Gender differences in sarcoplasmic reticulum calcium loading after isoproterenol

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Abstract
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 Ca2+ 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 NG-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.