H ARRIS1 has shown that dogs develop

Transcription

1 Ventrcular Arrhythmas Induced by Sympathommetc Amnes n Unanesthetzed Dogs Followng Coronary Artery Occluson By HARRIET M. MALING, PH.D., AND NEIL C. MORAN, Wth the assstance of Martha A. Wllams Epnephrne and noepnephne, n doses whch cause lttle ectopc actvty n unanesthetzed normal clogs, produce exaggerated ectopc responses about the fourth day after coronary lgaton, when the arrhythmas caused by the lgaton per se have subsded. These responses persst for approxmately 12 days after lgaton and suggest reactvaton of latent ectopc foc. Observatons wth methoxamne, soproterenol, and atropne ndcate that ventrcular tachycarda s easly nduced after occluson by drugs whch smultaneously stmulate the myocardum and slow the snus node rate. M.D. H ARRIS1 has shown that dogs develop ventrcular ectopc rhythms 3 to 10 hours after coronary artery lgaton f mmedate ventrcular fbrllaton s prevented by followng a twostage occluson procedure. The delayed ventrcular ectopc actvty reaches a maxmum wthn the frst 24 hours and then progressvely declnes, dsappearng n 3 to 5 days. Harrs postulated that schemc cells n a zone surroundng the central necrotc area of nfarct act as hyperexctable ectopc foc dschargng mpulses spontaneously, and that other factors such as released epnephrne, 1 norepnephrne, 2 hstamne, 1 and potassum 3 mght contrbute to the hyperactve state of the ectopc foc. Durng a study of the effects of antarrhythmc drugs on the delayed ventrcular ectopc actvty n dogs followng twostage occluson of the anteror descendng coronary artery, t was noted that ntravenous njectons of epnephrne, n doses whch cause lttle ectopc actvty n normal dogs, produce marked ventrcular tachycarda even several days after the arrhythmas nduced by the lgaton have dsappeared. These exaggerated responses to Prelmnary reports: Federaton of Amercan Socetes for Expermental Bology n Atlantc Cty, New Jersey, Aprl 16, 1956, and Ffth InterAmercan Congress of Cardology n Havana, Cuba, November 12, From Laboratory of Chemcal Pharmacology, Natonal Heart Insttute, Natonal Insttutes of Health, U.S. Publc Health Servce, Bethesda, Md. Receved for publcaton Aprl 5, epnephrne ndcate the exstence of hyperexctable ectopc foc for a perod longer than the 3 to 5 days descrbed by Harrs. Epnephrnenduced ventrcular tachycarda after coronary artery occluson has also been noted by Clark and Cummngs. 4 The present study was ntated, therefore, to study the electrocardographc responses to several sympathommetc amnes n unanesthetzed dogs before and after coronary artery lgaton. METHODS Mongrel dogs 6 to 22 Kg. were anesthetzed wth sodum pentobarbtal and the heart exposed. In 24 clogs the anteror descendng coronary artery was lgated by the twostage occluson procedure of Harrs 1 at the level of the tp of the left atrum, 1.5 to 3 cm. from the ostum. In 2 dogs, the margnal branch of the crcumflex artery was lgated by the same technc approxmately 1 cm. from ts juncton wth the crcumflex trunk. Two dogs were subjected to sham operatons. Penclln was admnstered daly for 4 days followng operaton. At least 20 hours elapsed before the testng of drugs. Electrocardograms were recorded ether wth a Sanborn VsoCardette or a Grass fourchannel oscllograph usng standard or augmented lmb leads. In some experments potental dfferences between the rght arm and a percardal electrode was also recorded. Femoral arteral pressure was recorded by a Statham transducer connected to an ndwellng polyethylene catheter. Responses to drugs were determned n each dog before and at varyng tmes after lgaton of the anteror descendng coronary artery. All drugs were njected ntravenously n a constant volume (2 ml.) followed by a salne wash (2 ml.) durng an nterval of about 10 sec. 1Norepnephrne and 1epnephrne 409 Crculaton Research, Volume V.July 1967

