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 μmol 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 μmol 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 μmol 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.