17beta-Estradiol decreases vulnerability to ventricular arrhythmias by preserving connexin43 protein in infarcted rats.

Epidemiological studies showed that a lower mortality rate of sudden cardiac death among women than among men may depend on the action of female sex hormones. This study assessed whether 17beta-estradiol exerts anti-arrhythmic effects through enhanced Connexin43 (Cx43) expression after infarction. Two weeks after ovariectomy, female Wistar rats were randomly assigned to coronary artery ligation or sham-operation. Twenty-four hours after coronary ligation, ovariectomized rats were randomized into vehicle, subcutaneous estradiol treatment, tamoxifen, or subcutaneous estradiol treatment+tamoxifen and followed for 4weeks. To verify the role of estradiol-related nitric oxide in modulating the expression of Cx43, N-nitro-L-arginine methyl ester was also assessed in an in vitro study. Myocardial Cx43 expression revealed a significant decrease in vehicle-treated infarcted rats compared with sham-operated rats at 24h and 4weeks after infarction. Attenuated Cx43 expression was blunted after administering estradiol, assessed by immunofluorescent analysis, Western blotting, and real-time quantitative RT-PCR of Cx43. The vulnerability for ventricular arrhythmia during programmed stimulation in estradiol-treated infarcted rats was significantly lower than in vehicle-treated infarcted rats. The beneficial effect of estradiol on Cx43 was abolished by tamoxifen. In addition, the invitro study demonstrated that the amount of Cx43 showed significant reduction after adding N-nitro-L-arginine methyl ester. Chronic administration of estradiol after infarction is associated with attenuated reduction of gap junction proteins probably through a nitric oxide-dependent pathway via the estrogen receptor and thus plays a critical role in the beneficial effect on arrhythmic vulnerability response to programmed electrical stimulation.