2 410 SYMPATHOMIMETIC AMINES AFTER CORONARY OCCLUSION were admnstered as btartrates (Levophed and Suprarenn) and methoxamne (Vasoxyl) and soproterenol (Isuprel) as the hydrochlordes. Dlutons were made daly from the commercal solutons. Doses are expressed n terms of the free bases. A quanttatve comparson of the effects of epnephne and norepnephne was made usng the followng procedure: Three or more days pror to coronary artery lgaton, the electrocardographc responses to graded equmolar doses of the two drugs were obtaned n 13 unanesthetzed dogs. There was an nterval of from 15 to 60 mn. between successve njectons. In 7 dogs each njecton of norepnephrne was followed by the equmolar dose of epnephrne, whle n the remanng 6 dogs ths order was reversed. Whenever doses greater than 90 xg./kg. were tested at least 10 days elapsed between the control njectons and coronary artery lgaton. On the fourth postoperatve day,.e., after subsdence of "spontaneous" ectopc actvty, electrocardographc responses to the same graded doses of epnephrne and norepnephne were agan determned. The response to each dose was analyzed by countng the total heart rate and the rate of all ectopc beats for each successve 30 sec. nterval over a perod of 2 mn. before and 5 or more mn. after njecton (fg. 1). The fastest ectopc rate recorded was consdered to be the maxmum produced by a gven dose. The number of ectopc beats durng the frst 5 mn. followng an njecton was defned as the "5 mn. ectopc response." The mean, maxmum and 5 mn. ectopc responses, were plotted on semlogarthmc paper to obtan doseresponse curves. RESULTS Drect Effects of Coronary Artery Lgaton. Wthn 24 hours after coronary artery lgaton all dogs developed ventrcular and atroventrcular nodal arrhythmas whch then progressvely declned untl about the fourth postoperatve day when lttle ectopc actvty remaned, a pattern smlar to that descrbed by Harrs.1 Lttle dfference n type or severty of arrhythmas was noted between the 24 dogs wth lgaton of the anteror descendng coronary artery and the 2 dogs wth occluson of the margnal branch of the crcumflex artery. Effects of Lgaton on Responses to Epnephrne and Norepnephrne. Followng lgaton of the anteror descendng coronary artery or the margnal branch of the crcumflex artery, marked cardac arrhythmas resulted from the ntravenous njectons of epnephrne and norepnephrne. These drugnduced arrhythmas were supermposed on the lgatonnduced "spontaneous" ectopc actvty untl the ds Fo. 1. Comparsons of the electrocardographc and blood pressure responses to equmolar closes (0.056 jum/kg.) of epnephrne (left arrow) and norepnephrne (rght arrow) before (upper charts) and 4 days after (lower charts) lgaton of the anteror descendng coronary artery. Ectopc beats, sold black areas; snus beats, stppled areas. appearance of the latter around the fourth postoperatve day. The drugnduced arrhythmas contnued to be exaggerated untl about the twelfth day, even though there was usually no spontaneous ectopc actvty after the fourth day. Wthn a mnute after the njecton of ether epnephrne or norepnephrne, runs of ventrcular tachycarda appeared, whch usually alternated among several foc. AV nodal rhythm frequently preceded the ventrcular rhythm. Interference dssocaton became promnent durng the declne of the ectopc actvty. Wthn 5 to 10 mn. snus rhythm usually had returned, although wth large doses the ectopc actvty sometmes lasted 20 mn. or more. The absence of exaggerated ectopc responses n the shamoperated dogs demonstrated that coronary artery occluson s the causal factor n the producton of hyperexctable ectopc foc. That epnephrne and norepnephrne produced exaggerated ectopc responses after lgaton s evdent from fgure 1, whch s a graphcal comparson of the electrocardographc and arteral pressure responses to equmolar doses of the two drugs before and on the fourth day after lgaton of the anteror descendng coronary artery. The responses of the two drugs were smlar before lgaton, consstng of a rse n arteral pressure, cardac

