Effects of Glucagon on Atrioventricular Conduction and ...circres.ahajournals.org/content/circresaha/24/2/167.full.pdfEffects of Glucagon on Atrioventricular Conduction and Ventricular

Effects of Glucagon on AtrioventricularConduction and VentricularAutomaticity in Dogs

By Charles Steiner, M.D., Andrew L. Wit, Ph.D.,

and Anthony N. Damato, M.D.

ABSTRACTThe effects of glucagon, 50 |iig/kg, on atrioventricular (A-V) conduction

and ventricular automaticity were studied in 14 dogs. Atrial pacing wasused to control the heart rate. The His bundle electrogram was recorded,and the interval from the pacing impulse (P) to the His bundle spike (H),the P-H interval, was used as a measure of A-V conduction. Ventricularautomaticity was estimated in four dogs by recording vagal escape time andidioventricular rate after 60 seconds of continuous vagal stimulation. Inthree dogs with experimentally produced, complete heart block the effectof glucagon on idioventricular rate was estimated. When the heart rate was250/minute, glucagon decreased the P-H interval by 30 ± 3%, from 126 ±5 to 85 ± 5 msec (P<0.01). When the heart rate was 310/minute, eightdogs demonstrated second-degree A-V block before glucagon; after glu-cagon, seven of the eight showed 1:1 A-V conduction. Glucagon increasedheart rate by 38 ± 3.5%, from 148 ± 6.6 to 205 ± 8 beats/min (P<0.01).Propranolol, 2 mg/kg, did not block these effects on rate and A-V conduc-tion. The vagal escape time and idioventricular rate with vagal stimulationand idioventricular rate in complete heart block did not change significantlyafter glucagon. Since glucagon profoundly increased the speed of A-V con-duction without increasing ventricular automaticity, it may be useful in thetreatment of A-V block especially in the presence of propranolol.

ADDITIONAL KEY WORDS His bundle electrogramcomplete heart block propranolol isoproterenol vagal escape timebeta-receptor blockade cyclic AMP

• The effects of catecholamines on theheart are well known. These effects havebeen shown to be mediated via beta-receptorstimulation (1). Recent studies aimed at de-lineating the biochemical mechanism of beta-receptor stimulation have implicated theadenyl cyclase system as a prime participant(2). It is well known that the catecholaminesare potent activators of this system (3). If

From the Cardiopulmonary Laboratory, U. S. Pub-lic Health Service Hospital, Staten Island, New York10304.

This work was supported in part by the Division ofDirect Health Services, Bureau of Health Service,U. S. Public Health Service Project No. Py 69-1,and U. S. Public Health Service Research CrantHE-11829 from the National Heart Institute.

Received for publication October 14, 1968. Ac-cepted for publication December 18, 1968.

activation of adenyl cyclase is the mechanismby which catecholamines exert their stimulat-ing effects on beta receptors, other substancesthat increase the production of cyclic 3',5'-AMP from ATP may also exert stimulatingactions on the heart similar to those of betareceptors. In two recent studies Glick et al.(4) and Lucchesi (5) have found that anotherpotent activator of the adenyl cyclase system,the pancreatic hormone glucagon, possessespositive inotropic and chronotropic effects,thereby confirming and extending reports ofearlier investigators (6-8). However, theseeffects could not be eliminated by blockingbeta receptors, indicating a possible differ-ence in the mechanism of catecholamines andglucagon on the heart.

The catecholamines are also known to exert

Circulation Research, Volume XXIV, February 1969 167

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168 STEINER, WIT, DAMATO

marked effects on certain electrophysiologicalproperties of the heart; namely, they increasethe speed of impulse transmission throughthe atrioventricular (A-V) node and increasethe automaticity of latent pacemakers in thespecialized conducting system of the ventricle(9-12). These effects are also believed to bemediated by beta-receptor stimulation andmay also involve the adenyl cyclase system.Since glucagon has been shown to exhibitcatecholamine-like effects on cardiac rate andforce of contraction, it was of interest to deter-mine its effects on these electrophysiologicalproperties and to determine whether its effectsif any, could be blocked by beta-receptorblockade.

