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

Philp, K.L. and Hussain, M. and Byrne, N.F. and Diver, M.J. and Hart, G. and Coker, Susan J. (2006) Greater antiarrhythmic activity of acute 17ß-estradiol in female than male anaesthetized rats: correlation with Ca2+ channel blockade. British Journal of Pharmacology, 149. pp. 233-242. ISSN 0007-1188

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Abstract

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, 17β-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 17β-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 17β-estradiol significantly reduced the number of ventricular premature beats (VPBs) and the incidence of ventricular fibrillation (VF). A ten fold higher dose of 17β-estradiol was required to cause similar effects in male rats. In vitro 17β-estradiol reduced peak ICaL in a concentration-dependent manner. The EC50 was ten-fold higher in male myocytes (0.66 μM) than in females (0.06 μM). Conclusions and implications: These results indicate that 17β-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 17β-estradiol and gender-selective protection against sudden cardiac death.