Electrophysiologic effects of nicorandil, a new antianginal agent, on action potentials and membrane currents of rabbit atrioventricular node

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Abstract
Electrophysiologic effects of nicorandil, a newly developed coronary vasodilator, on the atrioventricular (AV) node were studied using space-clamped small preparations of the rabbit AV node. At the concentrations of 10−6, 10−5 and 10−4 mol/l, this drug did not cause significant changes in the action potential characteristics including the spontaneous firing frequency, overshoot, maximum diastolic potential, maximum rate of depolarization and action potential duration. When the resting membrane potential of the AV node was obtained by a superfusion with verapamil and then nicorandil was added to the perfusate, no hyperpolarization was observed. This was in sharp contrast to the reported hyperpolarizing action of this drug on the atrial muscle, Purkinje fibres and vascular smooth muscle where the resting potential is much more negative. On the other hand, voltage clamp experiments using double microelectrode techniques revealed that 10−5 to 10−4 mol/l nicorandil increased the steady-state outward current at potentials positive to −40 mV and the steady-state inward current at potentials negative to −40 mV. Such a nicorandil-sensitive component of the steady-state current had an average reversal potential of −41.8 mV (n = 5). This component was considered to reflect changes in the time-independent background current, although, at more negative potential levels, it may partially reflect an increase in the hyperpolarization activated inward current (i h). Nicorandil, at the concentrations of 10−5 and 10−4 mol/l, increased the slow inward current (i si) by 10.8% (n = 5, p < 0.01). As the inactivation kinetics of the i si was not affected after the application of nicorandil, the increase in the may well be attributed to an increase in the fully activated i si (i si). It was also shown that the increase in the i si was not mediated by neurotransmitters, as an increase of a similar degree was again observed in the presence of either propranolol or atropine. The apparent discrepancy between the effects of nicorandil on the action potential configuration and on the membrane currents may have resulted from cancellations between the inward increase in the i si and the outward increase in the background current during the action potential. Possible implications of these nicorandil effects in modifying AV conduction were discussed.