Methods

The effects of glucagon on atrioventricularconduction and ventricular automaticity werestudied in 14 mongrel dogs weighing 15 to 25 kg.The dogs were anesthetized with pentobarbital,30 mg/kg, and after the trachea was cannulated,they were ventilated with room air by a Harvardrespirator.

A rigid teflon catheter 10 inches long waspassed into the left ventricle, via the right carotidartery, and connected directly to a StathamP23d strain gauge. Left ventricular pressure andits first time derivative (dP/dt) were recordedon an Electronics for Medicine switched-beamrecorder.

In seven dogs the chest was entered throughthe fourth right interspace, and the pericardiumwas opened and sutured to the chest wall toform a cradle for the heart. Bipolar stainlesssteel wires (0.08 inches in diameter) with tefloninsulation, except at the very tip, were placedinto the region of the His bundle across theright atrial free wall and atrial cavity as describedby Scherlag et al. (13). The position of theHis bundle was estimated by palpation of thecoronary sinus and tricuspid valve. With thewires in this position, a His bundle electrogram(Fig. 1) could be recorded; this consists of anatrial electrogram, followed by a sharp spikerepresenting activity in the common bundle (H)and later by the ventricular electrogram.

In seven dogs the chest was not opened, andthe His bundle electrogram was recorded viaa catheter. Under fluoroscopic guidance, a tri-polar pacing catheter was placed across thetricuspid valve with its tip in the apex of theright ventricle. While recording between the twoproximal electrodes, the catheter was moved back

and forth across the inflow tract of the rightventricle until a clear and stable His bundleelectrogram could be found (14). The low-frequency components below 500 cycles/sec werefiltered to increase baseline stability and allowrecognition of complexes resulting from depolar-ization of the specialized fibers (15). The record-ing of a His bundle electrogram enables the A-Vconduction time to be determined with a higherdegree of accuracy and reproducibility than bysimply measuring the P-R interval. The electricalactivity from the common bundle forms a dis-crete spike, signifying the end of A-V conductiontime, and enables this variable to be separatedfrom the conduction time in the His-Purkinjesystem of the ventricle, intraventricular conduc-tion being represented by the H-S interval. Inthis study the beginning of A-V conduction wastaken as the pacing artifact (P), although we

L2

HBE

H00 msec.FIGURE 1

Effect of glucagon on the P-H interval. P = pacemakerartifact, H = His bundle spike; A = atrial electrogram,S = ventricular electrogram, L2 = lead II of the elec-trocardiogram, and HBE = His bundle electrogram.Top: control, P-H interval = 116 msec. Bottom: after50 fig/kg glucagon, P-H interval = 80 msec.

Circulation Research, Volume XXIV, February 1969



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A-V CONDUCTION AND VENTRICULAR AUTOMATICITY 169

realize that our measurements include intraatrialconduction. The P-H interval is used rather thanthe A-H interval because the pacemaker spikeis discrete and can be readily identified at anyheart rate, even if the spike falls within theventricular electrogram. Also, in no case wasthe interval between the pacing artifact andonset of the atrial electrogram found to varyby more than 1 to 2 msec, a change which isinsignificant in comparison to the total intervalsbeing measured. Atrial pacing was performedusing an American Electronic Laboratories (model104 A) stimulator. The stimuli were deliveredvia a bipolar catheter placed just below thejunction of the right atrium and the superiorvena cava.

Glucagon (Eli Lilly, lyophilized gtucagon liy-drochloride with accompanying diluent) wasadministered in varying doses intravenously. Thesinus rate and A-V conduction time during atrialpacing at 200, 250, and 310/min were recordedbefore and after the glucagon administration.The conduction times were measured within 2minutes after drug administration and then every10 to 20 minutes for up to 60 minutes afteradministration of the drug to estimate its durationof action. In five dogs the effect of glucagonon A-V conduction was measured after beta-receptor blockade by propranolol, 2 mg/kg,(Ayerst Laboratories). Beta-receptor blockadewas considered complete if the isoproterenol,2 to 3 ^ig/kg, did not produce a significantinotropic or chronotropic effect.

