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

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, 17b-estradiol, on ischaemia-induced cardiac arrhythmias and on the L-type Ca 2 þ 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 17b-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 þ 30 ng kg À1 min À1 17b-estradiol significantly reduced the number of ventricular premature beats (VPBs) and the incidence of ventricular fibrillation (VF). A ten fold higher dose of 17b-estradiol was required to cause similar effects in male rats. In vitro 17b-estradiol reduced peak I CaL in a concentration-dependent manner. The EC 50 was ten-fold higher in male myocytes (0.66 mM) than in females (0.06 mM). Conclusions and implications:These results indicate that 17b-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 17b-estradiol and gender-selective protection against sudden cardiac death.

Effect of Female Sex on Cardiac Arrhythmias

“…120 Among patients with CAD and implantable cardioverter defibrillation, women are less likely to experience VT/VF although this may be due to higher ejection fractions and less diabetes in women. 124 Estrogen also reduces reperfusion-induced arrhythmia in dogs of both sexes by augmenting nitric-oxide release and opening of calcium-activated potassium channels. 122 Animal models suggest that estrogen protects against ventricular arrhythmias.…”

The Influence of Gender on Heart Rhythm Disease

“…Experimental studies have provided evidence which clarifies some of the underlying mechanisms of gender influences on myocardial cell electrophysiology. They have shown gender variation in the expression and function of ion channels that control cardiac excitability (Fig. ).…”

“…Animal model and in vitro investigation has demonstrated that acute administration of 17β‐oestradiol (E2, the most bioactive estrogen) has a protective effect on ischemia‐induced arrhythmias and reduces L‐type Ca 2+ current ( I CaL ) . This activity is dose‐dependent, and female animals require a lower dose of hormone than their male counterparts to achieve the antiarrhythmic effect.…”

Sex hormones and arrhythmia in myocardial ischemia

“…We do not know whether these effects are ER dependent or not. The data of Philp et al (2006) suggest that the shown effect of estrogen on I CaL in acute ischemia is rapid and non-genomic. Therefore, it might be related rather to rapid pathways such as calcium homeostasis or NO generation than to genomic mechanisms.…”

“…The myocardium contains both functional estrogen receptor a (ERa) and estrogen receptor b (ERb) (Grohé et al, 1998). These transcription factors can activate downstream target genes such as the endothelial/inducible isoforms of the nitric oxide (NO) synthase as well as connexin 43 in the heart (Strehlow et al, 2003).In their study, Philp et al (2006) address the issue of the effect of 17b-estradiol on ventricular vulnerability in a rat model of ischemia. Their data show that there is a dosedependent antiarrhythmic activity of 17b-estradiol administration with suppression of ventricular premature beats, ventricular tachycardia and ventricular fibrillation during ischemia.…”