Sex differences in myocardial infarct size are abolished by sarcolemmal KATP channel blockade in rat. Am J Physiol Heart Circ Physiol 290: H2644 -H2647, 2006. First published February 10, 2006 doi:10.1152/ajpheart.01291.2005.-This study was conducted to examine the relationship between myocardial ATP-sensitive potassium (KATP) channels and sex differences in myocardial infarct size after in vitro ischemia-reperfusion (I/R). Hearts from adult male and female Sprague-Dawley rats were excised and exposed to an I/R protocol (1 h of ischemia, followed by 2 h of reperfusion) on a modified Langendorff apparatus. Hearts from female rats showed significantly smaller infarct sizes than hearts from males (23 Ϯ 4 vs. 40 Ϯ 5% of the zone at risk, respectively; P Ͻ 0.05). Administration of HMR-1098, a sarcolemmal K ATP channel blocker, abolished the sex difference in infarct size (42 Ϯ 4 vs. 45 Ϯ 5% of the zone at risk in hearts from female and male rats, respectively; P ϭ not significant). Further experiments showed that blocking the KATP channels in ischemia, and not reperfusion, was sufficient to increase infarct size in female rats. These data demonstrate that sarcolemmal KATP channels are centrally involved in mechanisms that underlie sex differences in the susceptibility of the intact heart to I/R injury. heart; ischemia; reperfusion ISCHEMIC HEART DISEASE is the leading cause of death in both males and females in the industrialized world, with myocardial infarction being the most common manifestation of ischemic heart disease (18). Among humans, premenopausal women have a lower risk of cardiovascular disease than age-matched men, and there is growing evidence that there is a sex-specific difference in the susceptibility of the myocardium to infarction after ischemia in dogs (15), rats (1, 4), mice (10, 11), as well as in humans (19).The cellular basis for sex differences in the susceptibility of the heart to ischemia-reperfusion (I/R) injury has not been elucidated. However, there has been speculation that that sarcolemmal ATP-sensitive potassium (sarcK ATP ) channels are involved. This speculation derives from observations that, relative to males, the protein expression of sarcK ATP channel subunits [inwardly rectifying K ϩ (Kir)6.2 and sulfonylurea receptor (SUR)2a] is greater in hearts from females (4, 26). Additionally, treatment of heart-derived H9c2 cells with 17-estradiol elicits a marked increase in the expression of both Kir6.2 and SUR2a subunits and an increase in the resistance of those cells to hypoxia-induced Ca 2ϩ overload that, in turn, could be abolished by sarcK ATP channel blockade with HMR-1098 (25). Whereas these observations clearly implicate a role for sarcK ATP channels in the sex-dependent differences in the susceptibility of the heart to I/R injury, pharmacological blockade of sarcK ATP channels in the intact heart has not been performed to confirm their role in sex-dependent cardioprotection. Thus the major objective of this study was to determine whether blocking sarcK ATP channels would ab...