A New Class III Antiarrhythmic Drug Niferidil Prolongs Action Potentials in Guinea Pig Atrial Myocardium via Inhibition of Rapid Delayed Rectifier.

Abstract

A new class III antiarrhythmic drug niferidil (RG-2) has been introduced as a highly effective therapy for cases of persistent atrial fibrillation, but ionic mechanisms of its action are poorly understood. In the present study, the effects of niferidil on action potential (AP) waveform and potassium currents responsible for AP repolarization were investigated in guinea pig atrial myocardium. APs were recorded with sharp glass microelectrodes in multicellular atrial preparations. Whole-cell patch-clamp technique was used to measure K+ currents in isolated myocytes. In multicellular atrial preparations, 10-8M niferidil effectively prolonged APs by 15.2±2.8% at 90% repolarization level. However, even the highest tested concentrations, 10-6M and 10-5M failed to prolong APs more than 32.5% of control duration. The estimated concentration of niferedil for half-maximal AP prolongation was 1.13×10-8M. Among the potassium currents responsible for AP repolarization phase, I K1 was found to be almost insensitive to niferidil. However, another inward rectifier, I KACh, was effectively suppressed by micromolar concentrations of niferidil with IC50=9.2×10-6M. I KATP was much less sensitive to the drug with IC50=2.26×10-4M. The slow component of delayed rectifier, I Ks, also demonstrated low sensitivity to niferidil-the highest used concentration, 10-4M, decreased peak I Ks density to 46.2±5.5% of control. Unlike I Ks, the rapid component of delayed rectifier, I Kr, appeared to be extremely sensitive to niferidil. The IC50 was 1.26×10-9M. I Kr measured in ventricular myocytes was found to be less sensitive to niferidil with IC50=3.82×10-8M. Niferidil prolongs APs in guinea pig atrial myocardium via inhibition of I Kr.