The Initiation of Ventricular Tachycardiaand Fibrillation in Isolated Hearts by

Potassium ChlorideBy L. GRUMBACH, PH.D.

in collaboration icith L. K. Tanner, B3. and J. Wiyiibert, A.M.

An accelerating tachycardia ending in fibrillation can be initiated in isolated hearts by injectionsof KC1 after the administration of epinephrine, but not in untreated hearts. KC1 acts in two waysto do this. First, it causes an A-V block that enables epinephrine to cause a paroxysmal ventriculartachycardia. Secondly, it causes the latter to accelerate by delaying the recovery of excitabilityso that at least one premature systole can fall into the recoveiy phase of a preceding impulse. Thisevent is necessary and sufficient for the initiation of a self-sustaining accelerating tachycardia thatcan end in fibrillation.

PROCAINE is an effective antifibrilla-tory agent, as shown by suitable testsin experimental animals1 and, in addi-

tion, has been successfully used clinicallyfor this purpose.2 However, in certain circum-stances it can cause ventricular arrhythmias,both in experimental animals3 and in isolatedhearts.4 The mechanisms involved in this actionof procaine have been analyzed in the lattercase.4 In order to determine whether thesemechanisms are peculiar to antifibrillatoryagents of the local anesthetic type, the abilityof potassium salts to initiate ventricular ar-rhythmias in isolated hearts has been studied.They have long been known to have anti-fibrillatory actions6 and to cause ventricularfibrillation in intact animals.8

METHODS

The electrical activity of isolated rabbit heartsperfused with Krebs-Henseleit solution in a Langen-dorff apparatus was recorded by a previously de-scribed method.7 Epinephrine solutions were madeup in 1 per cent ascorbic acid to prevent oxidation.The vehicle alone had only a transient effect on theT wave which in control experiments was found tohave no bearing on the phenomena to be described.KC1 in a 0.77M solution was used for producingrapid alterations in the K+ concentration of thetissue fluid.

From the Pharmacology Section, Sterling-Winthrop Research Institute, Rensselaer, N. Y.

Received for publication December 14, 1955.

RESULTS

Injections of KCl into the perfusion streamnever produced ventricular arrhythmias whenthe hearts were well washed with perfusionfluid. The typical sequence of events causedby a KCl injection is shown in figure 1, partla and consists of a slowing of the sinus rateand of atrioventricular and intraventricularconduction. The latter is more clearly seen infigure 2, part 26 which shows the lengthenedP-R interval and widened QRS complex pro-duced by KCl. These effects are entirely simi-lar to those produced by procaine which areshown in fig. 2, part 16 and figure 2, part lc.

In hearts that have been treated with epi-nephrine, on the other hand, KCl injectionscan cause an accelerating ventricular tachycar-dia that more or less rapidly ends in fibrilla-tion. The fibrillation shown in part 2a offigure 1 continued for 5 minutes at which timeit was stopped by an injection of 0.8 ml. of0.77M KCl. That shown in part 3 of figure 1ended spontaneously a short time after itbegan. In general, spontaneous reversionsoccurred within a minute; past that time,fibrillation usually continued indefinitely untilstopped by some antifibrillatory treatment.When this was done, a normal sinus rhythmwas resumed (cf. part 26 with 16 of figure 1).

Certain characteristic effects of rapid KClinjections on the electrocardiogram were noted.One effect was the production of A-V blockade

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294 VENTRICULAR FIBRILLATION BY POTASSIUM CHLORIDE

F O Of O.77M KCI

1

.0 sec.Imin. after I Omg epinephnne

OmV1 Control

OmV

0.2CC of 0 77MKCI

I OmV

FIG. 1. Effects of KCI alone and after epinephrine. Discussed in text.

both in normal and in epinephrine-treatedhearts, as can be seen in parts la, 2a and 3 offigure 1. This also occurs with procaine injec-tions (fig. 2, part 16). A second effect that wasseen only in epinephrine-treated hearts was theoccurrence of premature ventricular systoles.These made their appearance coupled to thefirst supraventricular impulses to pass thedepressed A-V node. They are indicated at thearrows in parts 2a and 3 of figure 1. The runsof accelerating ventricular tachycardia pro-duced by KCI injections after epinephrineappear to consist on analysis of fast records of aseries of premature ventricular systoles coupledto the first and apparently emanating from thesame focus giving rise to the first one.

The rapidity with which the ventriculartachycardia accelerates and ends in fibrillationdepends on the amount of KCI used. Withlarger amounts of KCI the oscillations areinitially slow and regular and their accelera-tion is gradual (part 3 of fig. 1). With smaller

amounts the acceleration is more rapid andfibrillation supervenes more quickly (part 2oof fig. 1).

