Evidence for inhibition by ICS 205-930 and stimulation by BRL 34915 of K+ conductance in cardiac muscle

Abstract

Electrophysiological effects of the 5-HT3 receptor antagonist ICS 205-930 [(3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester] were investigated in guinea pig isolated heart preparations. ICS 205-930 prolonged the functional refractory period and decreased the force of contraction in left driven atria. It decreased spontaneous beating rate in right atria. These effects were concentration dependent between 3 X 10(-6) and 10(-4) mol/l of ICS 205-930. In fast action potentials of papillary muscles ICS 205-930 concentration-dependently depressed Vmax and prolonged the action potential duration (APD) between 10(-6) and 10(-5) mol/l. The action potential amplitude (APA) and the resting membrane potential (RMP) remained unchanged. In papillary muscles partially depolarized by high K+ (22 mmol/l) and reactivated by high voltage stimulation, slow response APs were prolonged by ICS 205-930 10(-6) to 3 X 10(-5) mol. Vmax, APA and RMP were not affected. Similar effects on APD were obtained with sotalol (3 X 10(-5) mol/l), an inhibitor of outward K+ current. The slow-APD prolongation induced by ICS 205-930 as well as by sotalol was reversed by BRL 34915 (6-cyano-3,4-dihydro-2,2-dimethyltrans-4-(2-oxo-1-pyrrolidyl )-2H-benzo[b]pyran-3-ol), known to open K+ channels. BRL 34915 alone reduced slow-APD stereoselectively. The results suggest that ICS 205-930 may inhibit and BRL 34915 may stimulate the K+ conductance of guinea pig myocardial cell membranes.(ABSTRACT TRUNCATED AT 250 WORDS)