CARDIAC ELECTROPHYSIOLOGIC AND ANTIARRHYTHMIC ACTIONS OF 3,4-DIHYDRO-1'-[2-(BENZOFURAZAN-5-YL) AMIDOSPIRO[(2H)-1-BENZOPYRAN-2,4'-PIPERIDIN]-4-ONE HCL (L-691, 121), A NOVEL CLASS-III AGENT

The cardiac electrophysiologic and antiarrhythmic actions of idos-piro [(H-2)-l-benzopyran-2,4'-piperidin]-4-one HCl (L-691,121), a novel spi robenzopyran piperidine class III agent, were assessed in vitro and in vivo. In ferret isolated papillary muscles, L-691,121 significantly p rolonged effective refractory period (EC25 = 13 nM) and elicited a mod est positive inotropic effect. In guinea pig isolated ventricular myoc ytes, L-691,121 prolonged action potential duration by selectively blo cking (IC50 = 4.4 nM) a rapidly activating and rectifying component of the delayed rectifier K+ current, I(Kr). The class III activity of L- 691,121 in isolated papillary muscles was reverse frequency-dependent, and reversed by hypoxic perfusion. L-691,121 modestly depressed spont aneous beating rate (-14%) in guinea pig isolated right atria at conce ntrations up to 3 muM. In anesthetized dogs, the i.v. administration o f 1 0 to 1 00 mug/kg of L-691,121 significantly increased atrial and v entricular refractoriness and prolonged the electrocardiographic Q-T i nterval, but did not alter atrioventricular nodal, His-Purkinje, atria l or ventricular conduction. In conscious dogs with spontaneous premat ure ventricular complexes at 48 hr after myocardial infarction, 10 to 1000 mug/kg i.v. of L-691,121 failed to reduce premature ventricular c omplex frequency. However, in anesthetized dogs studied chronically (7 .9 +/- 0.3 days) after infarction, 10 and 100 mug/kg i.v. of L-691,121 suppressed the induction of ventricular tachyarrhythmia by programmed stimulation in 8/14 (57%) and 11/14 (79%) dogs tested, respectively, and reduced the incidence of lethal ventricular arrhythmias triggered by a secondary myocardial ischemic event from 14/15 (93%) in vehicle c ontrols to 5/14 (36%; P < .01) in L-691,121 -treated (100 mug/kg i.v.) animals. The latter findings suggest the potential for L-691, 121 to prevent the development of malignant ventricular arrhythmias in the se tting of previous myocardial infarction.