NA-PIG VENTRICULAR CELLS( CHANNEL BLOCKING EFFECTS OF CIBENZOLINE ON GUINEA)

The effects of cibenzoline on transmembrane action potentials were exa mined in right ventricular papillary muscles and in single ventricular myocytes isolated from guinea-pig hearts. In papillary muscles, ciben zoline greater than or equal to 3 mu M caused a significant decrease i n the maximum upstroke velocity (V-max) of the action potential withou t affecting the action potential duration. The inhibition of V-max was enhanced at higher stimulation frequencies. In the presence of cibenz oline, trains of stimuli at rates greater than or equal to 0.2 Hz led to a use-dependent inhibition of V-max. The time constant for V-max re covery (tau(R)) from the use-dependent block was 26.2 a. The use-depen dent block of V-max with cibenzoline was enhanced and tau(R) was Short ened when the resting potential was depolarized by high (8, 10 mM) [K](o). The curve relating membrane potential and V-max in single myocyt es was shifted by cibenzoline (10 mu M) in a hyperpolarizing direction by 7.1 mV. In myocytes treated with cibenzoline (10 mu M), a 10-ms co nditioning clamp to 0 mV caused a significant decrease in V-max of the subsequent test action potential; the V-max inhibition was enhanced m odestly in association with a prolongation of the 0 mV clamp pulse dur ation. In the presence of cibenzoline (3 mu M), application of a train of depolarizing pulses (10 ms, 200 ms) to myocytes from the resting l evel (- 80 mV) to 0 mV resulted in a progressive V-max reduction in a pulse number-dependent manner. Unlike glibenclamide (30 mu M), cibenzo line (10 mu M) did not prevent the hypoxia-induced shortening of actio n potential duration in papillary muscles. These findings indicate tha t 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 comp ound on the ATP-sensitive K+ current (I-K,( ATP)) would be minimal or negligible at concentrations causing sufficient Na+ channel block. (C) 1998 Elsevier Science B.V. All rights reserved.