Isoproterenol amplifies 17β-estradiol-mediated vasorelaxation: Role of endothelium/nitric oxide and cyclic AMP

Objectives: Estrogen exerts cardiac protection via multiple cellular mechanisms. Estrogen modifies vasodilatation induced by certain relaxants such as β-adrenoceptor agonists. However, little is known whether low concentrations of β-adrenoceptor agonists would reciprocally influence the acute relaxant response to estrogen. The present study was designed to investigate the synergistic interaction between isoproterenol and 17β-estradiol, and the role of endothelium and cyclic AMP-dependent pathway in this interaction. Methods: Changes in vessel tone of the isolated rat mesenteric artery rings were measured using a force–displacement Grass transducer. Results: In 9,11-dideoxy-11α, 9α-epoxy-methanoprostaglandin F2α-preconstricted endothelium-intact rings, 17β-estradiol induced relaxations with p D 2 of 5.06±0.06. Pretreatment of endothelium-intact rings with isoproterenol (1–3×10−9 M, 1 h incubation time) significantly enhanced 17β-estradiol-induced relaxation. This effect was inhibited by Rp-cGMPS triethylamine (3×10−6 M), and abolished in the presence of 3×10−5 M N G-nitro-l-arginine methyl ester or in endothelium-denuded rings. The effect of isoproterenol was antagonized by propranolol (3×10−6 M), ICI 118,551 (3×10−6 M), but not by atenolol (10−5 M). 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. Conclusion: In endothelium-intact rat mesenteric arteries pretreatment with low concentrations of isoproterenol enhanced the acute relaxant response to 17β-estradiol. This enhancement was dependent on the presence of endothelium and abolished by l-NAME via a β2-adrenoceptor-mediated cyclic AMP-dependent mechanism.