512

Effects of Sodium Pentobarbital Anesthesia on LeftVentricular Function and Distribution of CardiacOutput in Dogs, with Particular Reference to the

Mechanism for TachycardiaW. THOMAS MANDERS AND STEPHEN F. VATNER, M.D.

SUMMARY Sodium pentobarbital (PB), 30 mg/kg, iv, wasadministered to 30 conscious dogs instrumented for measurement ofcardiac output and regional blood flow distribution, left ventricular(LV) diameter, LV pressure, dP/dt, and dD/dt, i.e., velocity ofmyocardial fiber shortening. Ventilation was controlled duringanesthesia to maintain arterial blood gases at control values forconscious dogs. The anesthetic produced an initial transient, periph-eral vasodilation but the steady state effects 15-30 minutes later werecharacterized by slight reductions in mesenteric flow and cardiacoutput and increases in mesenteric and systemic resistances, whereasiliac and renal resistances were not significantly different fromcontrol. When heart rate rose, PB increased end-systolic diameter

and decreased coronary resistance, LV end-diastolic diameter,dP/dt/P (42%), and shortening velocity (36%). When heart rate wascontrolled, PB still increased end-systolic diameter and decreasedshortening velocity and dP/dt/P, as occurred during spontaneousrhythm, but end-diastolic diameter rose instead of falling andcoronary resistance did not change. After recovery from bilateralcervical section of both carotid sinus and aortic nerves, PB failed toelicit tachycardia. Thus, PB affects systemic and regional hemody-namics only slightly, but depresses the myocardium markedly. Thetachycardia associated with PB anesthesia in intact, trained dogsappears not to be only vagolytic, as previously thought, but ispredominantly mediated through the arterial baroreceptor reflex.

SODIUM PENTOBARBITAL remains one of the mostwidely used anesthetics for experimental cardiovascularstudies. However, the effects of the anesthetic agent aregenerally disregarded in the interpretation of experimentaldata from studies in which PB is employed. This is due inpart to the fact that the effects of this anesthetic are notcompletely known. In addition, results from previous stud-ies, which indicated that the anesthetic has little effect oncardiac output and arterial pressure,1"3 have previously beenused as justification for disregarding its effects. The primarygoal of this study was to provide a comprehensive picture ofthe effects of sodium pentobarbital (PB) on left ventricular(LV) function, coronary dynamics, distribution of regionalblood flow, and regional vascular resistance. A secondarygoal was to examine the mechanism for the PB-inducedtachycardia, which is currently thought to be due to avagolytic action.4- 5

Methods

Thirty normal mongrel dogs, weighing 20-30 kg, wereanesthetized with intravenous (iv) PB, 30 mg/kg. Through aleft thoracotomy in the 5th intercostal space, a Doppler

From the Departments of Medicine, Harvard Medical School and PeterBent Brigham Hospital, the Department of Cardiology, Children's HospitalMedical Center, Boston, Massachusetts, and the New England RegionalPrimate Research Center, Southboro, Massachusetts.

Supported in part by U.S. Public Health Services Grants HL 15416.10436, and 17459 and by grant NSG-2136 from the National Aeronautics andSpace Administration.

Dr. Vatner is an Established Investigator, American Heart Association.Presented in part at the Fall Meeting of the American Physiological

Society, San Francisco. California, October 6, 1975.Address for reprints: Stephen F. Vatner, M.D., New England Regional

Primate Research Center, 1 Pine Hill Drive, Southboro, Massachusetts01772.

Received January 5, 1976; accepted for publication May 26, 1976.

