EFFECTS OF TEDISAMIL (KC-8857) ON CARDIAC ELECTROPHYSIOLOGY AND VENTRICULAR-FIBRILLATION IN THE RABBIT ISOLATED HEART

1 The direct cardiac electrophysiological and antifibrillatory actions of tedisamil (KC-8857) were studied in rabbit isolated hearts. 2 Tedi samil (1, 3, and 10 mu M), prolonged the ventricular effective refract ory period (VRP) from 120+/-18 ms (baseline) to 155+/-19, 171+/-20, an d 205+/-14 ms, respectively. Three groups of isolated hearts (n=6 each ) were used to test the antifibrillatory action of tedisamil. Hearts w ere perfused with 1.25 mu M pinacidil, a K-ATP channel activator. Hear ts were subjected to hypoxia for 12 min followed by 40 min of reoxygen ation. Ventricular fibrillation (VF) developed during hypoxia and reox ygenation in both the control and 1 mu M tedisamil treated groups (5/6 and 4/6, respectively). Tedisamil (3 mu M) reduced the incidence of V F (0/6, P=0.007 vs. control). 3 In a separate group of hearts, VF was initiated by electrical stimulation. The administration of 0.3 mi of 1 0 mM tedisamil, via the aortic cannula, terminated VF in all hearts, c onverting them to normal sinus rhythm. 4 Tedisamil (3 mu M) reversed p inacidil-induced negative inotropic effects in rabbit isolated atrial muscle which were equilibrated under normoxia, as well as in atrial mu scle subjected to hypoxia and reoxygenation. 5 The results demonstrate a direct antifibrillatory action of tedisamil in vitro. The mechanism responsible for the observed effects may involve modulation by tedisa mil of the cardiac ATP-regulated potassium channel, in addition to its antagonism of I-K and I-to.