Elsevier

Atherosclerosis

Volume 158, Issue 2, October 2001, Pages 391-397
Atherosclerosis

Estrogen replacement therapy in postmenopausal women augments reactive hyperemia in the forearm by reducing angiotensin converting enzyme activity

https://doi.org/10.1016/S0021-9150(01)00434-8Get rights and content

Abstract

The precise mechanism of the vasoprotective effect of estrogen replacement therapy in postmenopausal women is not fully understood. The present study sought to determine the role of nitric oxide (NO) and angiotensin-converting enzyme (ACE) in the vasodilator response of the forearm vessels induced by estrogen administration to postmenopausal women. Subjects were divided into two groups. One group received conjugated equine estrogen (0.625 mg daily) orally for 3 months (n=26), while the other received no treatment (control group, n=10). Forearm blood flow was measured by strain-gauge plethysmography. The concentrations of nitrite/nitrate (metabolites of NO), ACE activity, and lipid parameters were measured. Basal forearm blood flow, body weight, blood pressure, and heart rate were similar at baseline in both groups. After 3 months of estrogen administration, the maximal forearm blood flow response during reactive hyperemia and the serum level of nitrite/nitrate each showed a significant increase over baseline values: from 23.6±2.0 to 36.5±3.1 ml/min per 100 ml tissue (P<0.01), and from 24.8±2.3 to 38.6±3.6 μmol/l (P<0.01), respectively. Plasma levels of ACE activity were significantly reduced from baseline after 3 months of estrogen treatment (from 12.2±0.6 to 10.9±0.6 IU/l, P<0.01). No changes were seen in controls. The change in forearm blood flow after sublingual nitroglycerin was similar at baseline versus after 3 months of estrogen administration. The increase in the serum level of nitrite/nitrate after 3 months of estrogen therapy showed a significant inverse correlation (r=0.52, P<0.01) with the reduction in the plasma level of ACE activity. There was no significant correlation between the increase in serum nitrite/nitrate and any change in serum lipids, blood pressure, or other parameters. The administration of oral estrogen to postmenopausal women for 3 months increased the NO-mediated forearm endothelium-dependent vasodilatation. This was likely due, at least in part, to ACE inhibition. The latter may be one mechanism by which ERT provides its well-known cardiovascular benefit.

Introduction

Several observational studies [1], [2], [3], [4] suggest that the administration of estrogen replacement therapy (ERT) to postmenopausal women reduces the incidence of cardiovascular disease. Estrogen exerts many protective effects on the cardiovascular system, including a lipid-lowering effect [5], an antioxidant effect [6], and inhibition of fibrosis [7].

Some studies have shown that the immediate and long-term administration of estrogen enhances reactive hyperemia in the forearm in postmenopausal women [8], [9], [10], [11]. Reactive hyperemia in peripheral arteries is mediated by endothelial-derived nitric oxide [12]. Experimental study has shown that estrogen stimulates the release of endothelium-derived nitric oxide, which is known to mediate vascular relaxation in response to various endothelium-dependent vasodilators [13], [14]. Via its alpha-type receptor, estrogen may directly upregulate eNOS gene expression [15], [16]. Lipid-lowering and antioxidant effects of estrogen also may improve overall endothelial function and diminish vascular disease, thereby increasing vascular nitric oxide production [17], [18].

However, the mechanism by which estrogen augments endothelial function is thought to be complex and multifactorial.

The renin-angiotensin system is reportedly suppressed by hormone therapy in hypertensive postmenopausal women, with no increase in blood pressure, as well as in normotensive postmenopausal women [19], [20]. A decline in angiotensin converting enzyme (ACE) activity may be one of the factors that protects against cardiovascular disease [20]. ACE inhibitors have been shown in some clinical studies to improve endothelial function [21], [22]. ACE inhibitors induce the accumulation of bradykinin via the inhibition of kininase. Bradykinin causes nitric oxide to be released from endothelial cells [23], [24].

Recently, Sumino et al. [25] reported that the treatment of hypertensive postmenopausal women with conjugated estrogen plus medroxyprogesterone acetate increases the plasma level of bradykinin.

The present study measured forearm blood flow in normotensive postmenopausal women by means of strain-gauge plethysmography following the oral administration of estrogen for 3 months. The concentrations of nitrite/nitrate, which are metabolites of nitric oxide, were measured as was the plasma ACE activity. We evaluated the role of nitric oxide and ACE in the forearm circulation of postmenopausal women administered ERT as compared with untreated postmenopausal women.

Section snippets

Subjects

A total of 36 postmenopausal Japanese women, aged 48–57 years, were admitted to study. Each subject had experienced natural menopause for at least 1 year but not longer than 5 years. Each was of normal weight, with a body mass index (weight/height2, kg/m2)≤25. Menopausal status was confirmed by a serum concentration of follicle-stimulating hormone (FSH) >40 mIU/ml, and a serum concentration of estradiol <20 pg/ml. Excluded from study were patients with hypertension, diabetes, a cigarette

Effects of ERT on baseline clinical variables

Baseline clinical variables in the 26 postmenopausal women administered ERT and the 10 untreated control women, determined at baseline and again after 3 months, are summarized in Table 1. Baseline values for all parameters were similar in both groups. Twelve weeks of ERT significantly reduced the serum concentrations of total cholesterol and of LDL cholesterol (P<0.05), and increased the concentration of HDL cholesterol (P<0.01), as compared with baseline values. No such changes occurred in the

Discussion

The present study evaluated the response of forearm blood flow in estrogen-treated and untreated postmenopausal women to reactive hyperemia, an index of endothelium-dependent vasodilation, and to the sublingual administration of nitroglycerin, an index of endothelium-independent vasodilation. Strain-gauge plethysmograpy was used for this non-invasive arterial testing.

The administration of oral estrogen to postmenopausal women for 3 months augmented the endothelium-dependent vasodilation in

Acknowledgements

This study was supported in part by a Grant-in Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (No. 09771279). This study was supported by Tokyo Kasei Kogyo. The authors thank Hiromi Muraoka for her secretarial assistance.

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