ultrasonic flow transducer was implanted around the leftcircumflex coronary artery, stimulator electrodes weresutured to the left atrium, a miniature pressure transducer(Konigsberg P22) was implanted through a stab wound inthe apex of the left ventricle, and ultrasonic dimensiontransducers were implanted on opposing anterior and poste-rior endocardial surfaces of the left ventricle (14 dogs). Inthree of these 14 dogs and in six additional dogs, anelectromagnetic flow transducer (Zepeda) was implantedaround the ascending aorta. Through a midline laparotomy,Doppler ultrasonic transducers (10 dogs) or electromagnetictransducers (five dogs) were placed around the mesenteric,renal, and iliac arteries. In all dogs, a heparin-filled Tygoncatheter was chronically implanted in the thoracic aortathrough a lumbar branch. In an additional seven dogs, underPB anesthesia and through a midline cervical incision, thecarotid sinus nerves and aortic nerves were sectionedbilaterally, according to the technique described by Edis andShepherd.6 Completeness of denervation was confirmed sev-eral days after the operation by observing absence of a reflexheart rate response to bolus intravenous injections ofnitroglycerin (nitroglycerin U.S.P., Lilly, 48 /ig/kg) andmethoxamine (Vasoxyl, Burroughs Wellcome, 48 Mg/kg).Normally these drugs induced a tachycardia of 97 ± 5beats/min and a bradycardia of 46 ± 4 beats/min, respec-tively. After recovery from the operation electromagneticflow probes were implanted on the ascending aorta at asubsequent operation using PB anesthesia, 30 mg/kg, iv.

Arterial and left atrial pressures were measured withStatham P23Db strain gauge manometers. LV pressure wasmeasured with the implanted miniature gauges; diastolicpressure was calibrated against the measurement obtainedwith the left atrial catheter and Statham strain gauge. Animproved ultrasonic transit time dimension gauge was used

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PENTOBARBITAL AND CARDIOVASCULAR FUNCTION/Manders and Vainer 513

to measure LV diameter; the details of this technique havebeen published previously.7

Regional blood flow was measured with a Dopplerultrasonic flowmeter (10 dogs), which has been described indetail previously and has an accurate electronic zero refer-ence.*- * In 11 dogs, an electromagnetic flowmeter (Benton)was used to measure blood flow. In these dogs, zero wasdetermined by inflation of an occluding cuff implanted distalto the probe; zero was assumed to occur during late diastolein measurement of aortic blood flow.

The experiments were conducted 2 weeks to 2 monthsafter recovery from operation, when the dogs appearedvigorous and healthy. Continuous recordings of LV pres-sure, diameters, coronary blood flow, cardiac output,regional blood flow, arterial pressure and heart rate weretaken with the dogs lying in the right lateral position for theentire experiment, i.e., while conscious, during induction ofanesthesia (PB, 30 mg/kg, iv) and continuously for thefollowing 30 minutes. On induction of anesthesia with PBarterial Po2 fell from 80 ± 3 to 51 ± 4 mm Hg. Accordingly,the dogs were intubated after 2 V2 minutes and ventilationwas controlled to maintain arterial blood gases at controllevels for conscious dogs; pH remained at 7.42 and Pco, at30 ± 1 mm Hg. Arterial blood gases were measured on aBMS 3 MK 2 blood microsystem (Radiometer) and pH wasmeasured on a PHM 71 MK 2 acid-base Analyzer (Radiom-eter). In the dogs in which LV and coronary dynamics werestudied, heart rate was increased to 150 beats/min duringcontrol measurements and returned to this value by electri-cal stimulation for 1-minute intervals for each data pointafter anesthesia. To test the integrity of the parasympatheticnervous system, atropine (0.1 mg/kg) was administeredintravenously to conscious dogs both while intact and afterrecovery from denervation and also to these dogs in theanesthetized state. To determine whether the tachycardiainduced by the anesthetic was due to a vagolytic action ordue to a baroreceptor mechanism activated in response to areduction in systolic arterial pressure, methoxamine (10-20jig/kg per min) was administered intravenously to fiveanesthetized, intact dogs to return systolic arterial pressureto the preanesthetic control level.

The data were recorded on a Brush (Clevite Brush) Mark200 multichannel tape recorder and played back on adirect-writing oscillograph. A cardiotachometer, triggeredby a signal from the pressure pulse, provided instantaneousand continuous records of heart rate. Electronic resistor-capacitor filters with 2-second time constants were used toderive mean arterial blood pressure and mean regional andcoronary blood flows, and an 8-second time constant wasused to derive mean aortic flow. Mean regional vascularresistances were calculated as quotients of mean arterialpressure and regional blood flow, respectively.