3 MALING AND MORAN SO rl _ I / NOREPINEPHPINE lepincpmrine {3CF0R LIGATION STANDARD EKPOR Of MEANA } A I n / j V X ; 1 L FIG. 3. Duraton of "spontaneous" and norepnephrnenduced ectopc actvty after lgaton of the anteror descendng coronary artery. Each pont represents mean maxmum ectopc rate as determned on number of dogs gven n the parentheses. Norepnephrne, /M/Kg. (9.5 Ag./Kg.) was used throughout. Ordnate, maxmum ectopc rate; abscssa, da3's after coronary occluson. 0 DOSE" MICROMOLE/KCM 1 1.,., FIG. 2. Maxmum ectopc rate (upper chart) and 5 mn. ectopc response (lower chart) as a functon of molur dose of epnephrne and norepnephrne, before and 4 clays after lgaton of the anteror descendng coronary artery. Ordnates n the upper graph, maxmum ectopc rates; n the lower graph, 5 mn. ectopc responses. Abscssae, molar doses plotted on logarthmc scale. Each pont on the curves s mean of values obtaned from 5 to 13 dogs. slowng, and moderate ectopc actvty, whch was usually atroventrcular nodal n orgn. After lgaton, the same doses produced ventrcular tachycarda. Records wth welldefned Pwaves obtaned wth percardal electrodes ndcated that epnephrne and norepnephrne produced marked reflex slowng of the snus node both before and after coronary artery lgaton. Doseresponse curves to the two compounds were obtaned n 13 unanesthetzed dogs before and on the fourth day after coronary occluson when there was no apprecable spontaneous ectopc actvty. The maxmum ectopc rate and the 5 mn. ectopc response were found proportonal to the dose for both drugs before and after lgaton (fg. 2). Before lgaton the maxmum ectopc rates produced by epneph rne and norepnephrne were alke; 4 days after occluson the maxmum ectopc rate produced by norepnephrne exceeded that produced by the equmolar dose of epnephrne by approxmately 24 beats/mn., a sgnfcant dfference (p<0.001). Ths dfference s even more evdent n the case of the 5 mn. ectopc responses. As seen n the lower half of fgure 2, n the range of 0.02 to 0.2 jum/kg., norepnephrne produced 150 to 250 more ectopc beats durng the frst 5 mn. than epnephrne, a dfference due both to the greater maxmum ntensty and the longer duraton of acton of norepnephrne. Doses of epnephrne and norepnephrne greater than 0.1 jum/kg. produced hghly varable responses before lgaton, as seen by the large standard errors of the means for the maxmum ectopc rates n fgure 2. The dfference between the potency of epnephrne and norepnephrne after lgaton does not seem to be correlated wth the level of arteral pressure (fg. 1). Duraton of Ectopc Process Determned by Responses to Norepnephrne. The persstence of the ectopc process after the dsappearance of the spontaneous ectopc actvty was apparent from the contnued exaggerated ectopc responses to a standard dose of norepnephrne (0.056 jum/kg. = 9.5 /g./kg.). Fgure 3 compares the temporal declne of the spontaneous

