Characterization of the interaction of R 56865 with cardiac Na- and L-type Ca channels.

1. In isolated cardiac muscle, submicromolar concentrations of R 56865 (N-[1-[4-(4-fluorophenoxy)-butyl]-4-piperidinyl]-N-methyl-2- benzothiazolamine) have been shown to attenuate the toxicity of cardiac glycosides. 2. We studied the influence of R 56865 on calcium and sodium currents in single isolated ventricular cardiomyocytes. The effect of R 56865 on action potential and contractile force in the presence of increased sodium load was also tested by exposing papillary muscles to veratridine or Anemonia sulcata toxin ATX II. 3. The calcium current was not affected by R 56865 as assessed in slow action potentials of papillary muscles and current measurements in ventricular cardiomyocytes. 4. In papillary muscles, R 56865 (1 mumol l-1) abolished veratridine-induced aftercontractions and afterdepolarizations without affecting the profound prolongation of the action potential. When pretreated with R 56865, the occurrence of afterdepolarizations was prevented and the decline of the resting membrane potential was attenuated. 5. Pretreatment with R 56865 (1 mumol l-1) did not counteract the ATX II-induced prolongation of the action potential. 6. The sodium current (Nao 30 mmol l-1) was concentration-dependently decreased by R 56865 (0.1-10 mumol l-1). The blocking effect was more pronounced at less negative holding potentials. 7. Our results demonstrate that the protective effect of R 56865 against veratridine-induced electrical and mechanical oscillations is not due to a direct effect on the calcium current. A potential-dependent inhibition of the sodium current may contribute. Additional sites of action, like interference with intracellular calcium release and inhibition of potassium currents, remain to be investigated.