Continuous records of dP/dt and dD/dt were derivedfrom LV pressure and diameter signals using TeledynePhilbrick operational amplifiers connected as differentiatorsand having frequency responses of 700 and 140 Hz, respec-tively. However, when used in conjunction with the multi-channel oscillographic recorder, frequency response was 60Hz for both differentiators. A triangular wave signal with aknown slope was substituted for pressure and diameter

signals to calibrate directly the dP/dt and dD/dt signals.The effects of PB on myocardial force-velocity relationships,dP/dt, and dP/dt /P were assessed as described previ-ously. 10-la Results were compared with the preanesthetic con-trol by use of the paired r-test, and responses of intact anddenervated dogs were compared by the unpaired /-test."

Results

EFFECTS OF PB (INTACT DOGS)

Systemic Effects (n s= 9)

Mean arterial pressure fell initially from a control of 91 ±2 to 85 ± 3 mm Hg at 2 V2 minutes, returned to control at7 xh to 10 minutes, and then fell slightly below control at15-25 minutes. Systolic arterial pressure remained signifi-cantly depressed for the entire period of measurement (Fig.1). Cardiac output rose from 2.20 ± 0.16 to 2.73 ± 0.24liters/min, at 2 lh minutes then gradually fell, but wassignificantly reduced below the control only at 25-30minutes. Conversely, total peripheral resistance fell signifi-cantly below control at 2 V2 minutes (from 0.038 ± 0.003 to

MEANARTERIALPRESSURE

CmmHg)

SYSTOLCARTERIALPRESSUREUnnhtg)

CARDIACOUTPUT 12-(L/mtn)

TOTALPERIPHERALRESISTANCE

.030

ieo-1

-4P-

INTACTDENB*VATEDp<OJD1 from controlp<(X05 from control

—*= •! '

HEARTRATE

t p<0.01 d»n«rvat»d m p o r t M vs. intactp<0JJ5 darwvatad resports* vs. Intact

4)MINUTES

FIGURE 1 The effects of pentobarbilal, 30 mg/kg, iv, on meanarterial pressure, systolic arterial pressure, cardiac output, totalperipheral resistance, and heart rate of intact dogs (n - 9, solidlines) and denervated dogs (n - 7, dashed lines). Asterisks (*)denote changes that are significantly different from control. Dag-gers (t) represent responses ofdenervated dogs that are significantlydifferent from those of intact dogs. The vertical bars represent ±SEM. Intact dogs were able to maintain arterial pressure belter thandenervated dogs. In both cases systolic arterial pressure fellsignificantly. The heart rate response in the denervated dogs wasqualitatively different from that of the intact, since heart rale failedto rise in the denervaied dogs.

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514 CIRCULATION RESEARCH VOL. 39, No. 4, OCTOBER 1976

0.031 ± 0.002 mm Hg/ml per min, P < 0.05) rose abovecontrol at 15 minutes, and remained significantly elevated.Stroke volume fell from 33 ± 3.0 to 18 ± 2.8 ml, P < 0.01,and remained significantly depressed. Heart rate rose from80 ± 3 to 160 ± 4 beats/min at 2V% minutes, then fellgradually to 109 ± 5 beats/min at 30 minutes.

Left Ventricular Dynamics (n = 14)

Spontaneous Rhythm. Peak systolic LV pressure fellfrom 120 ± 3 to 106 ± 4 mm Hg (P < 0.01) at 2 Vi minutesand remained depressed. LV end-diastolic pressure rosefrom a control of 6 ± 1 to 8 ± 1 mm Hg (P < 0.05) at 2 Viminutes and remained significantly above control only until10 minutes. LV end-diastolic diameter fell from a controlvalue of 36.3 ± 1.3 to 35.4 ± 1.7 mm (P < 0.01), andremained depressed significantly. In contrast, LV end-sys-tolic diameter increased from a control of 24.7 ± 1.8 to 27.3± 1.8 mm at 2 Vi minutes, then gradually returned towardcontrol but remained significantly elevated (Fig. 2). Thus,stroke shortening fell substantially and remained signifi-cantly reduced. Peak shortening velocity fell from 78 ± 3 to50 ± 3 mm/sec, and remained significantly decreased. PeakdP/dt fell from a control of 3,350 ± 90 to 2,020 ± 150 mmHg/sec, and remained depressed significantly. LV dP/dt/Pfell from a control of 62 ± 2 to 41 ± 3 sec"1, and remaineddepressed.

