Nicorandil shortens action potential duration and antagonises the reduction of Vmax by lidocaine but not by disopyramide in guinea-pig papillary muscles.

Abstract

Conventional microelectrode techniques were used to examine whether or not nicorandil, which shortens action potential duration (APD), modifies the lidocaine- or disopyramide-induced time-dependent reduction of Vmax in guinea-pig papillary muscles. First, effects of 0.1 and 1 mmol/l nicorandil were examined on the frequency dependence of Vmax and on the recovery process of Vmax. Second, the frequency-dependent reduction of Vmax by 20 mumol/l antiarrhythmic drugs was examined in the presence and absence of 1 mmol/l nicorandil at stimulation frequencies of 1/120 Hz - 5 Hz. Third, the recovery process of Vmax in the presence of 20 mumol/l antiarrhythmic drugs was examined, with and without 1 mmol/l nicorandil, by applying test stimuli at various diastolic intervals after conditioning stimuli. 1 mmol/l nicorandil greatly shortened APD90 to 30-40% of control without changing the frequency dependence of Vmax, the recovery process of Vmax, and the resting potential. The lidocaine-induced, frequency-dependent reduction of Vmax was significantly antagonised by 1 mmol/l nicorandil, but the disopyramide-induced reduction was not. The recovery process of Vmax slowed in the presence of lidocaine was antagonised by 1 mmol/l nicorandil as follows: the time to get the full recovery of Vmax was shortened by nicorandil with a significant decrease in the zero time-intercept (from 0.54 to 0.38) but with an insignificant change in the recovery time constant (from 130 ms to 121 ms). In contrast, the recovery process of Vmax slowed in the presence of disopyramide (a zero time intercept of 0.13 and a recovery time constant of 50 s) was not significantly antagonised by 1 mmol/l nicorandil. In conclusion, nicorandil having an action potential-shortening action antagonises the lidocaine-induced, time-dependent reductions of Vmax, but not the disopyramide-induced reductions. These results suggest that: (1) lidocaine and disopyramide preferentially bind to inactivated and activated sodium channels, respectively, because lidocaine's effects are dependent on and disopyramide's effects are independent of APD (during which sodium channels are in the inactivated state); and (2) nicorandil is a useful drug for estimating whether a sodium channel-blocking action of class I antiarrhythmic drugs is due to an inactivated channel block or an activated channel block. These time-dependent reductions of Vmax by both lidocaine and disopyramide were well simulated by the guarded receptor hypothesis.