Distinct Roles of Estrogen Receptors &agr; and &bgr; Mediating Acute Vasodilation of Epicardial Coronary Arteries

This study investigated the contribution of estrogen receptors (ERs) &agr; and &bgr; for epicardial coronary artery function, vascular NO bioactivity, and superoxide (O2−) formation. Porcine coronary rings were suspended in organ chambers and precontracted with prostaglandin F2&agr; to determine direct effects of the selective ER agonists 4,4′,4″-(4-propyl-[1H]pyrazole-1,3,5-triyl)tris-phenol (PPT) or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) or the nonselective ER agonist 17&bgr;-estradiol. Indirect effects on contractility to U46619 and relaxation to bradykinin were assessed and effects on NO, nitrite, and O2− formation were measured in cultured cells. Within 5 minutes, selective ER&agr; activation by PPT, but not 17&bgr;-estradiol or the ER&bgr; agonist DPN, caused rapid, NO-dependent, and endothelium-dependent relaxation (49±5%; P<0.001 versus ethanol). PPT also caused sustained endothelium- and NO-independent vasodilation similar to 17&bgr;-estradiol after 60 minutes (72±3%; P<0.001 versus ethanol). DPN induced endothelium-dependent NO-independent relaxation via endothelium-dependent hyperpolarization (40±4%; P<0.01 versus ethanol). 17&bgr;-Estradiol and PPT, but not DPN, attenuated the responses to U46619 and bradykinin. All of the ER agonists increased NO and nitrite formation in vascular endothelial but not smooth muscle cells and attenuated vascular smooth muscle cell O2− formation (P<0.001). ER&agr; activation had the most potent effects on both nitrite formation and inhibiting O2− (P<0.05). These data demonstrate novel and differential mechanisms by which ER&agr; and ER&bgr; activation control coronary artery vasoreactivity in males and females and regulate vascular NO and O2− formation. The findings indicate that coronary vascular effects of sex hormones differ with regard to affinity to ER&agr; and ER&bgr;, which will contribute to beneficial and adverse effects of hormone replacement therapy.

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