Heart Rate Controlled (150 beats/min). When heart ratewas controlled peak systolic LV pressure fell, while LVend-diastolic pressure rose significantly from 3 ± 1 to 7 ± 1mm Hg at lYi minutes and remained significantly elevated.LV end-diastolic diameter, instead of falling as duringspontaneous rhythm, rose slightly but not significantly from31.4 ± 2.2 to 32.8 ± 2.3 mm (Fig. 3). LV end-systolicdiameter still rose significantly. The responses for peakdP/dt, dP/dt/P, and velocity were all essentially the same aswere observed during spontaneous rhythm (Fig. 3); allvalues fell and remained significantly depressed; P < 0.01.

Coro.nary Blood Flow and Resistance (n = 13)

Spontaneous Rhythm. Mean coronary blood flow rosefrom 44 ± 4 to 65 ± 7 ml/min (P < 0.01) at IVi minutes

7.5 min 30 min

LVDIAMETER

(mm)

FIGURE 2 The effects of pentobarbital, 30 mg/kg, iv, on leftventricular {L V) diameter, velocity, pressure, dP/dt, and heart ratein a conscious dog. The effects during induction, at 7 J minutes and30 minutes later, are shown. This figure demonstrates the potentmyocardial depressant effects of pentobarbital anesthesia.

OOHTflSC•*-*>

FIGURE 3 The effects of pentobarbital, 30 mg/kg, iv, on leftventricular (Z. V) pressure, dP/dt/P and shortening velocity, end-diastolic pressure, and diameters. Responses during spontaneousrhythm (MS/?) (n - 14, circles, solid line) are shown along withresponses with heart rate controlled (n = 6, triangles, broken lines).Asterisks (•) denote responses significantly different from control.Vertical bars represent SEM. There was significant depression of thecontractile state as shown by the marked reductions ofdP/dt/P andshortening velocity both during spontaneous rhythm and with heartrate controlled. End-diastolic diameter actually rose rather thanfalling when heart rate was controlled.

and gradually fell but remained significantly above control(Fig. 4). At 2 Vi minutes, late diastolic coronary resistancefell from 1.63 ± 0.09 to 0.92 ± 0.06 mm Hg/ml per min (P< 0.01) and remained significantly depressed.

Heart Rate Controlled. In contrast to results obtainedduring spontaneous rhythm, when heart rate was controlled,coronary flow decreased instead of rising and remainedbelow control until 15 minutes. Late diastolic coronaryresistance, in contrast to results for spontaneous rhythm, didnot fall, but remained essentially constant (Fig. 4). A slightreduction in coronary resistance may have occurred withinduction, but heart rate was not controlled prior to 7 V%minutes.

Regional Flows and Resistances (n - 15) (Fig. 5)

Initially mesenteric flow rose slightly but not signifi-cantly, then fell and remained significantly below controlafter 10 minutes. Conversely mesenteric resistance rosesignificantly after 10 minutes. Changes in renal blood flowand resistance were not significant. Iliac flow rose signifi-cantly at 2V4 minutes (P < 0.01) and then remainedsignificantly above the control value only through 10minutes. Conversely, initially iliac resistance fell sharply andremained significantly below control only until 10 minutes.

EFFECTS OF PB AFTER SECTION OF ARTERIALBARORECEPTOR NERVES (n - 7)

After the dogs had recovered from section of arterialbaroreceptor nerves, responses to PB were significantlydifferent for arterial pressure, heart rate, and cardiac outputbut not for total peripheral resistance (Fig. 1). Heart raterose initially in six of seven dogs studied, but after artificialventilation had restored arterial Po, to control values, heart

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PENTOBARBITAL AND CARDIOVASCULAR FUNCTION/Manders and Vainer 515

80r

MEAN CORONARYBLOOD FLOW

Onl/min)

DBBNkTED

LATE CKASTOLCCORONARY RESISTANCE

l mirf")

• P<01 from control•• p<.OS from control

• NSR'PACED

4 F

I 25CONTWX

75 10 15 20

MINUTES

25 30

FIGURE 4 The effects of pentobarbilal, 30 mg/kg, iv, on meancoronary blood flow (top) and late diastolic coronary resistance(bottom) in dogs with spontaneous rhythm (NSR) (n = 13, solidlines) and dogs with heart rate controlled (n - 9, dashed lines).Asterisks (*) denote changes significantly different from the controllevel in either slate.

rate was actually slightly but not significantly lower than thepreanesthetic control level of 107 ± 11 beats/min. Thisresponse was significantly different for the entire 30-minuteperiod from that found for intact dogs.