The effect of glucagon on ventricular auto-maticity was assessed in three ways. First, theright vagus was isolated in the neck and sectioned.Bipolar electrodes were placed on the peripheralcut end and 6- to 10-v rectangular pulses of3-msec duration were applied at a frequencyof 30/sec (Grass Instruments Stimulator S8).The vagal escape time (16-18) (the time fromthe onset of vagal stimulation to the first ven-tricular escape beat) was recorded before and2 to 5 minutes after the administration of varyingdoses of glucagon. Only those dogs that hada stable, reproducible vagal escape time withthe same idioventricular focus appearing eachtime were used. Ten experiments were performedon four dogs.

In twelve experiments on five dogs vagalstimulation was continued for 60 seconds andthe idioventricular rate recorded at that time.Glucagon was given and the procedure repeatedwithin 2 minutes. The idioventricular rates wereused only if the same focus was controlling theventricles.

In three dogs complete heart block was pro-duced by injecting 0.1 ml of 40% formaldehydeinto the region of the His bundle (19). Once


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a stable idioventricular rhythm was established,and at least 30 minutes after the productionof complete heart block, glucagon was given,and its effects on the idioventricular rate wererecorded. In all these studies on automaticity,when more than one experiment was performedon the same dog, there was an interval of atleast 60 minutes between doses of glucagon.

In each series of experiments, three dogs weregiven the diluent alone (1 ml).

ResultsEFFECTS OF GLUCAGON ON ATRIOVENTRICULARCONDUCTION AND HEART RATE

Glucagon was administered to 11 dogs asa single bolus or in cumulative doses withthe total dose being given in less than 10minutes. As the results in the open- andclosed-chested dogs did not differ, they willbe presented together. Five of these dogshad both vagi cut, but as the results inthese dogs were the same as those with thevagi intact, they will also be presented to-gether. The maximal effect on A-V conductiontime (P-H interval) along with its effectson heart rates is shown in Table 1. The H-Sinterval is not reported as it was not affectedby glucagon administration.

Glucagon increased mean heart rate by38%. Of the dogs whose heart rate was slowenough to allow pacing at 200/min beforeglucagon, only five could by paced afterglucagon because of the increase in heartrate. In these five dogs the P-H intervaldecreased by an average of 26%. At a controlpacing rate of 250/min, three dogs showedsecond-degree heart block. However, they alldemonstrated 1:1 A-V conduction after glu-cagon administration. In the eight dogsthat could be paced with 1:1 A-V con-duction both before and after glucagonat 250/min, the P-H interval decreasedby an average of 30%. Figure 1 shows thepronounced shortening of the P-H intervalin the His bundle electrogram of one dogin this series. When pacing at 310/min, eightof the eleven dogs showed second-degreeheart block but after glucagon ten of theeleven dogs demonstrated 1:1 A-V conduction.In Figure 2 2:1 heart block is evident inthe control tracings of a typical experiment,as indicated by the absence of a His bundledeflection and QRS complex after every al-

100 msec.FIGURE 2

Abbreviations as in Figure 1. Top: control tracing showing 2:1 A-V block, with a Hisbundle spike appearing only after the conducted beats. Bottom: after 50 /ig/kgglucagon, tracing shows 1:1 A-V conduction, each pacemaker artifact being followedby a His bundle spike.




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TABLE 2Effect of Increasing Doses of Glucagon on Heart Rate and Atrioventricular Conduction

Expt.no .

1

2

3

4

5

6

7

8

Total doseof glucagon

(/IB/kg)

0102050

0102050

05

1050

05

2050

05

2050

05

1550

012

420

0124

20

Heart rate(beals/min)

180220250250135195200200128215215215190220230230135175206206150200215215190195200212230135135145165206

% Increaseheart rate

223939

454848

686868

162121

306060

334343

35

1121

72260

Heart rateP-H interval

(msec)

10087NN

1301001001009063636383707070

155989090

1067070708378737070

15513211010090

250/min% DecreaseP-H interval

13

232323

303030

161616

374242

343434

6121616

15293542

Heart rateP-H interval

(msec)

125928787B

140140140B73737399787575B

1501201001358585859994887875BBB

175100

310/min% DecreaseP-H interval

263030

212525

373737

4102125

Each dose given at 2-minute intervals with the total dose being given in less than 10 minutes.

ternate pacing spike. This block was abolishedby administration of 50 /xg/kg of glucagonas can be seen in the lower tracing whereeach pacing spike is now followed by theHis bundle deflection and ventricular depo-larization. In the three dogs with 1:1 con-duction before and after glucagon, at a cardiacrate of 310/min the average decrease in P-Hinterval was 30%. It can be seen from Table 1that all dogs showed a substantial decreasein P-H interval and that most dogs couldbe paced at a faster rate with 1:1 A-V con-duction after glucagon had been administered.

