Gender differences in sarcoplasmic reticulum calcium loading after isoproterenol

Males exhibit enhanced myocardial ischemia-reperfusion injury versus females under hypercontractile conditions associated with increased sarcoplasmic reticulum (SR) Ca²⁺. We therefore examined whether there were gender differences in SR Ca²⁺. We used NMR Ca ²⁺ indicator 1,2-bis(2-amino-5,6-difluorophenoxy)-ethane-N,N,N′ ,N′-tetraacetic acid to measure SR Ca²⁺ in perfused rabbit hearts. Isoproterenol increased SR Ca²⁺ in males from a baseline of 1.13 ± 0.07 to 1.52 ± 0.24 mM (P < 0.05). Female hearts had basal SR Ca²⁺ that was not significantly different from males (1.04 ± 0.03 mM), and addition of isoproterenol to females resulted in a time-averaged SR Ca²⁺ (0.97 ± 0.07 mM) that was significantly less than in males. To confirm this difference, we measured caffeine-induced release of SR Ca²⁺ with fura-2 in isolated ventricular myocytes. Ca²⁺ release after caffeine in untreated male myocytes was 377 ± 41 nM and increased to 650 ± 55 nM in isoproterenol-treated myocytes (P < 0.05). Ca²⁺ release after caffeine addition in untreated females was 376 ± 27 nM and increased to 503 ± 49 nM with isoproterenol, significantly less than in male myocytes treated with isoproterenol (P < 0.05). Treatment of female myocytes with N ^G-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase (NOS), resulted in higher SR Ca²⁺ release than that measured in females treated only with isoproterenol and was not significantly different from that measured in males with isoproterenol. Female myocytes also have significantly higher levels of neuronal NOS. This gender difference in SR Ca²⁺ handling may contribute to reduced ischemia-reperfusion injury observed in females.