STUDIES ON THE MECHANISM OF TACHYCARDIAINDUCED BY PB (FIG. 6)

Atropine (n = 4)

Administration of atropine, 0.1 mg/kg, to conscious dogsafter recovery from denervation increased heart rate from103 ± 6 to 157 ± 2 beats/min. When atropine wasadministered 30 minutes after anesthesia, heart rate rose by

FLOW (rel/raln) RE8STAN

FIGURE 5 The effects of pentobarbiial anesthesia, 30 mg/kg, iv, oncardiac output and mesenteric, renal, and iliac blood flows (n = 15,left panel), and on systemic, mesenteric, renal, and iliac resistances(n - IS, right panel). Asterisks (*) denote changes significantlydifferent from control. The vertical bars represent SEM. Althoughsignificant vasodilation occurred initially with induction, only theslight decreases in cardiac output and mesenteric blood flow andincreases in systemic and mesenteric resistances were significantduring the later stages.

HARTRATE

h

FIGURE 6 The relative effects of anesthesia and atropine on heartrate in denervated dogs (left, n - 4) and intact dogs (right, n = 4).Atropine increased heart rale to the same level in conscious andanesthetized dogs with and without baroreceptors. This also showsthat when systolic arterial pressure was returned to preanesthesiacontrol levels with methoxamine in intact anesthetized dogs, heartrate also then returned to control values.

a similar amount, indicating that release of vagal tone canbe induced in conscious and anesthetized dogs withoutarterial baroreceptor pathways.

Conscious intact dogs responded to atropine by increasingheart rate from 86 ± 6 to 160 ± 4 beats/min, whereas afteranesthesia the heart rate rose from 105 ± 13 to 157 ± 2beats/min.

Methoxamine (n = 5)

When systolic arterial pressure of intact dogs wasreturned to the control level for conscious dogs by infusionof methoxamine (10-20 Mg/kg per min) 15-30 minutes afterPB anesthesia, heart rate returned to the control level for theconscious dogs (Fig. 6).

Discussion

The majority of studies on PB anesthesia have examinedeffects on pressure, heart rate, and cardiac output. Althoughthere is universal agreement that the anesthetic inducestachycardia, reports of its effects on arterial pressure andcardiac output are divergent. For instance, arterial pressurehas been reported to rise after administration of PB14 andalso generally is found to be elevated in studies in which PBis used as an anesthetic. In contrast, mean arterial pressureactually fell slightly as a result of injection of PB in thepresent study. A recent report by Fray et al.15 explains inpart the discrepancy among these results for arterial pres-sure, since it was observed that pressure rose with surgicaltrauma or if the dogs were excited prior to induction ofanesthesia. In contrast, when trained dogs were studiedarterial pressure did not rise after administration of P B , " aresult which is consistent with our findings.

In general, the changes in cardiac output and totalperipheral resistance were not striking. PB induced atransient vasodilation in all beds immediately after adminis-tration. Renal flow and resistance were not significantlychanged from control during the sustained response. Iliacflow and resistance returned to control by 15 minutes andremained there. In contrast, mesenteric flow fell below

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516 CIRCULATION RESEARCH VOL. 39, No. 4, OCTOBER 1976

control for 10-30 minutes, while mesenteric resistance roseat this time.

