Abstract
Pre-menopausal women have a reduced risk from ischemic heart disease compared to men; this protection is lost after ovariectomy or menopause. Estrogen has been found to confer protection in whole-heart studies in animal models. ATP-sensitive K+ (KATP) channels act as metabolic sensors, opening when cellular energy levels fall and are thought to play a role in cardioprotection. We investigated whether the cardiac KATP currents play a role in the cardioprotective effects of 17β-estradiol in isolated cardiomyocytes. Ventricular myocytes were isolated from adult male Wistar rats by enzymatic digestion. The ability of myocytes to recover contractile function after simulated ischaemia/reperfusion injury was calculated by video microscopy. Contracting myocytes (1Hz) were continuously superfused with Tyrode solution, then subjected to 7 minutes of similated ischaemia by perfusion with a metabolic inhibition solution, comprising substrate-free Tyrode with cyanide (2mM) and idoacetic acid (1mM), followed by 10 minute reperfusion with Tyrode to simulate reperfusion. A 5 minute pre-treatment of 17β-estradiol (500nM) significantly increased contractile recovery; control 30% n=100, 17β-estradiol 68% n=185, DPN (ERβ agonist) 53% n= 111. Using the whole-cell patch-clamp mode we investigated the effect of estrogen on KATP channel activity. P1075 (10μM) elicited a KATP current which was completely blocked by bath application of estradiol (500nM). Both the classical estrogen receptors; ERα and ERβ have been implicated in several rapid effects of 17β-estradiol. DPN is a specific agonist of ERβ and application of DPN (500nM) following opening of KATP by P1075 (10μM) also resulted in 100% decrease in KATP current. We show that rapid estrogen signalling has a cardioprotective effect in isolated ventricular myocytes. Application of estradiol resulted in complete loss of KATP current recorded in cardiomyocytes; therefore questioning the role of KATP in estrogen-dependent cardioprotection. This work was supported by funding by The British Heart Foundation.
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