Effects of flecainide (a class IC antiarrhythmic drug) on the maximum rate of rise (Vmax) of action potentials (APs) were studied in guinea-pig papillary muscles, with special reference to their time, voltage, and action potential duration (APD) dependence in the presence and absence of nicorandil. Nicorandil was used to shorten APD, i.e., the time period of inactivation state of sodium channels. APs were recorded from the preparations using standard microelectrode techniques. Flecainide (5 mumol/l) reduced Vmax without changing resting potential, AP amplitude, APD50, and APD90 examined at 1 Hz. The drug shifted the normalized Vmax-membrane potential curve (examined at 1/60 Hz) in the hyperpolarizing direction by 3.1 +/- 0.8 mV (n = 6) (voltage dependence). The drug caused a frequency-dependent reduction of Vmax at greater than or equal to 0.1 Hz, developed a use-dependent reduction of Vmax at 1 Hz with an onset time constant of 11.7 +/- 0.4 s (n = 6), and slowed the recovery process of Vmax, whose resultant recovery time constant was 19.9 +/- 1.2 s (n = 6) (time dependence). These flecainide-induced time-dependent reductions of Vmax were not antagonized by nicorandil (1 mmol/l) which shortened APD to about 1/4 of control (APD independence). These results suggest that flecainide is primarily an open channel blocker because its channel-blocking actions are independent of APD or the time period of inactivation.
1. The effects of 14 lignocaine homologues on the maximum upstroke velocity (Vmax) of the action potentials (AP) were studied in guinea-pig papillary muscles. These drugs possess one, two or three methyl groups in different positions: an ortho-chloro, -carbomethoxy or -ethyl group instead of an ortho-methyl group; or an N-butyl group instead of an N-diethyl group in lignocaine molecules. 2. At 50-100 mumol/L, six drugs possessing two ortho substituents (but not the other eight) reduced Vmax more prominently at 2-4 Hz than at 1 Hz, and slowed the time courses of recovery of the premature responses. None of the drugs affected resting potential. 3. Besides the two-state piecewise exponential model (models I and II) frequently used, a time-dependent and time-independent, two-state model (model III) was formulated and applied to these experimental data. The above two groups were effectively distinguished by the difference of the estimated association and dissociation rate constants (model II) and equilibrium constants for phasic state (model III) and for resting (model II) or tonic (model III) states. 4. The equilibrium constants for resting or tonic state correlated well with log P (where P = the n-octanol: water partition coefficients), but correlated better with an indicator variable that denotes the existence of two ortho substituents, suggesting the importance of the contribution of steric factors to the activity.
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