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

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Summary 1. Electrophysiological effects of the 5-HT3 receptor antagonist ICS 205-930 [(3α-tropanyl)-1H-indole-3-carboxylic acid ester] were investigated in guinea pig isolated heart preparations. 2. 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 × 10−6 and 10−4 mol/1 of ICS 205-930. 3. In fast action potentials of papillary muscles ICS 205–930 concentration-dependently depressed V max and prolonged the action potential duration (APD) between 10−6 and 10−5 mol/1 The action potential amplitude (APA) and the resting membrane potential (RMP) remained unchanged. 4. In papillary muscles partially depolarized by high K+ (22 mmol/1) and reactivated by high voltage stimulation, slow response AN were prolonged by ICS 205-930 10−6 to 3 × 10−5 mol. V max, APA and RMP were not affected. Similar effects on APD were obtained with sotalol (3 × 10−5 mol/1), an inhibitor of outward K+ current. 5. 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. 6. The results suggest that ICS 205–930 may inhibit and BRL 34915 may stimulate the K+ conductance of guinea pig myocardial cell membranes. In addition, ICS 205–930 may inhibit the rapid inward Na+ current. These findings are discussed in view of the antiarrhythmic effects of ICS 205–930.

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