We examined the effects of the potassium channel openers (PCOs) pinacidil and lemakalim (BRL 38227) on action potential (AP) configurations and outward currents in atrial and ventricular myocytes isolated from rabbit and guinea pig hearts, using the whole-cell configuration of the patch clamp technique at 33 degrees-35 degrees C. The PCOs known to activate ATP-sensitive K+ current (IKATP) in various tissues, induced this current and decreased AP duration (APD) in rabbit ventricular myocytes. In contrast, in rabbit atrial myocytes, PCOs either had no effect or increased duration and plateau amplitude of the AP. The predominant outward current in rabbit atrial myocytes is a 4-aminopyridine (4-AP)-sensitive transient outward current (Ito). The PCOs caused a decrease in Ito without inducing IKATP in rabbit atria. In identical experimental conditions, PCOs activated IKATP in both guinea pig atrial and ventricular myocytes. Our results suggest that (a) a species as well as cardiac tissue difference exists in responsiveness to PCOs, and (b) the decrease in Ito without concomitant induction of IKATP can lead to changes in AP configuration opposite to that expected from IKATP activation. Different effects of PCOs on distinct parts of the heart could lead to disparity in APD and refractoriness that may contribute to arrhythmogenesis.