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(Hypertension. 1997;30:1538-1543.)
© 1997 American Heart Association, Inc.

Articles

Estrogen Supplementation Decreases Norepinephrine-Induced Vasoconstriction and Total Body Norepinephrine Spillover in Perimenopausal Women

Krishnankutty Sudhir; Murray D. Esler; Garry L. Jennings; ; Paul A. Komesaroff

From the Alfred and Baker Medical Unit and Menopause Clinic, Baker Medical Research Institute and Alfred Hospital, Melbourne, Australia.

Correspondence to Dr. K. Sudhir, Baker Medical Research Institute, Commerical Rd, Prahan, Melbourne, VIC3181, Australia.

	Abstract

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Abstract Estrogens are reported to provide protection against the development of cardiovascular disease in women, but the mechanisms underlying these effects are not well defined. We hypothesized that estrogen might reduce neural cardiovascular tone. We therefore studied responses to exogenous norepinephrine and norepinephrine spillover in 12 perimenopausal women randomized to 8 weeks of estrogen supplementation (estradiol valerate, 2 mg daily, n=7) or placebo (n=5). Forearm blood flow was measured by venous occlusion plethysmography, and vasoactive agents were infused through a brachial artery cannula in doses that did not influence blood pressure or heart rate. Total body and forearm norepinephrine spillover were measured by radiotracer methodology. Forearm vasoconstrictor responses to norepinephrine (25, 50, and 100 ng/min) were attenuated after estrogen supplementation (P=.002). Vasoconstrictor responses to angiotensin II (8, 16, and 32 ng/min) were unchanged postestrogen. There was a significant reduction in total body spillover of norepinephrine after estrogen supplementation (pre-estrogen, 700±152; postestrogen, 439±150 ng/min; P<.05), but there was no change after placebo. Total body clearance and forearm spillover of norepinephrine were unchanged by either estrogen or placebo. Estrogen supplementation also significantly decreased both systolic and diastolic blood pressures. Therefore, estrogen supplementation in perimenopausal women selectively attenuates vasoconstrictor responses to norepinephrine and reduces total body norepinephrine spillover, which is an index of sympathetic neural activity.

Key Words: estrogen • sympathetic nervous system • norepinephrine • vasoconstriction • angiotensin II

	Introduction

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Observational studies of chronic estrogen replacement therapy in postmenopausal women show a significant reduction in the risk of coronary events, lending support to the hypothesis that estrogen may exert cardioprotective effects.¹ However, the precise mechanism underlying its benefits is unclear. Estrogen is reported to be a vasodilator in peripheral² and coronary circulation,^{3 4} at least at high doses. Previous studies⁵ have suggested that estrogen-induced increases in uterine blood flow may result in part from a decrease in ₁-adrenoceptor binding. By contrast, studies in the coronary circulation have demonstrated that acute estrogen administration does not influence the response to 1-adrenoceptor stimulation.⁴ Estrogen is also reported to block extraneuronal norepinephrine reuptake⁶ and thereby cause an increase in local norepinephrine concentrations, which may influence vascular tone in some regional circulations.

In young menstruating women, estrogen administration results in an enhanced cardiovascular response to mental stress.⁷ In contrast, studies comparing responses to mental stress in pre- and postmenopausal women suggest an increased response to mental stress after the menopause.⁸ Further, Lindheim et al⁹ reported that transdermal estrogen therapy in postmenopausal women attenuates responses to mental stress. These studies suggest an interaction between ovarian steroids and catecholamines; however, to date, no direct measurements of the effect of estrogens on the reactivity to or release of catecholamines have been made in human subjects.

In the present placebo-controlled study, we examined the effect of 8 weeks of estrogen supplementation on total body and forearm norepinephrine spillover, a measure of regional sympathetic activity. We also studied the effect of estrogen on vasoconstrictor responses to norepinephrine in the forearm circulation. Finally, we examined the effect of estrogen on forearm vascular responses to another vasoconstrictor agent, Ang II.

