Greater antiarrhythmic activity of acute 17β‐estradiol in female than male anaesthetized rats: correlation with Ca²⁺ channel blockade

BACKGROUND AND PURPOSE: Female sex hormones may protect pre-menopausal women from sudden cardiac death. We therefore investigated the effects of the main female sex hormone, 17beta-estradiol, on ischaemia-induced cardiac arrhythmias and on the L-type Ca2+ current (ICaL). EXPERIMENTAL APPROACH: In vivo experiments were performed in pentobarbital-anaesthetized rats subjected to acute coronary artery occlusion. ICaL was measured by the whole-cell patch-clamp technique, in rat isolated ventricular myocytes. KEY RESULTS: Acute intravenous administration of 17beta-estradiol as a bolus dose followed by a continuous infusion, commencing 10 min before coronary artery occlusion, had dose-dependent antiarrhythmic activity. In female rats 300 ng kg(-1) + 30 ng kg(-1) min(-1) 17beta-estradiol significantly reduced the number of ventricular premature beats (VPBs) and the incidence of ventricular fibrillation (VF). A ten fold higher dose of 17beta-estradiol was required to cause similar effects in male rats. In vitro 17beta-estradiol reduced peak ICaL in a concentration-dependent manner. The EC50 was ten-fold higher in male myocytes (0.66 microM) than in females (0.06 microM). CONCLUSIONS AND IMPLICATIONS: These results indicate that 17beta-estradiol has marked dose-dependent antiarrhythmic activity that is greater in female rats than in males. A similar differential potency in blocking ICaL in myocytes from female and male rats can account for this effect. This provides an explanation for the antiarrhythmic activity of 17beta-estradiol and gender-selective protection against sudden cardiac death.