The results just described Avere obtained intwo out of every three hearts (the total num-ber studied was 21). The negative result wasusually an abortive train of premature sys-toles which nonetheless was not counted assuccessful. However, in some hearts treatedwith epinephrine the only effect of KCI was toslow the i"ate and conduction as described foruntreated hearts at the beginning of thissection.

KCI was also tested for its ability to replaceepinephrine in the epinephrine-procaine se-quence of injections that leads to an accelerat-ing ventricular tachycardia ending in fibrilla-tion.4 The procedure was the same as that justdescribed for the epinephrine-KCl sequence.Part 2o of figure 2 shows the effect on theelectrocardiogram 25 seconds after an injec-

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GRUMBACH 295

"0. sec >4cc 2 % procaine

p. I sec

1

25sec after 0.2cc of 0.77M KCI

0.4cc 2% procaine

Ill1

i

1!ir li ||!f

f.

r>.C)n

6min after I.Omg/L atropine sulfateI I O.I sec I |

0.4cc 2 % procainei ' I

L25sec after lOQug acetylcholinei I

f I.OmV

FIG. 2. Effects of procuine injections alone and after KCI injection. Discussed in text.

tion of 0.2 ml. of 0.77M KCI solution. Record2b demonstrates the effect of 0.4 ml. of 2 percent procaine solution given 5 seconds later.Record 2c, taken 20 seconds later, shows aseries of irregular idioventricular beats fol-lowed by a regular accelerating tachycardiawhich ended abruptly, as shown in 2e, 65seconds later. The electrocardiograms of thereverted beats 15 seconds afterwards (2/)showed that that heart was still depressedby the combined effect of excess K+ and pro-caine. The strongly depressant effect of thecombination of procaine with excess K+ was

undoubtedly responsible for the fact that theresult shown in part 2 of figure 2 was hardto obtain.

Part 3 of figure 2 shows that acetylcholinecan also substitute for epinephrine in theepinephrine-procaine sequence of injectionsif the heart is atropinized. The accelerationof the sinus rate and the appearance of a Udeflection in the ventricular complex seenin part 36 mdicates that a considerable amountof a sympathomimetic substance M'as re-leased. In parts 3c, d, e it can be seen thatenough was liberated to allow procaine to

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29C VENTRICULAR FIBRILLATION BY POTASSIUM CHLORIDK

initiate ventricular tachycardia and fibrilla-tion in the usual manner.

DISCUSSION

The results of KCl injections in epinephrine-treated hearts are entirely analogous to thoseobtained with procaine injections in the samecircumstance. The first action of both sub-stances in initiating ventricular tachycardiaand fibrillation is the production of some degreeof A-V block which allows a latent action ofepinephrine to become manifest, namely, thatof initiating premature ventricular systoleseither singly or in trains of constant frequency.'*A second action of procaine and KCl is totransform this paroxysmal tachycardia intoan accelerating one. Fibrillation occurs whenthe latter reaches a critical frequency. Theessential feature of this second action of KClis that recovery of excitability is delayed with-out a concomitant decrease in the frequencyof the premature ventricular systoles. As aresult successive impulses fall into the recoveryphase of the impulses just preceding each one.This is sufficient for the acceleration of a par-oxysmal tachycardia and the eventual initiationof fibrillation.

The concept developed here, that KCl canonly produce an accelerating ventriculartachycardia and fibrillation in hearts thathave been treated with epinephrine and thatit does so in this circumstance by depressingconduction and recovery of excitability, doesnot accord fully with older interpretations ofthe mechanism of K+ fibrillation in experi-mental animals.8'9

In some cases the injection of KCl followedby a suitable amount of procaine caused anaccelerating ventricular tachycardia. Our in-terpretation of this result is that KCl causedthe release of an epinephrine-like substancefrom the chromaffin tissue of the heart. Hoff-mann and his collaborators10 showed thatmeasurable amounts of such a substance werereleased when acetylcholine was injectedinto isolated, atropinized hearts.

SUMMARY

The ability of KCl to initiate ventriculararrhythmias was studied electrocardiographi-

cally in isolated rabbit hearts perfused withKrebs-Henseleit solution in the Langendorffapparatus.

In about two-thirds of the hearts studied,an accelerating ventricular tachycardia couldbe initiated by injections of KCl into the per-fusion stream after treatment of the heartswith epinephrine, but not in untreated hearts.In the majority of cases the tachycardia endedin a transient or persistent fibrillation.