PB anesthesia elicited its most dramatic effect on cardiacdynamics. Myocardial contractility fell significantly asreflected by 30-40% decreases in dP/dt, dP/dt /P , andshortening velocity. Since the reduction in myocardialcontractility was similar when heart rate varied and LVend-diastolic size fell or when heart rate was controlled andend-diastolic size rose, the decrease in contractility cannotbe attributed to the indirect effect of a decrease in preload.Stroke volume fell significantly with induction of anesthesiaand remained significantly depressed for the entire period ofobservation, as has been reported previously.16"" However,the manner in which ventricular dimensions change toaccount for the reductions in stroke volume has not beenestablished. We found that this marked decrease in strokevolume was associated with a smaller LV end-diastolicdiameter and a larger end-systolic diameter, resulting in adecrease of approximately 25% in stroke shortening. Rush-mer20 and Van Citters et al.21 also found a reduction in LVend-diastolic diameter during anesthesia. This is surprising,since one would expect that a powerful myocardial depres-sant such as PB would increase LV end-diastolic diameter.However, tachycardia decreases LV end-diastolic size22 andthus could have masked the opposing myocardial depressanteffects of the anesthetic on dimensions. This hypothesis wassupported by the studies with heart rate controlled, in whichwe found that LV end-diastolic diameter actually increasedslightly.

The fact that LV end-diastolic diameter fell while LVend-diastolic pressure rose with PB in dogs in spontaneousrhythm suggests that there was a change either in ventricularshape or in diastolic compliance of the ventricle. A recentstudy by Templeton et al.2' also suggested that barbituratesaltered diastolic ventricular compliance and supports thelatter hypothesis.

With induction of anesthesia we found a transient markedincrease in coronary blood flow that was associated withsubstantial tachycardia and initial hypoxia; there was areciprocal reduction in late diastolic coronary resistance.Even after 2 '/2 minutes, when the dogs were ventilated andthe hypoxia had been corrected, coronary resistanceremained reduced. Coronary dilation following PB anes-thesia was reported initially by Essex et al.24 for one dog,and subsequently by Ericsson" for dogs and by Forsyth andHoffbrand28 for monkeys. However, previous studies did nottake into account changes in cardiac function, which wouldaffect myocardial oxygen consumption the primary determi-nant of coronary flow and resistance. In the present studythe effects of tachycardia, which would in itself increasecoronary flow and decrease coronary resistance,2' wereeliminated by studying dogs with heart rate controlled. Inthese experiments, no significant change in coronary flow orcalculated resistance was observed 7'/2-30 minutes afteradministration of PB. However, if under these circum-stances myocardial oxygen consumption fell, this could beinterpreted to mean that coronary vessels actually dilated.

To determine what role the arterial baroreceptor reflexesplay in the maintenance of cardiovascular dynamics, seven

dogs were studied after recovery from section of carotidsinus and aortic nerves in the neck. As expected, indenervated dogs arterial pressure fell by a significantlygreater amount during PB anesthesia.

The most surprising effect of denervation was the lack oftachycardia after PB anesthesia. It generally has beenthought that the tachycardia that occurs during PB anes-thesia is due to a vagolytic action of the anesthetic.4-' If thiswere the case, then heart rate should have risen andremained elevated in the denervated dogs during anesthesiabecause the vagi were intact. Since heart rate did not remainelevated during PB anesthesia in denervated dogs, themechanism for the tachycardia appeared to be mediated byarterial baroreceptor reflexes rather than by a vagolyticeffect of PB. To test this hypothesis, we gave atropine (0.1mg/kg) to conscious and anesthetized denervated dogs andfound a substantial increase in heart rate in both cases,indicating that the vagi were not "turned off." Since meanarterial pressure was not significantly different from controlin intact dogs and systolic arterial pressure was significantlydepressed, it appeared that arterial baroreceptor reflexeswere responding to the decreased systolic arterial pressure,or pulse pressure. To return systolic arterial pressure tocontrol levels methoxamine (10-20 fig/kg per min) wasinfused intravenously. When systolic arterial pressurereturned to control levels, heart rate fell to the control value.These experiments further support the hypothesis that thesustained tachycardia of PB anesthesia in intact, traineddogs appears to be due not to a vagolytic mechanism butrather to be mediated predominantly by arterial barorecep-tor reflexes. This is not to say that a vagolytic effect will notmanifest itself, when (1) untrained or excited animals arestudied, (2) in the presence of surgical trauma in addition tothe anesthetic, or (3) when larger doses approaching thelethal dose of PB are used. It has been pointed outpreviously that with larger doses of the anesthetic moreimpressive vagolytic actions can be elicited.4-B We chose thedose of 30 mg/kg for this study because it produces asurgical level of anesthesia in the absence of preanestheticmedication.