	Methods

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Twelve perimenopausal women were recruited through an advertisement in a local newspaper. All were within 2 years of their last period and were actively experiencing vasomotor symptoms of menopause. Women with one or more cardiovascular risk factors or clinical evidence of vascular disease were excluded. The study was approved by the Alfred Hospital Ethics Committee, and all subjects gave written, fully informed consent.

Subjects were randomized to receive 8 weeks of either estrogen supplementation as oral estradiol valerate (Progynova, Schering) at a dose of 2 mg daily (n=7, mean age 48±2 years) or placebo (n=5, mean age 50±2 years). Hemodynamic studies and assessment of forearm vascular reactivity were performed on two separate occasions, 8 weeks apart. Subjects were unaware of the treatment that they were receiving, and all measurements of hemodynamics, norepinephrine kinetics, and vascular reactivity were made by investigators who were blind to the treatment regimen. On each study day, subjects underwent the following procedures.

Hemodynamic Measurements
Subjects rested in the supine position throughout each study in a quiet, temperature-controlled room maintained at 22°C. After 20 minutes of rest, baseline supine SBP and DBP were measured using an automated sphygmomanometer (Dinamap, Critikon, Johnson & Johnson). For intra-arterial measurement of blood pressure (Spacelabs, Inc) and infusion of drugs, the brachial artery of the left arm was then cannulated with a 21-gauge, 5-cm catheter (Cook) under strict aseptic conditions after local anesthesia (1% lignocaine, Astra). Heart rate was monitored continuously by ECG. After brachial cannulation, subjects rested for 30 minutes before commencement of the study.

Assessment of Total Body Norepinephrine Clearance and Spillover
Total body norepinephrine clearance and spillover to plasma were measured by a radiotracer method as previously described.^{10 11} This method involves the continuous intravenous infusion of a tracer dose of tritiated norepinephrine (L-7[³H]norepinephrine, DuPont NEN, 0.7 µCi/min, specific activity 12 to 20 Ci/mmol) to a steady-state concentration in plasma. The total norepinephrine spillover to plasma and total plasma norepinephrine clearance rate can then be calculated as follows:

where NE is norepinephrine, [³H]NE is tritiated norepinephrine, and dpm is disintegrations per minute of [³H]NE.

Assessment of Forearm Norepinephrine Spillover
Forearm spillover rates were calculated according to the Fick principle, with adjustment for norepinephrine uptake across the forearm, using the fractional extraction of [³H]NE as previously described:¹²

where NE_a and NE_v are the norepinephrine concentrations in the arterial and venous effluent plasma, NE_ex is the fractional extraction of [³H]NE in a single passage through the forearm, and FPF is the forearm plasma flow (mL/min).

Assay of Endogenous and Radiolabeled Catecholamines
Blood samples were transferred immediately to ice-chilled tubes containing EDTA and reduced glutathione and centrifuged at 4°C. The plasma was stored at –70°C before assay (always within 2 months). Plasma concentrations of endogenous norepinephrine were determined by high-pressure liquid chromatography with electrochemical detection, as previously described.¹³ The intra-assay coefficient of variation was 5.6%. Plasma [³H]NE was assayed by liquid scintillation counting.

Assessment of Forearm Vascular Reactivity
Forearm vascular responsiveness to vasoactive agents was assessed by venous occlusion plethysmography with a sealed, alloy-filled (gallium and indium), double-stranded strain gauge (Medasonic). Hand blood flow was excluded via a wrist cuff inflated to 200 mm Hg, and venous occlusion pressure on the arm was 50 mm Hg. Before each drug dose, basal blood flow was obtained from an average of at least three measurements. Drugs were infused at the rate of 2 mL/min via an infusion pump.

