Na + channel blocking effects of cibenzoline on guinea-pig ventricular cells

Abstract

The effects of cibenzoline on transmembrane action potentials were examined in right ventricular papillary muscles and in single ventricular myocytes isolated from guinea-pig hearts. In papillary muscles, cibenzoline ≥3 μM caused a significant decrease in the maximum upstroke velocity ( V max) of the action potential without affecting the action potential duration. The inhibition of V max was enhanced at higher stimulation frequencies. In the presence of cibenzoline, trains of stimuli at rates ≥0.2 Hz led to a use-dependent inhibition of V max. The time constant for V max recovery ( τ R) from the use-dependent block was 26.2 s. The use-dependent block of V max with cibenzoline was enhanced and τ R was shortened when the resting potential was depolarized by high (8, 10 mM) [K +] o. The curve relating membrane potential and V max in single myocytes was shifted by cibenzoline (10 μM) in a hyperpolarizing direction by 7.1 mV. In myocytes treated with cibenzoline (10 μM), a 10-ms conditioning clamp to 0 mV caused a significant decrease in V max of the subsequent test action potential; the V max inhibition was enhanced modestly in association with a prolongation of the 0 mV clamp pulse duration. In the presence of cibenzoline (3 μM), application of a train of depolarizing pulses (10 ms, 200 ms) to myocytes from the resting level (−80 mV) to 0 mV resulted in a progressive V max reduction in a pulse number-dependent manner. Unlike glibenclamide (30 μM), cibenzoline (10 μM) did not prevent the hypoxia-induced shortening of action potential duration in papillary muscles. These findings indicate that the onset and offset kinetics of use-dependent Na + channel block by cibenzoline are slow. Given its state dependence, cibenzoline may be a blocker of activated Na + channels. The inhibitory action of this compound on the ATP-sensitive K + current ( I K, ATP) would be minimal or negligible at concentrations causing sufficient Na + channel block.