In conclusion, PB anesthesia elicits relatively minoreffects on cardiac output and regional blood now distribu-tion, while exerting a major myocardial depressant effect.Controlling heart rate prevents the reductions in LV end-diastolic diameter and coronary resistance. Finally, theresponse to PB anesthesia in the absence of arterial barore-ceptor reflexes is different in that mean arterial pressurecannot be maintained as well and the tachycardia induced bythis anesthetic is not observed. The latter finding suggeststhat the mechanism for the sustained tachycardia of PBanesthesia in intact, trained dogs is mediated by thebaroreceptor reflex rather than a vagolytic action.

References

1. Nash CB. Davis F. Woodbury RA: Cardiovascular effects of anestheticdoses of pentobarbital sodium. Am J Physiol 185: 107-112, 1956

2. Sterner SH, Calvin JR: The effects of anesthesia with pcntobarbital onhemodynamics and arterial blood gases in splenectomized dogs. J ThoracCardiovasc Surg 54: 592-598, 1967

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3. Cox RH: Influence of penlobarbilal anesthesia on cardiovascular func-tion in trained dogs. Am J Physiol 223: 651-659, 1972

4. Koppanyi T, Lincgar CR, Dille JM The peripheral actions of barbitu-rates. Science 82: 232, 1935

5. Shafcr GD, Underwood FJ. Gaynor EP The action of Amytal inimpairing vagus cardiac inhibitory effects and of ether in increasing therespiratory rate after its depression by Amytal. Am J Physiol 91:461-466, 1930

6. Edis AJ, Shepherd JT: Selective denervation of aortic arch barorcccptorsand chemorcccptors in dogs J Appl Physiol 30: 294-296, 1971

7. Patrick TA, Vatner SF. Kemper WS, Franklin D- Telemetry of leftventricular diameter and pressure measurements in unrestrained animalsJ Appl Physiol 37: 276-281, 1974

8. Franklin DE, Watson NW, Picrson KE, Van Citters RL: Technique forradio telemetry of blood-flow velocity from unrestrained animals Am JMed Electronics 5: 24-28, 1966

9. Vatner SF, Franklin D, Van Cilters RL Simultaneous comparison andcalibration of the Dopplcr and electromagnetic flowmeters. J ApplPhysiol 29: 907-910, 1970

10. Glick G, Sonncnblick EH, Braunwald E Myocardial force-velocityrelations studied in intact unaneslheuzed man. J Clin Invest 44: 978-988,1965

11 Vatner SF, Higgins CB, Patrick T, Franklin D, Braunwald E Effects ofcardiac depression and of anesthesia on the myocardial action of acardiac glycosidc J Clin Invest 50: 2585-2595, 1971

12. Mason DT, Braunwald E, Covell JW, Sonnenblick EH, Ross J JrAssessment of cardiac contractility: the relation between the rate ofpressure rise and ventricular pressure during isovolumic systole. Circula-tion 44: 47-58, 1971

13. Snedecor GW, Cochran WG: Statistical Methods, Ed 6. Ames, IowaState University Press, 1967, pp 91-98

14. -Barlow G, Knoll DH: Hemodynamic alterations after 30 minutes of

pcntobarbital sodium anesthesia in dogs. Am J Physiol 207: 764-766,1964

15. Fray, CS, Stellar PN, Wilson JM, Burger AC: Arterial pressure andrenin activity during pentobarbital anesthesia Fed Proc 33: 340, 1974

16. Abel FL. Waldhausen JA: Effects of anesthesia and artificial ventilationon caval flow and cardiac output J Appl Physiol 25: 479-484, 1968

17. Ericsson BF- Effect of pentobarbital sodium anesthesia, as judged withaid of radioactive carbonized microspheres, on cardiac output and itsfractional distribution in the dog. Acta Chir Scand 137: 613-620. 1971

18. Olmstead F, Page IH: Hemodynamic changes in dogs caused by sodiumpentobarbital anesthesia Am J Physiol 210: 817-820, 1966

