Document 8gngpNxE3RgN61Q80N7RJjvd

nil kshay, am. PHARMACOLOGY (3176-3181) im IBfab 779Abs Cardiac Rhythm I "`""ACO'.OOY -utiofment or autonomic keukoeffector transmission to jjCIMAKER CELLS OF THE EMBRYONIC HEART. E. LSff.lliol** And A rifP*QQ" Department of Pharmacology, University of ^,Becicuc Health Canter, Farmington, CT 06032. Intraeallular mambrane potentials were recorded from pacacells In the alnus vaooaua of chick hearts from the fifth incubation day to the first week sfter hatching. Trains of impulses (1-100 Hs) were applied to the sinus venoaue re lion of isolated atria bathed in Tyrode solution at 30*C. In litres incubated for 11 days or more, stimulation for 2-5 sec caused cardloinhlbitlon that vaa accompanied by membrane hyftrpolarlaatlon and reduced ectlon potential duration. These ffeeta were blocked by etroplne (lCT7g/ml) and by TTX (10" |/sl) but not by hexamethonlua (KT^g/ml). These dete Indi cated that acetylcholine was released from Intracerdlac poatiae|llnnlc cholinergic exons by propagated action potentials. Stieuletlon for 2-5 sec evoked cardioecceleretlon after hatching (21 days). The acceleration vas associated with an increased rate of slow diastolic depolarization *nd vas blocked by propranolol (10~g/al). Previous studies have shown that postjunctional cholinergic and adrenergic recep tors are present by the third incubation day. It is conclud ed that during ontogenesis of the chick heart: 1) the post junctional receptors for the neurotrensaltters are operative before the appearance of autonomic neuroeffector transmis sion, and 2) adrenergic transmission develops later then does cholinergic transmission. (Supported by US?US Grant So* HL-13339.) TIKI COURSE OF SUSCEPTIBILITY TO EPINEFHBIHE-INDUCED TACHY ARRHYTHMIAS IK THE CAT FOLLOWING INHALATION OF AEROSOL PRO- PFTi'AWT. TWitflnwl B. Thompson* and Willard S. Harris* Univ. of Illinois Med. Ctr., Chicago, Illinois 60612 (Spec: T. C, Vest). Inhalation of high concentrations of aerosol propellants, e.g., CCl^Fg* is known to cause sudden death in man, some- tines minutes after the end of exposure, and to sensitize dogs to severe epinephrine (Epl)-induced ventricular tachy arrhythmias. To assess the duration and disappearance rate of zyocardial sensitization, we injected 13 pentobarbital- anesthetized cats i.v. with k or 8 yg/kg Epi before a k min Inhalation of 37? CCI2F2 Og Ng and periodically for 10 sin after the end of the Inhalation. Electrocardic*i ass anc intraarterial pressures were recorded,end arterial blood levels of CCI9F2 were measured by gas chromatography Before exposure to Cft^Fg* 00 cat* Epl-lnduced ventricular tacnyarrhythsilas; after CCljFg, all developed Epl-lnduced ventricular tachyarrhythmias. With 8 yg/kg Epi, 8 of 8, 7 of 3, 2 of 7* nnd 1 of k cats had Epl-lnduced ventricular tachyarrhythmias at 3, 5, 8 and 10 min post CClgFg respec tively. In summary, susceptibility to Epl-lnduced ventricular tachyarrhythmias persisted after the end of CCI2F2 exposure, varied inversely with time as did the CCl^Fg fc*00* levels, and sometimes lasted as long as 10 min postinhalation of CCl^' 3177 HUIttUCOLOCY DIFFERENCES IN EFFECTS OF ANTIARRHYTHMIC AGENTS ON CELL CULTURES. R. J. Ercel, G. Ouyang* P. Gifford* f. R. Franks* and D. E. Clarke. Unlv. of Pittsburgh. Sch. of Pharmacy and The Western Pennsylvania Hosp, Pittsburgh, Pa. 15213 Various concentrations of qutnidlne (Q), procaineamide (PA), diphenylhydantoin (0), ltdocalne (L), propranolol (P) and hr**y!turn (6) vers studied on cultured myocardial cells obtain ed from 7-day old chick embryos. The effects obtained on the spontaneous beating rate (S8R) and number of beating cells (NIC) in cultures derived from whole hearts are shown. SBR NBC Q,PA H * increase 0,L + 4- 4 - decrease B,P *-* + *+ no change Q and PA changed the monolayer of synchronously beating cells into two distinct cell populations, one showing an enhanced rate whereas the other exhibited a decreased rate. This phen omenon was absent In cell cultures derived solely from ventri cular cells, whereas the effects of the other antlarrhythmics were not qualitatively altered. Surprisingly, B exhibited an Anti-adrenergic action which appears to occur at the level of the 3-adrenotropic receptor. The experimental observations provide a classification of the antlerrhythmic agents which is closely allied to that based on e!ectro*phy$iologica! data and clinical usage tn man. This close correlation suggests that responses of chick myocardial cell cultures are highly repre sentative of adult mammalian myocardial mechanisms. (Supported by NIH Grant No. HL-14823). 