Dofetilide enhances the contractility of rat ventricular myocytes via augmentation of Na+-Ca 2+ exchange.

ABSTRACT

PURPOSE: Dofetilide (DOF), a novel Class III antiarrhythmic drug, prolongs the action potential duration (APD) and shows a positive inotropic effect in guinea pig papillary muscle. The present experiments were designed to study the positive inotropic effect of DOF on rat ventricle and explore its possible mechanism(s). METHODS: Hearts from male Wistar rats (260-320 g) were divided into five groups and perfused in Langendorff mode. Ventricular myocytes were enzymatically isolated from male Wistar rats. Whole-cell voltage-clamping technique was used to test the Na(+)-Ca(2+) exchange (NCE) current (I(NCX)); Calcium transients and cell shortening provoked by field stimulation or using calcium current command waveform were observed synchronously with an ionic imaging system. RESULTS: DOF (0.03-1.0 microM) increased left ventricular function in isolated rat hearts in a concentration-dependent manner. DOF (0.03-1.0 microM) also concentration-dependently increased both inward and outward I (NCX) in isolated rat ventricular cells. The EC(50) values of DOF were 0.149 microM for the inward I(NCX) and 0.249 microM for outward I(NCX), respectively. DOF 0.2 microM significantly enhanced Ca(2+) transient and cell shortening in single rat ventricular myocytes driven by field electric stimulation. When the patch clamp system was connected to the ionic imaging system, Ca(2+) current (I(Ca)), Ca(2+) transient and cell shortening amplitude in a same cell were recorded synchronously. Application of DOF 0.2 microM had no effect on I(Ca), but significantly increased Ca(2+) transient and cell shortening. NCX inhibitor KB-R7943 0.6 microM significantly depressed the effects of DOF on Ca(2+) transient and cell shortening. CONCLUSIONS: We conclude that DOF enhanced contractility of rat ventricular myocytes. The enhancement of NCE may be involved in the positive inotropic action of DOF.