Chronic estrogen treatment in female transgenic (mRen2)27 hypertensive rats augments endothelium-derived nitric oxide release

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 17 beta-estradiol (E-2) 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 E-2 (1.5 mg/rat, subcutaneously, for 3 weeks) or placebo. Chronic 17 beta-estradiol treatment lowered mean blood pressure in both Tg hypertensive (159 +/- 4 v 145 +/- 4 mm Hg, P<.05, placebo v E-2) and normotensive rats (119 +/- 4 v 108 +/- 2 mm Hg, P<.05, placebo v E-2). Presser responses to intravenous injection of phenylephrine were augmented in the Tg(+) as compared with Tg(-) rats. With chronic E-2 treatment the presser 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. E-2 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 E-2 in Tg(+) and Tg(-), respectively). After E-2 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 E-2 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-L-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. E-2 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. (C) 1997 American Journal of Hypertension, Ltd.