Modelling frequency- and voltage-dependent effects of a class I antiarrhythmic drug (nicainoprol) on Vmax of the cardiac action potential from guinea-pig papillary muscle.

Frequency- and voltage-dependent effects of a class I antiarrhythmic agent (nicainoprol) on the maximal upstroke velocity (Vmax) of the action potential of guinea-pig papillary muscle are compared with the effects predicted by a kinetic model of frequency- and voltage-dependent block of fast sodium channels. The model is based on the guarded-receptor hypothesis, which assumes a constant affinity binding site with the drug access to and egress from the binding site being controlled by the channel conformational state. At normal resting membrane potential (RMP approximately -86 mV) nicainoprol (3.3 x 10(-6) mol/l and 10(-5) mol/l) causes no Vmax-reduction after a resting period (i.e. no resting block) but a frequency-dependent decrease of Vmax (frequency-dependent block), which saturates at above 2.0 Hz. Both, resting and frequency-dependent block strongly depend on the RMP in a way that the frequency-dependent block decreases with depolarizing RMP while the resting block increases. Development of and recovery from frequency-dependent block is faster at depolarized RMP. These results can be interpreted in terms of the guarded-receptor hypothesis with nicainoprol preferentially binding to inactivated sodium channels. All its effects on Vmax can be fully described by only three model parameters: a binding rate coefficient (kB = 8.49 x 10(3) mol-1.1.s-1), an unbinding rate coefficient (k-B = 6.24 x 10(-2).S-1), and a parameter with the meaning of an electrical location of the binding site (about 35% on the way through the membrane field from the extracellular surface).