4 412 SYMPATHOMIMETIC AMINES AFTER CORONARY OCCLUSION and norepnephrnenduced ectopc actvty after lgaton. The maxmum ectopc rate produced by norepnephrne was greatest on the frst postoperatve day, as was the spontaneous ectopc rate. Both types of ectopc actvty then progressvely declned, the spontaneous one more rapdly. Thus, by the fourth postoperatve day, the spontaneous arrhythmas had vrtually dsappeared, whereas the electrocardographc responses to norepnephrne perssted 12 days after occluson. Electrocardographc Responses to Methoxamne and Isoproterenol. Snce the drugevoked arrhythmas mght have resulted from a combnaton of myocardal stmulaton and slowng, two other sympathommetc amnes wth dfferent propertes were tested. Methoxamne, a pressor amne wth neglgble cardac stmulant acton, 6 caused marked snus bradycarda wth only moderate ectopc actvty, both before and 4 days after lgaton. Ventrcular tachycarda dd not occur wth methoxamne. Isoproterenol, a vasodepressor amne wth strong myocardal stmulant acton, 6 produced marked snus acceleraton and almost no ectopc actvty, ether before or 4 days after lgaton. Effect of Atropne on Arrythmas. Atropne, n dose of 0.1 to 0.3 mg./kg. ntravenously, whch caused acceleraton to levels equal or greater than the ectopc rates, reduced or abolshed both the spontaneous and drugnduced arrhythmas after occluson. Other nvestgators have reported a smlar acton of atropne aganst epnephrne arrhythmas n conscous normal dogs 7 and anesthetzed cats. 8 DISCUSSION An analyss of the effects of several drugs ndcates that ventrcular tachycardas are most easly nduced after occluson by drugs whch stmulate the myocardum and also produce snus bradycarda. Thus, epnephrne and norepnephrne nduce a reflex slowng of the snus node rate concomtant wth myocardal stmulaton. Both drugs elct ventrcular tachycarda after coronary artery occluson. In contrast, soproterenol, although a strong myocardal stmulant, nduces a pronounced acceleraton of the snus node rate, both drectly and reflexly as a result of the fall n blood pressure. Isoproterenol causes only neglgble ectopc actvty n the unanesthetzed dog before or 4 days after coronary lgaton.* Methoxamne, on the other hand, produces a rse n blood pressure and reflex bradycarda, but no myocardal stmulaton, 6 and causes only moderate ectopc actvty after occluson. Fnally, atropne, by blockng vagus nerve mpulses, produces snus tachycarda and abolshes the spontaneous arrhythmas nduced by coronary artery lgaton per se as well as those elcted by norepnephrne. Two aspects of the present study warrant menton n connecton wth myocardal nfarcton n human bengs. Frst, the total perod of exaggerated drugnduced ectopc actvty n the dog s approxmately 12 days, a close correspondence wth the clncal observaton that the frst 2 weeks followng myocardal nfarcton n man s the most lkely perod for the development of paroxysmal ventrcular tachycarda. 9 Secondly, the use of large doses of norepnephrne n the treatment of shock resultng from myocardal nfarcton may nvolve a rsk of nducng arrhythmas. In general, however, snce the concentratons and rates of nfuson of norepnephrne used clncally are much less than those used n the present study, the potental danger s probably slght. The close correspondence n potency between epnephrne and norepnephrne n regard to elctng ventrcular arrhythmas after coronary artery occluson agrees wth the demonstratons of the equpotency of the two drugs on cardac exctablty, 10 cardac contractle force, 11 and the producton of atroventrcular rhythms durng vagal stmulaton. 12 SUMMARY Twostage occluson of ether the anteror descendng coronary artery or the margnal *Prelmnary work n ths laboratory wth soproterenol n dogs anesthetzed 4 days after coronary artery lgaton has shown that ths amne produces ventrcular arrhythmas durng the snus slowng produced by vagal stmulaton. These arrhythmas are more ntense than those produced by soproterenol n anesthetzed normal dogs durng vagal stmulaton. 12 Thus, soproterenol, lke epnephrne and norepnephrne, produces ventrcular tachycardas n dogs after coronary lgaton, provded that the snus node rate s slowed through vagal stmulaton.

