did not findevidence that efferent vagal stimulation al-tered the relationship between mean atrialpressure and stroke work and concluded thatsuch stimulation does not modify the con-tractility of the ventricle, a conclusion re-affirmed by our present experiments. It isnot entirely clear, however, why these authorsdid not obtain a higher mean left atrial pres-sure for any given level of left ventricularstroke work, as shown in figures 8 and 10.A partial explanation appears to be that sincesome of their experiments were performedin dogs with complete heart block and withan atrial rate much higher than the ventricu-lar rate, the depression of atrial contractilityduring vagal stimulation was perhaps lesslikely to diminish ventricular filling. This isespecially true when, as in some dogs withheart block, the mitral valve apparently doesnot close after each of the several a waves thatoccur during diastole. Other experiments intheir study were done with ventricular pacingwhich, by itself, can eliminate or diminishthe contribution of atrial systole to ventricu-lar filling prior to vagal stimulation.

The above experiments on vagal stimulationare not consonant with the experiments ofWang, Blumenthal and Wang,40 or with thesuggestion of Peterson41 that vagal fibers pro-duce a negative inotropic effect on the ven-tricle. They do support the recent observa-tions of Carlsten, Folkow and Hamberger inman,42 suggesting that vagal stimulation doesnot influence the ventricular myocardium, andare in essential agreement with the elegantexperiments of Gesell in 1.91.6,17 who attrib-uted the changes in arterial pressure duringvagal stimulation to the diminished contribu-tion of the atrium to ventricular filling.

Nervous Control of the Frank-Starling Mechanism:Principles of the Innervated Heart

As a formal means of broadening the basicFrank-Starling relationship and of integrat-ing it with the activity of the central nervous


o250

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AP,

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\r

kFigure 11

Upper: Surgically induced heart block and bilat-eral cervical vagotomy. LA = left atrial and LVD= left ventricular diastolic pressure in cm.RgO;AP = aortic pressure in mm.Hg. Stimulation ofdistal cut end, of left vagus nerve during signalat bottom. Chart speed = 10 mm./sec. Middle:Surgically induced heart block and bilateral cer-vical vagotomy. Atrium paced at 164/min. L.A. =left atrial, Ao = aortic and L.V.-D. = left ven-tricular diastolic pressure. M.S.L. = myocarrdialsegment length. + = elongation, - = shortening;full scale deflection = segment length change ofS mm. Chart speed = 50 mm./sec. Control tracingat left. Tracing at right taken 1.6 minutes laterduring stimulation of distal act end of left vagusnerve with 7 volts, 15/sec; atrium still beingpaced at 164/min. Lower: Symbols as in middlepanel. Sino-atrial node crushed. Chart speed =100 mm./sec. Bilateral cervical vagotomy. Controltracing at left; arroirs in third beat indicate atriala loawe and the consequent increase in left ventric-ular end-diastolic pressure and myocardial seg-ment length. Tracing at right taken during stimu-lation of distal cut end of left vagus nerve witli3 volts 10/sec. and 5 msec, which reduced heartrate to 57/mi.n.



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system in relation to acutely induced changes,2 concise statements now appear to be appro-priate for the heart operating at any givenrate and in the absence of abnormal conditionssuch as hypoxia and acidosis: 1. If the effec-tive catecliol amine stimulus remains constant,the contraction of the ventricle varies direc-tionally with its end-diastolic pressure andfiber length; if the end-diastolic pressure andfiber length remain constant, the contractionof the ventricle varies directionally with theeffective catechol amine stimulus. 2. The cen-tral nervous system has direct neural connec-tions to the heart by means of ivhich it canvary the left ventricular end-diastolic pres-sure and fiber length ivhile keeping the effec-tive catechol amine stimulus constant (atrialsystole), means by ivhich it can vary the effec-tive catechol amine stimulus, or both.

These general principles are best regardedas describing mechanisms which initiate, andare important for sustaining, changes in theperformance of the heart. Their operationcan better be predicted, however, if they areappropriately interrelated with other knownmechanisms of intrinsic myocardial regula-tion. For example, in the experiments de-scribed above, when the stellate ganglion wasstimulated, there ensued an elevation ofaortic pressure (figs. 1 and 2) which, of itself,is known to produce an increase in ventricularcontractility by homeometric autoregulation.43

It cannot be reasoned that the rise in aorticpressure was the primary cause of this in-creased contractility, since it did not precedebut followed the onset of stellate stimulation.Further, experiments are available in whichit was demonstrated that, with aortic pres-sure, heart rate and stroke volume held con-staut, left Arentrieular end-diastolic pressurefell substantially during stellate stimulation.34

It should be recognized, however, that, sincenorepinephrine improves the ventricle's ca-pacity for utilizing its intrinsic mechanisms,43

some relationship of re-enforcement betweenthe 2 mechanisms undoubtedly exists, i.e.,when sympathetic stimulation increases theforce of contraction as the result of the localelaboration of norepinephrine, the increase in

activity thereby produced contributes to theincreased myocardial contractility observed inthe new equilibrium state and, further, theincreased norepinephrine facilitates this proc-ess. Similar considerations apply to changesin rate.

