The detailed antiischemic pharmacology of the potassium channel activator cromakalim was determined in isolated globally ischemic rat hearts and a canine model of coronary occlusion and reperfusion. Cromakalim significantly improved reperfusion function in rat hearts starting at a concentration of 1 microM; this effect peaked at 7 microM. No cardiodepressant effects were observed in nonischemic tissue with cromakalim until a concentration of 100 microM was achieved, and this effect was reversed by glyburide. The antiischemic effect of 7 microM cromakalim was also completely reversed by glyburide and the novel ATP-sensitive potassium channel blocker sodium 5-hydroxydecanoate (5-HD). Glyburide did not reverse the antiischemic effects of 1 microM diltiazem. Cromakalim not only improved reperfusion contractile function in rat hearts, but improved the functional reserve and efficiency of O2 utilization. In anesthetized dogs, intracoronary cromakalim (0.1 micrograms/kg/min given throughout ischemia and reperfusion) significantly reduced infarct size in hearts subjected to 90-min coronary occlusion and 5-h reperfusion. Along with this reduced infarct size, the frequency of ectopic beats and the proportion of animals fibrillating during reperfusion were significantly reduced by cromakalim. In isolated globally ischemic and reperfused rat hearts, cromakalim was significantly profibrillatory. Thus, cromakalim is significantly cardioprotective, and may have the propensity for profibrillatory activity, although this is not true under all conditions.