Circulation Research, Volume XXIV, february 1969

The effects of increasing doses of glucagonare shown in Table 2. The doses were givenin increments every 2 minutes with the totaldose being given in less than 10 minutes.The maximal or near maximal effect on theP-H interval was obtained with relativelysmall doses (5 to 10 /xg/kg). In experiment7 and 8 it is shown that very small doses(2 to 4 ^,g/kg) may produce significant effectsin A-V conduction even before they producemarked effects on heart rate.

In three dogs given only the amount ofdiluent given with doses of glucagon greater



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than 50 /xg/kg, no effect on the P-H intervalwas seen.EFFECT OF GLUCAG0N ON ATRI0VENTRICULARCONDUCTION AFTER BETA-RECEPTOR BLOCKADE

Five dogs were given propranolol, 2 mg/kg,to produce effective beta-receptor blockade.This caused an increase in A-V conductiontime so that only two of five dogs couldbe paced at 250/min, and none couldbe paced at 310/min without some degreeof block. After glucagon (Table 3) all dogsshowed 1:1 A-V conduction at heart ratesof both 250 and 310/min. In the two dogswho could be paced at 250 beats/min beforeand after glucagon the decrease in the P-Hinterval was 43% and 40%. Figure 3 showsthe results of one propranolol experiment.After 2 mg/kg of propranolol at a pacedrate of 250/min, this dog exhibited Wencke-bach periodicity, and every fourth beat wasdropped. The completeness of the beta-re-ceptor blockade is demonstrated by the per-sistence of block, even after 2 /u,g/kg ofisoproterenol. The administration of 50 /ig/kgof glucagon quickly restored 1:1 A-V con-duction. In the five dogs, heart rate increasedby an average of 48% (Table 3). Thereforethe effects of glucagon on heart rate andA-V conduction were not blocked by effectivebeta-receptor blockade.

The duration of action of glucagon on A-Vconduction is shown in Figure 4. The durationof action is dose-dependent. The effect ofa 50 fig/kg dose decreased significantly after20 to 30 minutes and returned approximatelyto base line by 60 minutes. The four dogsgiven 20 yug/kg had all returned to controllevels by 30 minutes.

The increase in dP/dt after 50 /Ag/kg ofglucagon was of the same order as that de-scribed by Lucchesi (5) and by Glick et al.(4) (Fig. 5).

EFFECT OF GLUCAGONON VENTRICULAR AUTOMATICITY

The change in vagal escape time (Table 4)is not statistically significant.

The effect of glucagon on idioventricularrate (Table 4) also showed a small but notstatistically significant increase. Figure 6 showsthe effects of vagal stimulation on a typical




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HBE

•< 100 msec

FIGURE 3

dP/dt = first derivative of the left ventricular pressure, LVP = left ventricular pressure (inmm Hg), other abbreviations as in Figure 1. Left: effect of 2 mg/kg propranolol. With atrialpacing at 250/min there is second-degree A-V block with dropped beats. Middle: effect of 2iLg/kg isoproterenol. The second-degree block persists. The blocked beats are followed by anatrial electrogram but not htj a His bundle spike suggesting that the block is in the region ofthe A-V node. The decrease in left ventricular pressure and dP/dt probably reflects anincreasing effect of propranolol with time. The lack of improvement in A-V conduction orcontractility suggests that the beta-receptor blockade is complete. Right: effect of 50 ng/kgglucagon. Atrioventricular conduction is now 1:1, and the left ventricular pressure and dP/dthave increased. In each conducted beat the pacemaker spike is followed by an atrial electrogramand a His bundle spike.

TABLE 4Effect of Glucagon on Vagal Escape Time and ldioventricular Rate Produced by VagalStimulation

Expt.no.

