Chronic Estrogen Treatment in Female Transgenic (mRen2)27 Hypertensive Rats Augments Endothelium-Derived Nitric Oxide Release

Abstract Postmenopausal estrogen replacement therapy is associated with a reduction in cardiovascular events in women, but the mechanisms for this protection are unclear, especially in hypertensive subjects. In this study we investigated the effects of -estradiol (E2) treatment on blood pressure and endothelial function of transgenic [(mRen2)27] hypertensive and normotensive rats. Thirty female transgenic negative [Tg(−)] and hypertensive positive [Tg(+)] rats were ovariectomized and received either E2 (1.5 mg/rat, subcutaneously, for 3 weeks) or placebo. Chronic 17 -estradiol treatment lowered mean blood pressure in both Tg hypertensive (159 ± 4 v 145 ± 4 mm Hg, P< .05, placebo v E2) and normotensive rats (119 ± 4 v 108 ± 2 mm Hg, P< .05, placebo v E2). Pressor responses to intravenous injection of phenylephrine were augmented in the Tg(+) as compared with Tg(−) rats. With chronic E2 treatment the pressor responses to phenylephrine were attenuated in both groups. Isometric tension of aortic rings was measured in vitro in organ chambers. The acetylcholine (Ach)-induced endothelium-dependent vascular relaxation was less potent in Tg(+) versus Tg(−) rats. E2 treatment significantly enhanced the Ach-induced relaxation of both Tg(+) and Tg(−) groups (ED50: 55.5 ± 11.7 v 10.3 ± 2.6; 23.8 ± 6.5 v 5.1 ± 1.2 nmol/L, placebo v E2 in Tg(+) and Tg(−), respectively). After E2 treatment the ED50 response in Tg(+) rats was no different from Tg(−) rats. However, the maximum vasodilation elicited by Ach was attenuated in Tg(+) as compared with Tg(−) rats. The calcium ionophore (A23187)-induced endothelium-dependent relaxation was less potent in Tg(+) as compared to Tg(−) rats and was enhanced by E2 treatment only in Tg(+) animals. There were no differences in the vasodilator responses elicited by sodium nitroprusside. Removal of endothelium and blockade of NO production abolished the endothelium-dependent vasodilation. The selective NO synthase inhibitor, NG-monomethyl- -arginine (LMMNA), was used to evaluate indirectly the basal contribution of NO in vascular rings. The response to LMMNA was attenuated in untreated Tg(+) as compared to Tg(−) rats. E2 treatment augmented the contraction response to NOS inhibition in both Tg(+) and Tg(−) rats, resulting in a response in Tg(+) rats that was no different from Tg(−) rats. These results indicate that untreated, surgically ovariectomized hypertensive rats show deficiencies in endothelial function, which can be improved by estrogen replacement.