Chronic 17 beta-estradiol replacement increases nitric oxide-mediated vasodilation of guinea pig coronary microcirculation

Background-Estrogen is cardioprotective of the coronary circulation by mech anisms incompletely understood. This study determined the effect of chronic 17 beta-estradiol replacement on dilator responses to acetylcholine and so dium nitroprusside of the isolated coronary microcirculation. Methods and Results-Adult female guinea pigs were ovariectomized, and a 21- day-release pellet containing 0.0, 0.1, 0.25, 0.5, or 1.0 mg 17 beta-estrad iol was implanted subcutaneously. Serum estradiol concentrations ranged fro m 3.9 to 74.9 pg/mL, increasing with the dose of estradiol. After 19 to 20 days, the animals were euthanized, and their hearts were removed and perfus ed with buffer at constant flow on an isolated heart apparatus. Both perfus ion pressure and contractile force were measured in prostaglandin F-2 alpha -constricted hearts. Vasodilation to the cumulative addition of the endothe lium-dependent agonist acetylcholine (10(-9) to 10(-5) mol/L) and the nitri c oxide (NO) donor sodium nitroprusside (10(-9) to 10(-5) mol/L) was measur ed before and after NO synthesis inhibition by nitro-L-arginine (LNA, 10(-4 ) mol/L). Baseline coronary resistance was unaltered by estradiol, although LNA increased resistance in estradiol-treated hearts more than in ovariect omized controls. Chronic 17 beta-estradiol increased sensitivity (measured by -log EC50 values) but not maximal response to acetylcholine compared wit h ovariectomized controls. Differences were abolished by LNA at all doses o f estradiol. Sodium nitroprisside-induced dilation was unaffected by estrad iol replacement. Conclusions-Chronic 17 beta-estradiol replacement, at dose s producing hormone levels within the physiological range, enhances dilator sensitivity of the coronary microcirculation through enhanced NO productio n by the endothelium, independent of changes in NO sensitivity of the vascu lar smooth muscle. Thus, estradiol enhances NO production as a protective m echanism of the coronary microcirculation.