Antiarrhythmic effects of MS-551, a new class III antiarrhythmic agent, on experimental canine atrial flutter

J Mol Cell Cardiol 22 (Supplement

111)(1990)

PF43 ANTIARRHYTHMIC

EFFECTS OF MS-551, A NEW CLASS III ANTIARRHYTHMIC AGENT, EXPERIMENTAL CANINE ATRIAL FLUTTER. Joji Kamiya, Makoto Hirayama, Masaaki Ishii, *Tatsuro Yokoyama and *Tsutomu Katakami. Institute of Biological Science, Mitsui Pharmaceuticals Inc., Chiba. and *Central Research Institute, Mitsui Toatsu Chemicals Inc;, Yokohama, Japan. MS-551 shows prolongation of the action potential duration without affecting parameters of action potential depolarization in various preparation5 (atrium, ventricle, Purkinje fiber, pacemaker cell) of different species (guinea-pig, dog, rabbit). Therefore, we studied antiarrhythmic effects of MS-551 on canine atria1 flutter, which was reproducibly induced in the open-chest anesthetized dog with intercaval crush and rapid pacing. MS-551 (0.03-0.3 mg/kg i.v.) converted atria1 flutter to sinus rhythm in 7 of 8 (88%) dogs. In one animal of 8 dogs, MS-551 (0.3 mg/kg i.v.) failed to convert flutter to sinus rhythm, but prolonged atria1 cycle length of flutter from 102 to 133 msec (30%). MS-551 (0.03-0.3 mg/kg i.v.) produced dose-dependent increases in the effective refractory period (2-32%), but did not change the interatrial conduction time during sinus rhythm. These data indicate that MS-551 may convert atria1 flutter to sinus rhythm by lengthening of atria1 refractoriness. ON

EFFECTS OF CLASS III PF44 COMBIPJEU

ANTIC AGENT E4031 AND VERAPAMIL ON VENTRICULAR IMXJCEU BY 24 hr CDRONARY ARTJZRYLIGATION. Hiroshi Katoh, Ken-ichi Nomoto and Kohei Sawada. Department of Pharmacology, Eisai Tsukuba Research Laboratories, Tsukuba, Japan. We examined the effects of E403l(E), verapamil (V) and the combination of these two compounds on the premature ventricular contractions (PVCs) in enflurane-anesthetized dogs in which the left descending coronary artery had been ligated for 24 hr. E at 10 ug/kg (i.v. bolus) reduced both ventricular rate (from 135+21 to 9Okl8 beats/min, pt0.01, n=ll) and total rate (from 165klO to 132*8 beats/min, p
PF45 ELEcrRoPHYsIoIxJGI~

ANTIARRHYTHMIC, AND HEWODYNAMIC PROPWZ OF SEMA’IlLIDE HCl IN CANINE CARDIAC TISSUES. M.E. Sullivan, T.M. Argentieri, RJ. Reiser. Dept. of Pharmacology, Berlex Laboratories, Inc., cedar Knolls, NJ, USA Sematilidc HCl (Se@ was examined in isolated canine cardiac tissues using standard microelectrode techniques. Sempmduced a concentration-dependentincxeaSe in action potential duration of atrial, venaicular, and Purkinje fiber preparations without affecting V,, (0.1-100 JAM). In canine models of arrhythmias thought to be due to enhanced automaticity produced either by ouabain (n=3) or 24hrs following acute infarction (n=lO). Sem was ineffective at doses up to 10 mg/kgj.v. In conscious dogs (n=19) studied 3-8 days following infarction by a reperfusion technique in which reentrant tachycaxlias m induced by programmed stimulation @&VT), in~venous Sem was effective in 8 of 9 dogs at a dose of 1 mgkg, and oral Sem was effective in 7 of 10 dogs at a &se of 2.5 mg/kg. Hemodynamic effects were evaluated in anesthetized (3-30 mg/kgj.v.; n=4) and conscious (100 mgkgj.v.; n4) dogs. In anesthetized dogs, Sem had no significant effect on blood pressute, cardiac output, dP/dt, or coronary flow. In conscious dogs, Sem at a &se 100X the effective andarrhythmic PS-VT dose increased HR, but had no effect on other hemodynamic parameters. No adverse CNS effects were seen at any dose. These nsults indicate that Sem is a class lIl ant&rhythmic agent which is effective against lifethreatening reentrant hythms with no adverse hemodynamic or CNS effects. s.70