Summary
Frequency- and voltage-dependent effects of a class I antiarrhythmic agent (nicainoprol) on the maximal upstroke velocity (max) 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 ≈ −86 mV) nicainoprol (3.3 × 10−6 mol/l and 10−5 mol/l) causes no max-reduction after a resting period (i. e. no resting block) but a frequency-dependent decrease of max (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 max can be fully described by only three model parameters: a binding rate coefficient (k B= 8.49 × 103 mol−1 · l · s−1), an unbinding rate coefficient (k −B = 6.24 × 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).
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Supported by the Forschungs-Schwerpunkt-Programm des Landes Baden-Württemberg Nr. 14
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Weirich, J., Antoni, H. Modelling frequency- and voltage-dependent effects of a class I antiarrhythmic drug (nicainoprol) on max of the cardiac action potential from guinea-pig papillary muscle. Naunyn-Schmiedeberg's Arch Pharmacol 340, 456–464 (1989). https://doi.org/10.1007/BF00167049
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DOI: https://doi.org/10.1007/BF00167049