19. Priano LL, Traber DK, Wilson RD: Barbiturate anesthesia: an abnormalphysiologic situation. J Pharmacol Exp Ther 165: 126-135, 1969

20. Rushmer RF: Shrinkage of the heart in anesthetized, thoracotomizeddogs. Circ Res 2: 22-27, 1954

21. Van Citters RL, Franklin DL, Rushmer RF" Left ventricular dynamics indogs during anesthesia with alpha-chloralosc and sodium pcntobarbital.Am J Cardiol 349: 354-358. 1964

22. Higgins CB, Vatner SF, Franklin D, Braunwald E: Extent of regulationof the heart's contractile state in the conscious dog by alteration in thefrequency of contraction. J Clin Invest 52: 1187-1194, 1973

23. Templeton GH, Wildenthal K, Willerson JT, Mitchell JH: Influence ofacute myocardial depression on left ventricular stiffness and its clasticand viscous components. J Clin Invest 56: 278-285, 1975

24. Essex HE, Wcgria RGE, Hcrrick JF, Mann FC The effect of certaindrugs on the coronary blood flow of the trained dog Am Heart J 19:554-565, 1940

25 Forsyth RP, Hoffbrand Bl Redistribution of cardiac output aftersodium pentobarbital anesthesia in the monkey Am J Physiol 218:214-217, 1970

26 Pitt B, Gregg DE: Coronary hemodynamic effects of increasing ventricu-lar rate in the unanesthcuzed dog. Circ Res 22: 753-76-L, 1968

Bioassay in Vivo for Circulating Vasoactive Agentsafter Renal Artery Constriction in Dogs

MOTILAL B. PAMNANI, M.D., PH .D . , GEZA SIMON, M.D., PH.D. , AND

HENRY W. OVERBECK, M.D., P H . D .

S U M M A R Y We used the gracilis muscle vascular bed to bioassayblood from the two renal veins, vena cava, and aorta continuously forthe presence of rasoactive agents before and for 45 minutes afterpartial occlusion of the left renal artery in dogs. Compared tocomparable blood samples from control dogs, left renal venous, venacaral, and aortic blood, but not right renal venous blood, from dogswith renal artery constriction developed vasoconstrictor activity. Thiswas associated with increased renin concentration in plasma from toe

left renal vein and the vena cava and an increase in systemic arterialpressure. In dogs pretreated with indomethacin, blood from the rightrenal vein also snowed vasoconstrictor activity. Pretreatment withantirenin serum abolished all of the differences between control andexperimental dogs. These findings suggest that during acute unilat-eral renal artery constriction the constricted kidney releases reninand the contralateral kidney releases prostaglandins in sufficientquantity to produce systemic vascular effects.

DATA FROM a number of laboratories indicate that theearly development of hypertension following unilateral renalartery constriction is associated with increased renal releaseof renin and systemic generation of angiotensin II.1"3

From the Departments of Physiology and Medicine, Michigan StateUniversity, East Lansing, Michigan.

The present address of Dr. Pamnani and Dr. Overbeck js: Department ofPhysiology, Uniformed Services, University of the Health Sciencel, Be-thesda, Maryland 20014. The present address of Dr. Simon is: Departmentof Medicine, Veterans Administration Hospital, Minneapolis, Minnesota55417.

Supported by U.S. Public Health Service Grant HL-I5I46 from theNational Heart and Lung Institute and by a research grant from theMichigan Heart Association

Removal of the contralateral kidney intensifies the hyper-tension;4 thus the presence of an intact contralateralkidney may attenuate the hypertension, perhaps by releasingantihypertensive substances. In this regard, it has beendemonstrated recently that vasodilator prostaglandins arereleased by both kidneys following acute unilateral renalartery constriction in dogs;1 prostaglandins in renal venous

The work reported in this paper was submitted by Dr. Pamnani in partialfulfillment of the requirements for the degree of Doctor of Philosophy atMichigan State University.

Portions of this work were published in abstract form in Physiologist 16:416, 1973.

Received January 5, 1976; accepted for publication June 8, 1976

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W T Manders and S F Vatnercardiac output in dogs, with particular reference to the mechanism for tachycardia.

Effects of sodium pentobarbital anesthesia on left ventricular function and distribution of

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