3180 ACUTE AMD QIRONIC ADMINISTRATION OF MORPHINE SO4 EFFECT ON HEART RATE AND VENTRICULAR CONTRACTILE FORCE. A. E. Lucas*. J. Hlnkebeln*. R. Kimbler* and T. t>- Darby. Department of Pharmacology, University of Louisville Health Scieoces Center, Louisville, Kentucky 40201. The studies were carried out In anesthetized mongrel dogs. Vfficricular contractile force (1ST) was measured by the strain rgMug Midi Ldi&iqua (r,S.2.5*M. 04:263, 1953). Ar+mriitl blood preesure (BF) was obtained from the femoral artery. Heart rate was determined from these recordings. Alterations in the cardlovaacular status were produced by administration of cardiovascular drugs: Methoxamlne and Nitroglycerin. The response to norepinephrine was obtained* After these control procedures the animals were challenged with 10 mg/kg of mor phine SO4 IV* The alterations In cardiovascular status were repeated. Vagotomy was completed and the procedure repeated. These same studies were carried out in dogs which were treated with increasing doses of morphine for 28 days. It vas found morphine stimulates the parasympathetic reflex control (PRC) of heart rate in the acute studies, while In the chronic animals the PRC vas markedly depressed, suggesting sympathetic predominance. pTetreatment with reserplne for 3 days or concomitant administration of morphine and reserplne for the last 14 days of the 28-day morphine treatment enhanced the PRC In the acute animals and abolished the PRC depression in the chronic animals. (Supported by Kentucky, Louisville end Jefferson County Heart Association Grant #64315.) SMAMueotoov kethylchloroform-induced fibrillation in the mouse. A.M, Strosberq* L*G. Johnson* and L.M* Miller*(Spon: k,K. Richards)* Dept, of Pharmacology! Inst* of Clin. Med., Syntex Research# Palo Alto Cal. 94304 Kethylchloroform-induced fibrillation in the mouse has been employed as a screening procedure for the evaluation of antiarrhythmic properties of compounds (Hermanaen, Acta pharmacol* et toxicol* ?8: 17# 1970). We have attempted to clarify the Mechanism of this fibrillation. Adrenalectomized bice and mice pretreated with 10 mg/kg of P-286 (a compound which blocks the release of adrenal cate cholamines) were not protected against roethylchloroform-induced fibrillation* Mice pretreated with reserplne (5mg/kg) and reserplne pretreated adrena lectomized mice were protected. The greatest pro tection was observed following intraperitoneal pre treatment with 8-blockers (e.g* propranolol, 3mg/ kg), Commonly used antiarrhythmic drugs protected Only at enormous and near toxic dose levels (e.g. lidocaine, 50mg/kg and quinidine, 50mg/kg)* Our results suggest that methylchloroforrn-induced fib rillation in the mouse cannot serve as a test for compounds effective against non-adrenergic mediated Arrhythmias. However, it does appear to be a rapid And inexpensive screening procedure for detecting cardiac ^-receptor blocking activity. 3igi fHASMACOtOGY THE EFFECTS OF ISOPROTERENOL OR CARDIAC CGNDUCTICM IN MAN Raoesh Dhlnera*. Edward Winslow*. Shahbudln Rahlmtoola*. Maurice Poueet*. and Kenneth Rouen* (SPON: Lawrence Isaac). Unlv, of Illinois Hospitals, Chicago, IL 60612 His bundle (H) recordings were obtained In 43 patients (pts) during Isoproterenol (lap) infusion. The group consisted of 5 with normal end 38 with conduction diaturbances. The mean $Qf A-H interval in 30 pts with normal A-H (<130 msec) was 98 3.1 msec prior to and 77 3*1 msec during lsp. Mean A-H in 9 pts vith prolonged A-H was 192 17.1 msec prior to and 146 14.6 natc during lsp. The mean H-V in 29 pts with nor mal H-V (<55) was 46 1.0 msec prior to and 41 1.0 msec dur ing Infusion. In ll pcs with prolonged H-V, the mean valuaa were 68 2.7 msec prior to and 59 2.7 msec during lsp. All these decreases were significant (p<.01). The following im provements in conduction were noted in pts with 2 and 3 A-V blocks doTlng lsp: 1) total reversal of 2 block proximal to H in 2 of 3 pts, and in L of 2 pts with block distal to H, 2) development of 2:1 conduction in 1 of 3 pts with 3 A-V block and 'split' H potentials, and 3) development of 3:1 conduction In 1 of 3 pts with 3 A-V block distal, to H. In summary, phar macological actions of lsp include facilitation of both normal and depressed conduction in the A-V node and the His Furklnje system, ** SL 036646