Role of Endothelium/Nitric Oxide and Cyclic AMP in Isoproterenol Potentiation of 17ß‐Estradiol‐Mediated Vasorelaxation

Abstract

Estrogen exerts vasorelaxation and cardiac protection via multiple cellular mechanisms. Estrogen modifies vasodilatation induced by certain relaxants such as s-adrenoceptor agonists. However, little is known whether low concentrations of s-adrenoceptor agonists would also influence the acute relaxant response to estrogen. The present study was designed to investigate the synergistic interaction between isoproterenol and 17s-estradiol, and to study the role of endothelium and cyclic AMP-dependent pathway in this interaction. Changes in vessel tone of the isolated rat mesenteric artery rings were measured by force-displacement Grass transducer. In 9,11-dideoxy-11α, 9α-epoxy-methanoprostaglandin F2α- preconstricted endothelium-intact rings, 17s-estradiol induced concentration-dependent relaxation with pD2 of 5.074 ± 0.043. Pretreatment of endothelium-intact rings with isoproterenol (1-3 × 10-9 M, 1-h incubation time) significantly enhanced 17β-estradiol-induced relaxation. Longer incubation (2.5 h) did not produce further amplifying effect. This effect was inhibited by Rp-cGMPS triethylamine (3 × 10-6 M), and disappeared in the presence of 3 × 10-5 M NG-nitro-L-arginine methyl ester or in the endothelium-denuded rings. The effect of isoproterenol was partially antagonized by propranolol (3 × 10-6 M), ICI 118,551 (3 × 10-6 M) but not by atenolol (10-5 M). None of three β-adrenoceptor antagonists affected 17s-estradiol-induced relaxation in the absence of isoproterenol. Rp-cAMPS triethylamine (3 × 10-6 M) abolished the effect of isoproterenol. Besides, exposure to 3 × 10-9 M forskolin for 1 h also potentiated the relaxant response to 17β-estradiol. In summary, this isoproterenol enhancement was dependent on the presence of endothelium and abolished by L-NAME via a β2-adrenoceptor-mediated cyclic AMP-dependent mechanism. These data also indicate the possible existence of cyclic AMP-dependent nitric oxide-producing pathway in the regulation of the vascular response to vasodilators. (supported by UPGC Direct Grant)