123456789

101112

MEAN ±

P value

Dose ofglucagon

555

10102020505050

SEM

Vagal(s

C

10.23.33

181054

291.58

8.3 ± 2.8>0.8

escape timeieconds)

G

2

42

1621.52

3832.8

7.3 ± 3.7

DoseglucagonUg/kg)

52020205050505050505050

I V R(beats/min)

C

655342534646305865725250

53 ± 3.3>0.6

G

605852554654306570705052

55 ± 3.2

IVR = idioventricular rate after 60 seconds of continuous vagal stimulation, C = control, andC = glucagon.

experiment showing a small decrease in vagalescape time and a slight increase in heartrate.


The idioventricular rate in stable, completeheart block showed no significant change.Figure 7 demonstrates the effects of glucagon,



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TIME IN MINUTES

FIGURE 4

The duration of the effect of glucagon on A-V con-duction. Abscissa: time in minutes after a singleintravenous injection of glucagon. Ordinate: decreasein P-H interval expressed as a percent of the controllevel. In the four dogs given 20 ng/kg, all had returnedto control levels in 30 minutes. In the five dogs given50 tig/kg, all had returned to within 5% of control by60 minutes.

localize the effect more precisely, and thisimportant aspect must await microelectrodestudies.

The increased chronotropic affect on thesinus node is in agreement with other in-vestigators (4, 5, 7). In this study the chrono-tropic effect was not blocked or diminishedby beta-receptor blockade. Glick et al. (4)found a decrease in the chronotropic effectof glucagon, but no change on the inotropiceffect, after beta-receptor blockade and sug-gested that these two effects may be producedby different mechanisms. Our findings arein agreement with Lucchesi (5) who alsoshowed no change in the chronotropic re-sponse to glucagon after propranolol. Theseeffects of glucagon on the sinus and A-Vnodes are qualitatively similar to the effects

L2

HBE

dP/dt

LVP

50 /u,g/kg, on a dog in complete heart block.The marked increase in sinus rate and dP/dtcan be seen with a very slight increase inidioventricular rate. At no time after theadministration of glucagon in any of theseexperiments were ventricular premature con-tractions noted.

Discussion

This study shows that glucagon increasesthe speed of A-V conduction and abolishesvarious degrees of A-V block without in-creasing ventricular automaticity. The de-crease in the P-H interval may be due toan increased rate of conduction in the atria,at the atrial A-V node region, in the A-Vnode itself, or at the A-V node to His bundlejunction. Using our techniques, we could not

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FIGURE 5

Abbreviations as in Figure 3. Top: control, P-Hinterval = 105 msec. Bottom: after 50 ng/kg glucagon.The P-H interval has decreased to 80 msec. The leftventricular pressure and its first derivative, dP/dt,have increased.




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A-V CONDUCTION AND VENTRICULAR AUTOMATICITY

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FIGURE 6

Vagal escape time (VET) decreased slightly afterglucagon, 50 pig/kg. The idioventricular rate (IVR)after 60 seconds of continuous vagal stimulation in-creased very slightly. These very small changes are notsignificant.

of the catecholamines. Catecholamines alsodecrease A-V conduction time, having theirmajor effect on the A-V node (9-12). Cat-echolamines may speed A-V conduction byas much as 40% (12), a figure comparableto the maximal effect of glucagon. Since themechanisms underlying the A-V nodal actionpotential is still uncertain, the means wherebyany agent enhances A-V conduction cannotyet be precisely defined (20). It has been sug-gested that the action of the catecholamineson A-V transmission may be related to theirknown hyperpolarizing effect on Purkinjefibers with low resting potentials, wherebythese agents may speed decremental conduc-tion (21). In this context it would be ofinterest to ascertain the effects of glucagonon the A-V nodal action potentials. The effectsof glucagon on the heart may be due toactivation of the phosphorylase system byincreasing the production of cyclic 3',5'-AMPthrough adenyl cyclase activation (22). Some


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FIGURE 7

The effect of glucagon on the idioventricular rate ina dog in complete heart block. HR = heart rate, otherabbreviations as in Figure 3. Top: control. Bottom:after glucagon which increased the sinus rate (Pwaves in L2j from a control of 110 to 200 beats/min.Left ventricular dP/dt also increased. A similar in-crease was seen in those cases where the idioventricu-lar rate did not increase.

