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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+–Ca2+ 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 μM) increased left ventricular function in isolated rat hearts in a concentration-dependent manner. DOF (0.03–1.0 μM) also concentration-dependently increased both inward and outward I NCX in isolated rat ventricular cells. The EC50 values of DOF were 0.149 μM for the inward I NCX and 0.249 μM for outward I NCX, respectively. DOF 0.2 μM significantly enhanced Ca2+ 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, Ca2+ current (I Ca), Ca2+ transient and cell shortening amplitude in a same cell were recorded synchronously. Application of DOF 0.2 μM had no effect on I Ca, but significantly increased Ca2+ transient and cell shortening. NCX inhibitor KB-R7943 0.6 μM significantly depressed the effects of DOF on Ca2+ 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. [ABSTRACT FROM AUTHOR]