Chronic 17b-Estradiol Replacement Increases Nitric Oxide–Mediated Vasodilation of Guinea Pig Coronary Microcirculation

Background—Estrogen is cardioprotective of the coronary circulation by mechanisms incompletely understood. This study determined the effect of chronic 17b-estradiol replacement on dilator responses to acetylcholine and sodium 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 17b-estradiol was implanted subcutaneously. Serum estradiol concentrations ranged from 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 perfused with buffer at constant flow on an isolated heart apparatus. Both perfusion pressure and contractile force were measured in prostaglandin F2a–constricted hearts. Vasodilation to the cumulative addition of the endothelium-dependent agonist acetylcholine (10 to 10 mol/L) and the nitric oxide (NO) donor sodium nitroprusside (10 to 10 mol/L) was measured before and after NO synthesis inhibition by nitro-L-arginine (LNA, 10 mol/L). Baseline coronary resistance was unaltered by estradiol, although LNA increased resistance in estradiol-treated hearts more than in ovariectomized controls. Chronic 17b-estradiol increased sensitivity (measured by 2log EC50 values) but not maximal response to acetylcholine compared with ovariectomized controls. Differences were abolished by LNA at all doses of estradiol. Sodium nitroprusside–induced dilation was unaffected by estradiol replacement. Conclusions—Chronic 17b-estradiol replacement, at doses producing hormone levels within the physiological range, enhances dilator sensitivity of the coronary microcirculation through enhanced NO production by the endothelium, independent of changes in NO sensitivity of the vascular smooth muscle. Thus, estradiol enhances NO production as a protective mechanism of the coronary microcirculation. (Circulation. 2000;102:445-451.)