investigators believe that this effect can ex-plain many of the known actions of thecatecholamines on the heart, although thismatter is far from settled (22). It has alsobeen suggested that adenyl cyclase may bethe adrenergic receptor or closely involvedin adrenergic receptor activation (2). If adenylcyclase activation and cyclic 3',5'-AMP for-mation are indeed involved in adrenergicreceptor activation and form the commondenominator for both the catecholamines andglucagon effects on the heart, the ability ofpropranolol to block the actions of the formerwithout impairing the effects of the lattermust be explained. Propranolol in doses ashigh as 3 mg/kg did not prevent the glucagon



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facilitation of A-V conduction. Previous re-ports by Lucchesi (5), and confirmed in thisstudy, also indicate a failure of propranololto block the inotropic and chronotropic effectsof glucagon. It is possible that the activationof the beta receptor requires a series of stepswith the catecholamines and glucagon actingat different sites in the pathway. Propranololmay block at the catecholamine receptor site,whereas glucagon may act after this site.However, this is a matter of conjecture.

If glucagon acts through beta-receptorstimulation, it also becomes difficult to ex-plain its failure to increase ventricular auto-maticity. When the sinus pacemaker is in-hibited by vagal stimulation, injection of 1 to2 /^g/kg of isoproterenol results in a markedshortening of ventricular pacemaker escapetimes and a multifocal ventricular tachycardia(18). This effect is prevented by beta-receptorblockade (23). These actions of isoproterenolmay be explained by the effect of the cat-echolamines on increasing the slope of spon-taneous phase-4 depolarization of Purkinjefibers in the ventricles (9, 10, 21). Our re-sults indicate that glucagon does not shortenventricular pacemaker escape time nor doesit induce ventricular tachycardia, and thusit probably does not increase phase-4 de-polarization of the Purkinje fiber.

Glucagon, then, appears to have effectssimilar to those of catecholamines on thesinus and A-V nodes but differs from drugswith known beta-receptor stimulating actions(e.g., isoproterenol) in two important ways.First, its effects are not inhibited by beta-receptor blocking drugs, and second, it doesnot appear to have a significant effect onlatent pacemakers in the His-Purkinje system.This suggests that the cardiac effects of glu-cagon may not be due to stimulation of thebeta receptors, but may be caused by aseparate, direct effect of the hormone itself.

The ability of this drug to increase therate of A-V conduction and inotropism with-out increasing ventricular automaticity makesglucagon a potentially useful drug in certainclinical circumstances. For example, it mayprove to be of value after acute myocardial

infarction with conduction disturbances wherethe increase in ventricular automaticity makesthe use of catecholamines undesirable. Be-cause propranolol is becoming widely usedclinically, the occurrence of heart block ina patient receiving propranolol will becomemore common, and glucagon may be usefulin these patients.

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LAND, E. W.: Adenyl cyclase as an adrenergicreceptor. Ann. N. Y. Acad. Sci. 139: 703,1967.

3. SUTHERLAND, E. W., AND RALL, T. W.: Relation

of adenosine 3', 5' phosphate and phosphoryl-ase to the actions of catecholamines and otherhormones. Pharmacol. Rev. 18: 181, 1966.

4. CLICK, C , PARMLEY, W. W., WECHSLER, A. S.,

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5. LUCCHESI, B. R.: Cardiac actions of glucagon.Circulation Res. 22: 777, 1968.

6. FARAH, A., AND TUTTLE, R.: Studies on the

pharmacology of glucagon. J. Pharmacol. Ex-ptl. Therap. 129: 49, 1960.

7. WHITEHOUSE, F. W., AND JAMES, T. N.: Chron-

otropic action of glucagon on the sinus node.Proc. Soc. Exptl. Biol. Med. 122: 823, 1966.

8. REGAN, T. J., LEHAN, P. H., HENNEMAN, D. H.,

BEHAB, A., AND HELLEMS, H. K.: Myocardial

metabolic and contractile response to glucagonand epinephrine. J. Lab. Clin. Med. 63: 638,1964.

9. HOFFMAN, B. F., AND SINGER, D. H.: Appraisal

of the effects of catecholamines on cardiacelectrical activity. Ann. N. Y. Acad. Sci. 139:914, 1967.

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CHARLES STEINER, ANDREW L. WIT and ANTHONY N. DAMATOEffects of Glucagon on Atrioventricular Conduction and Ventricular Automaticity in Dogs

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