Estrogen derivative relaxes rabbit aorta via the endothelial receptor system.
BACKGROUND: It is well known that sexual hormones, in particular estrogens, may influence the cardiovascular system. Experimental and clinical studies have shown that estrogen directly or indirectly modulates the reactivity of vascular smooth muscle but at present the mechanism of action of this hormone has yet to be clarified. The aim of this study was to evaluate the vascular effects of a synthetic non-steroid estrogen, diethylstilbestrol, and the possible involvement of endothelial function. METHODS: We investigated, on aortic strips of a female rabbit, the inhibitory effects of diethylstilbestrol on the contractions induced by different spasmogenic agents, noradrenaline (10(-6) M), angiotensin II (10(-6) M), serotonin (10(-6) M), and KCl (10(-1) M). Some experiments were performed in high K+, Ca++-free solution. In some experiments endothelial function was abolished by mechanical ablation. Another series of experiments was incubated (30 min) with N(G)-monomethyl-L-arginine, which inhibits nitric oxide synthase or with tamoxifen, a specific antagonist of estrogen receptors. RESULTS: At doses from 10(-6) M to 10(-4) M, diethylstilbestrol showed an evident spasmolytic action on contractions induced by noradrenaline, angiotensin II and serotonin but no significant effect was observed on KCl spasm. The inhibitory response of diethylstilbestrol to increased vascular tone induced by noradrenaline disappeared when the endothelial function, validated by the acetylcholine test, was abolished by mechanical ablation. When tested in high K+, Ca++-free solution, diethylstilbestrol did not significantly shift the cumulative dose-response curve of calcium. In the experiments performed with N(G)-monomethyl-L-arginine, diethylstilbestrol failed to induce vasodilation suggesting that its action may be related to synthesis of nitric oxide. Moreover, in the presence of tamoxifen, diethylstilbestrol was unable to induce vasodilation. CONCLUSIONS: The early occurrence of vasodilation is in favor of a direct effect and seems to exclude a regulation of gene expression. These results suggest that estrogens may directly regulate vascular tone interacting with its specific endothelial cell receptors through the release of nitric oxide.