In an address21 which seems to be lesswidely known than his other work, Starlingsaid: ''No understanding of the circulatoryreactions of the body is possible unless westart first with the fundamental properties ofthe heart muscle itself, and then find out howthese are modified, protected and controlledunder the influence of the mechanisms—nerv-ous, chemical and mechanical—which undernormal conditions play upon the heart."These general guidelines still seem to havemerit as the basis for continuing investigation.

SummaryAt constant heart rates, efferent stimulation

of the vagus nerve and of the left stellateganglion revealed the following: 1. Vagalstimulation exerts a profound depressant ef-fect on the strength of the atrial contractionand can thereby influence ventricular fillingand ventricular stroke work; it elevates meanatrial pressure at any given level of ven-tricular stroke work. This occurs under ex-perimental conditions wherein the vagal stim-ulation used does not produce an alterationin the performance characteristics of the ven-tricle. The effects of vagal stimulation areblocked by atropine. 2. Stellate ganglion stim-ulation or norepinephrine infusion augmentsthe strength of atrial contraction and thusthe atrial contribution to ventricular filling.The augmented atrial contraction takes placein a shorter period of time. 3. Stellateganglion stimulation or norepinephrine infu-sion increases the external stroke work andpower produced by the ventricle from anygiven mean atrial pressure and from anygiven end-diastolic pressure or fiber length.4. There is a family of curves representingthe relation between end-diastolic fiber lengthand stroke work, as well as a family of curvesrepresenting the relation between mean atrialor end-diastolic pressure and stroke work.

Circulation Research, Volume Vlll, September 196Q



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5. When taken together with the well-knownsympathetic and parasympathetic effects onheart rate, the above data are believed tocomprise a reasonably comprehensive descrip-tion of the means available to the centralnervous system for directly inducing acutechanges in the activity of the heart.

AcknowledgmentThe authors gratefully acknowledge the valuable

assistance of Mr. Eugene Purcell in the preparationand execution of these experiments.

Summario in InterlinguaA fixe frequenting cardiac, le stimulation efferento

del norvo vagc e del ganglion stellate sinistre revolavale soquento factos: (1) Stimulation vagal exerce unprofunde effecto doprossori super le fortia del con-traction atrial e pote assi influential le replenationvontricular e le travalio de pulso ventricular. Uloaugments, le tension atrial modie a omne date nivellodo travalio de pulso ventricular. Tsto occurre subconditiones experimental in quo le stimulation vagalusate non produce un alteration in le cliaracteristicasofiicacia del vontriculo. Le effectos del stimulationvagal os blocate per atropina. (2) Le stimulation delganglion stellate o lo infusion de norepinephrina aug-menta le fortia del contraction atrial e assi le contri-bution atrial al replenation ventricular. Le augmen-tate contraction iitrial occurre in un plus curte inter-vallo de temporc. (3) Le stimulation del ganglionstellate o lo infusion do norepinephrina augmenta letravalio e le potentia del pulso externe que es pro-ducite per le ventriculo ab omne date tension atrialmodie o ab omne date tension termino-diastolic olongor de libra. (4) II existe un familia de curvasque rcprosenta le relation inter le termino-diastoliclongor de fibra e le travalio per pulso e etiam unfamilia do curvas que representa le relation inter letension atrial medic o le tension termino-diastolic ele travalio per pulso. (5) Es opinate que iste datos—in combination con le bon-cognoscite effoctos sympa-thic e parasympathic super le frequentia cardiac—constituc un sensibilemente complete description delmedios disponibile al systema nervosc central pro in-ducer directomente alterationes acnte in le activitatedel corde.

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S. J. SARNOFF, S. K. BROCKMAN, J. P. GILMORE, R. J. LINDEN and J. H. MITCHELLStimulation on Atrial and Ventricular Dynamics

Regulation of Ventricular Contraction: Influence of Cardiac Sympathetic and Vagal Nerve

Print ISSN: 0009-7330. Online ISSN: 1524-4571 Copyright © 1960 American Heart Association, Inc. All rights reserved.is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation Research

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