5 MALING AND MORAN 413 branch of the crcumflex artery produces both "spontaneous" ventrcular arrhythmas and exaggerated ectopc responses to epnephrne and norepnephrne. Both spontaneous and drugnduced ectopc actvty reach a maxmum ntensty wthn 24 hours after lgaton. The spontaneous ectopc actvty gradually dsappears over a perod of about 4 days, whle the exaggerated drugnduced ectopc actvty perssts for about 12 days. Observatons wth soproterenol, methoxamne, and atropne ndcate that ventrcular tachycardas are easly nduced after occluson by drugs whch smultaneously stmulate the myocardum and slow the snus node rate. A quanttatve comparson suggested that norepnephrne s slghtly, but sgnfcantly more actve than epnephrne n producng arrhythmas after coronary artery lgaton. SUMMAKIO IN INTERLINGUA Le occluson bphasc del artera coronar anteror descendente o del branca margnal del artera crcumflexe produce (1) "spontanee" arrhythmas ventrcular e (2) exaggerate responsas ectopc a epnephrna e norepnephrna. Le actvtate spontanee o nducte per drogas attnge un maxmo de ntenstate ntra un perodo de 24 horas post lgaton. Le spontanee actvtate ectopc gradualmente dspare durante un perodo de crca 4 des, durante que le exaggerate actvtate ectopc nducte per drogas persste durante crca 12 des. Observatones n expermentos con soproterenol, methoxamna, e atropna ndca que post occluson tachycardas ventrcular es faclemente nducte per drogas que smultaneemente stmula le myocardo e retarda le rhythmo del nodo snusal. Un comparaton quanttatve ndcava que norepnephrna es, a basse sed sgnfcatve grado, plus actve que epnephrna n producer arrhythmas post lgaton de arteras coronar. ACKNOWLEDGMENT The authors wsh to express ther apprecaton to Mr. Jerome Cornfeld, Bometrcs Branch, Natonal Insttutes of Health, for hs advce and assstance wth the statstcal evaluaton of the experments. REFERENCES 1 HARRIS, A. A.: Delayed development of ventrcular ectopc rhythms followng expermental coronary occluson. Crculaton 1: 1318, AND BISTENI, A.: Effects of sympathetc blockade drugs on ventrcular tachycarda resultng from myocardal nfarcton. Am. J. Physol. 181: 559, ,, RUSSELL, R. A., BKIGHAM, J. C, AND FIRESTONE, J. E.: Exctatory factors n ventrcular tachycarda resultng from myocardal schema. Potassum a major exctant. Scence 119:, CLARK, B. B. AND CUMMINGS, J. R.: Arrhythmas followng expermental coronary occluson and ther response to drugs. Ann. New York Acad. Sc. 64: 543, GOLDBERG, L. I., COTTEN, M. DEV., DARBY, T. D., AND HOWELL, E. V.: Comparatve heart contractle force effects of equpressor doses of several sympathommetc amnes. J. Pharmacol. & Exper. Therap. 108: 177, "LANDS, A. M., NASH, V. L., MCCARTHY, H. M., GRANGER, H. R., AND DERTINGER, B. L.: The pharmacology of nalkyl homologues of epnephrne. J. Pharmacol. & Exper. Therap. 90: 110, WlLBURNE, M., SURTSHIN, A., RODBART, S., AND KATZ, L. N.: Inhbton of paroxysmal ventrcular tachycarda by atropne. Am. Heart J. 34: 860, RIKER, W. F., DEPIERRE, F., ROBERTS, J., ROY, B. B., AND REILLY, J.: The epnephrne and hydrocarbonepnephrne dsturbance n the cat. J. Pharmacol. & Exper. Therap. 114: 1, ARMBRUST, A. A., JR., AND LEVINE, S. A.: Paroxysmal ventrcular tachycarda. A study of one hundred and seven cases. Crculaton 1: 28, SIEBENS, A. A., HOFFMAN, B. F., ENSON, Y., FARRELL, J. E., AND BROOKS, C. M.: Effects of 1epnephrne and 1norepnephrne on cardac exctablty. Am. J. Physol. 175: 1, COTTEN M. DEV. AND PINCUS, S.: Comparatve effects of a wde range of doses of 1epnephrne and 1norepnephrne on the contractle force of the heart n stu. J. Pharmacol. & Exper. Therap. 114: 110, "ROBERTS, J., STANDAERT, F., KIM, Y. I., AND RIKER, W. F., JR.: The ntaton and pharmacologc reactvty of a ventrcular pacemaker n the ntact anmal. J. Pharmacol. & Exper. Therap. 117: 374, 1956.