Cromakalim has been shown to have anti-ischemic properties, but it also produces profound hypotension upon systemic administration. We hypothesized that U-89,232, a cromakalim analog, would reduce infarct size in an ischemia-reperfusion injury model without hemodynamic alteration. Twenty-four anesthetized, open chest New Zealand White rabbits were instrumented for occlusion of a marginal branch of the left coronary artery. All animals were subjected to coronary artery occlusion (30 min) and reperfusion (2 hr). Study animals received either cromakalim (20 micrograms/kg, i.v.) or U-89,232 (20 micrograms/kg, i.v.), which was given as a pretreatment 30 min before occlusion. Control animals (n = 10) received vehicle (10% dimethyl sulfoxide). At termination of the experiment, the necrotic area and the area at risk were determined with tetrazolium and India ink staining, and infarct size was calculated using planimetry. Treatment with cromakalim produced profound hypotension (greater than 30% decrease in mean arterial pressure), whereas U-89,232 had no such hemodynamic effect. With comparable areas at risk, infarct size (as a percent of risk area) in the control animals was 46.8 +/- 3.4%. Treatment with cromakalim or U-89,232 reduced infarct size to 33.1 +/- 4.4 and 24.4 +/- 4.0%, respectively (P < .05, both compared to control). In vitro studies demonstrate that although both of these compounds shorten the duration of the cardiac action potential, only cromakalim is active in vascular smooth muscle. We conclude that U-89,232 exhibits myoprotection without hypotension, and that its mechanism of action is most likely due to ability to affect cardiac electrophysiology.