The mechanism by which KCl produces thisresult is entirely similar to the mechanism bywhich procaine effects the same result in simi-lar circumstances. First, it causes an A-Vblock which permits epinephrine to initiate aparoxysmal ventricular tachycardia. Secondly,it transforms the latter into an acceleratingtachycardia by delaying the recovery of ex-citability so that at least one epinephrine-induced premature ventricular systole canfall into the recovery phase of a precedingimpulse.

KCl can also replace epinephrine in theepinephrine-procaine sequence of injectionsthat leads to the initiation of ventriculartachycardia and fibrillation. Evidence wasadduced to support the view that this excita-tory effect of KCl is an indirect one, being onintracardiac adrenergic structures and noton cardiac tissue proper.

SUMMARIO IN INTKHLINGUA

Le capacitate de chlorido de kalium deinitiar arrhythmias ventricular csseva studiateelectrocardiographicamente in isolate cordesde conilio perfundite con le solution de Krebs-Henseleit in le apparato de Langendorff.

In circa duo tertios del cordes studiate, ilesseva possibile initiar un tachycardia ven-tricular accelerative per injicer chlorido dekalium in le currente perfusional post que lecordes habeva essite tractate con epinephrina.In cordes non assi tractate le mentionate ef-fecto non se produceva. In le majoritate delcasos le tachycardia se terminava in un fibrilla-tion transiente o persistente.

Le mechani8mo per que chlorido de kaliumproduce iste effecto es integrementc simile almechanismo per que procaina effectua lemesme resultato sub simile conditiones. Primo,

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GRUMBACH 297

illo causa un bloco atrio-ventricular que per-mitte al cpinephrina de initial' un tachycardiaventricular paroxysmal. Secundo, illo trans-form le tachycardia ventricular paroxysmalin un tachycardia accelerative per retardarle recuperation del excitabilitate de manieraque al minus un prematur systole ventricularinducite per epinephrina occurre in le phase derecuperation del impulso precedente.

Chlorido de kalium pote etiam prender leplacia de epinephrina in le sequentia de in-jectiones de epinephrina e procaina que duceal initiation de tachycardia e fibrillation ven-tricular. Es presentate datos in supporto delconception que le efTecto excitatori de chloridode kalium es un effecto indirecte que age superstructuras adrenergic intracardiac e non superhistos cardiac per se.

REFERENCES1 DAWKB, S. C : Experimental ciu-diuc arrhythmias

and quinidine-like drugs. Pharmacol. Rev. 4:43, 1952.

1 SCHERF, D.: Treatment of cardiac arrhythmias.

Circulation 8: 7.50, 1953.1 LONG, J. H., OPPENHKIMER, M. J., WESTER, M. R.,

AND DUKANT, T. M.: The effect of intnivenous

procuine on the heart. Anesthesiol. 10: 406,1949.

4 GRUMBACH, L.: The initiation of ventricular

tachycardia and fibrillation by procaine in theisolated, perfused rabbit heart. Circulation Re-search 4: 112, 1956.

'HBRING, H. E.: Ueber die Wirksamkeit desAccelemns auf die von Voihofen abgetrenntenKammern isolirter Saugethierherzen. Zentmlbl.f. Physiol. 17: 1, 1903.

8—: Uber eri'egende Wirkungen des Kalium aufdas Siiugethierherz. (Extrasystolische Tachy-kardie, Flimmem.) Pfliiger's Arch. ges. Physiol.161: 544, 1915.

'GRUMBACH, L., HOWARD, J. W., AND MERRILL,V. I.: Factors related to the initiation of ven-tricular fibrillation in the isolated heart: Effectof calcium and potassium. Circulation Research2: 452, 1954.

8 NAHUM, L. H., AND HOFF, H. E.: Observations on

potassium fibrillation. J. Pharmacol. & Exper.Therap. 65: 322, 1939.

' WIGGKRS, C. J.: Studies on ventricular fibrillationproduced by electric shock. III. The action ofantagonistic salts. Am. J. Physiol. 93: 197,1930.

10 HOFFMANN, F., HOFFMANN, E. J., MIDDLKTON, S.,AND TALF.SNIK, J.: The stimulating effect ofacetylcholine on the mammalian heart and theliberation of an epinephrine-like substance bythe isolated heart. Am. .1. Physiol. 144: 189,1945.

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L. GRUMBACHChloride

The Initiation of Ventricular Tachycardia and Fibrillation in Isolated Hearts by Potassium

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

doi: 10.1161/01.RES.4.3.2931956;4:293-297Circ Res. 

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