Greater antiarrhythmic activity of acute 17 β ‐estradiol in female than male anaesthetized rats: correlation with Ca 2+ 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, 17 β ‐estradiol, on ischaemia‐induced cardiac arrhythmias and on the L‐type Ca 2+ current (I CaL ). Experimental approach: In vivo experiments were performed in pentobarbital‐anaesthetized rats subjected to acute coronary artery occlusion. I CaL was measured by the whole‐cell patch‐clamp technique, in rat isolated ventricular myocytes. Key results: Acute intravenous administration of 17 β ‐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 17 β ‐estradiol significantly reduced the number of ventricular premature beats (VPBs) and the incidence of ventricular fibrillation (VF). A ten fold higher dose of 17 β ‐estradiol was required to cause similar effects in male rats. In vitro 17 β ‐estradiol reduced peak I CaL in a concentration‐dependent manner. The EC 50 was ten‐fold higher in male myocytes (0.66 μ M ) than in females (0.06 μ M ). Conclusions and implications: These results indicate that 17 β ‐estradiol has marked dose‐dependent antiarrhythmic activity that is greater in female rats than in males. A similar differential potency in blocking I CaL in myocytes from female and male rats can account for this effect. This provides an explanation for the antiarrhythmic activity of 17 β ‐estradiol and gender‐selective protection against sudden cardiac death. British Journal of Pharmacology (2006) 149 , 233–242. doi: 10.1038/sj.bjp.0706850