Gender-Specificity of Delayed Preconditioning by Isoflurane in Rabbits: Potential Role of Endothelial Nitric Oxide Synthase

In Brief INTRODUCTION: Female gender confers cardioprotection against ischemia-reperfusion injury, in part because estrogen enhances nitric oxide production by endothelial nitric oxide synthase (eNOS). Whether ischemic preconditioning occurs in females remains controversial. Delayed myocardial preconditioning by isoflurane is mediated by eNOS in male rabbits, but whether females are similarly protected by isoflurane is unknown. We tested the hypothesis that gender-specific reductions in myocardial infarct size occur in female rabbits, but that this inherent cardioprotection abrogates further beneficial effects of isoflurane-induced delayed preconditioning. METHODS: Rabbits (n = 115) underwent a 30 min coronary artery occlusion and 3 h reperfusion with or without a 2 h administration of 1.0 minimum alveolar concentration isoflurane one day before experimentation. Rabbits received saline or a nonselective, selective inducible, or selective neuronal NOS inhibitor [N-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), aminoguanidine (AG, 300 mg/kg), or 7-nitroindazole (7-NI, 50 mg/kg), respectively]. RESULTS: Isoflurane reduced infarct size in males (mean± sd, 26 ± 5% of the left ventricular area at risk) versus saline (45 ± 2%). L-NAME, but not AG or 7-NI, abolished isoflurane-induced protection in males (41 ± 9, 24 ± 4 and 22 ± 2%, respectively). Infarct size was reduced, and eNOS protein expression was greater, in female versus male rabbits. Infarct size was unchanged in female rabbits with, versus without, isoflurane pretreatment (27 ± 9 and 27 ± 10%, respectively). L-NAME, but not AG or 7-NI, increased infarct size with or without isoflurane pretreatment in females. CONCLUSIONS: Female gender-induced reductions in infarct size are mediated by eNOS, but remote isoflurane exposure (1.0 MAC) before ischemia and reperfusion does not produce additional cardioprotection in vivo. IMPLICATIONS: Female rabbits demonstrated smaller myocardial infarct size concomitant with upregulation of endothelial nitric oxide synthase as compared to their male counterparts. However, remote isoflurane exposure before ischemia and reperfusion did not produce additional cardioprotection in female in contrast to male rabbits. These data suggest that isoflurane-induced delayed preconditioning is gender-specific.