Combined class I antiarrhythmic agents have differential effects on tonic and use dependent block of maximum rate of depolarisation of action potentials in guinea pig cardiac muscle

Abstract

Objective: The aim was to study the difference between tonic and use dependent block of the cardiac sodium channel produced by the combined application of the same subclass of antiarrhythmic agents (class Ia or Ib).

Methods: Conventional glass microelectrode technique was used to record the maximum rate of depolarisation (dV/dtmax) of action potentials reflecting sodium channel availability, before and after the combined application of quinidine plus disopyramide, aprindine plus lignocaine, aprindine plus mexiletine, and lignocaine plus mexiletine. Guinea pig papillary muscles (n = 4-8 per experiment) were used for the study.

Results: All combinations increased tonic block additively compared to use of a single drug. On the other hand, use dependent block was increased by the combination of quinidine 10 microM plus disopyramide 30 microM compared to a single drug, and was not changed by lignocaine 50 microM plus mexiletine 20 microM, whereas it was decreased by aprindine 3 microM plus lignocaine 50 microM or mexiletine 20 microM. When concentrations of mexiletine and lignocaine were increased, both tonic and use dependent block in a single drug were increased dose dependently, whereas the combination produced an additive increase in tonic block but no change in use dependent block compared to a single drug.

Conclusions: The results suggested that the binding and unbinding process of the drug to produce tonic block was different from that to produce use dependent block, and that combination of different drugs produced diverse effects on use dependent block even though state dependent affinity of individual drugs seemed similar. These two factors must be born in mind in evaluating the combination therapy.