Calcium preconditioning (CPC), like ischemic preconditioning (IPC), reduces myocardial infarct size in dogs and rats. ATP-sensitive potassium (K(ATP)) channels induce cardioprotection of IPC in these animals. To determine whether K(ATP) channels mediate both IPC and CPC, pentobarbital sodium-anesthetized rabbits received 30 min of coronary artery occlusion followed by 180 min of reperfusion. LPC was elicited by 5 min of occlusion and 10 min of reperfusion, and CPC was elicited by two cycles of 5 min of calcium infusion with an interval period of 15 min. Infarct size expressed as a percentage of the area at risk was 38 +/- 3% (mean +/- SE) in controls. IPC, CPC, and pretreatment with a K(ATP) channel opener, cromakalim, all reduced infarct size to 13 +/- 2, 17 +/- 2, and 12 +/- 3%, respectively (P < 0.01 vs. controls). Glibenclamide, a K(ATP) channel blocker administered 45 min (but not 20 min) before sustained ischemia, attenuated the effects of IPC and CPC (31 +/- 4 and 41 +/- 6%, respectively). Thus K(ATP) channel activation appears to contribute to these two types of cardioprotection in rabbits.