Norepinephrine was infused through the brachial artery cannula at sequential doses of 25, 50, and 100 ng/min. Each dose was infused for a period of 2 minutes. Ang II was then infused through the arterial cannula at sequential doses of 8, 16, and 32 ng/min. The peak response was determined as the average of three consecutive steady-state measurements. Rest periods of 15 minutes between interventions was sufficient for flow to return to resting levels. Intra-arterial brachial mean blood pressure was recorded both during measurement of basal flows and immediately after each intervention.

Measurement of Hormone and Lipid Levels
In all subjects, venous blood was sampled on both study days for measurement of estradiol, total and HDL cholesterol, triglycerides, and glucose.

Calculations and Statistical Analysis
Results are expressed as mean±SEM. Vascular reactivity data for each drug dose are expressed both as absolute values and as the percentage change from the basal FBF measured before each administration. Vascular reactivity dose-response curves pre- and postestrogen or placebo were compared by a two-way repeated-measures ANOVA. Other data were compared by Student's t test for paired observations. The null hypothesis was rejected at P<.05.

	Results

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Effect of Estrogen on Norepinephrine-Induced Vasoconstriction
Norepinephrine induced a dose-dependent decrease in FBF. After estrogen supplementation, the degree of vasoconstriction induced by norepinephrine was attenuated (P=.002 from two-way ANOVA, pre-estrogen versus postestrogen), suggesting a decrease in noradrenergic responsiveness. There was no significant change in the norepinephrine dose-response relationship after administration of placebo (Fig 1). Blood pressure and heart rate were unchanged during norepinephrine infusions, at baseline, and after estrogen or placebo.

View larger version (29K): [in this window] [in a new window]   Figure 1. Absolute values for FBF (top) and percentage increase in FBF above baseline (bottom) in response to intrabrachial infusion of norepinephrine before and after 8 weeks of estrogen supplementation (left) or placebo (right), showing an attenuation of norepinephrine-induced vasoconstriction after estrogen administration, but no change with placebo.

Effect of Estrogen on Ang II–Induced Vasoconstriction
Ang II induced a dose-dependent decrease in FBF. After estrogen supplementation, the degree of vasoconstriction induced by Ang II was unchanged. There wasno also significant change in the Ang II dose-response relationship after administration of placebo (Fig 2). Blood pressure and heart rate were unchanged during Ang II infusions, at baseline, and after estrogen or placebo.

View larger version (27K): [in this window] [in a new window]   Figure 2. Absolute values for FBF (top) and percentage increase in FBF above baseline (bottom) in response to intrabrachial infusion of Ang II before and after 8 weeks of estrogen supplementation (left) or placebo (right), showing no change in the dose-response relationship with either estrogen or placebo.

Effect of Estrogen on Total Body Norepinephrine Clearance and Spillover
Total body clearance of norepinephrine was not influenced by either estrogen supplementation (pre-estrogen, 2.03±0.24; postestrogen, 1.98±0.16 L/min; P=NS) or administration of placebo (preplacebo, 2.00±0.19; postplacebo, 2.00±0.29 L/min; P=NS). Total body norepinephrine spillover decreased significantly after estrogen supplementation (P<.05) but did not change after administration of placebo (Fig 3).

View larger version (12K): [in this window] [in a new window]   Figure 3. Total body spillover of norepinephrine before and after 8 weeks of estrogen supplementation (left) or placebo (right), showing a decrease in total body norepinephrine spillover after estrogen administration, but no change with placebo.

Effect of Estrogen on Forearm Norepinephrine Spillover
Forearm norepinephrine spillover was unchanged after estrogen supplementation. There was also no significant change in norepinephrine spillover after administration of placebo (Fig 4).

View larger version (13K): [in this window] [in a new window]   Figure 4. Forearm spillover of norepinephrine before and after 8 weeks of estrogen supplementation (left) or placebo (right), showing no change in forearm norepinephrine spillover with either estrogen or placebo.

Effect of Estrogen Supplementation on Blood Pressure and Serum Estradiol Levels
In subjects receiving estrogen supplementation, there was a significant drop in both SBP and DBP, as evidenced by both noninvasive and intra-arterial measurements (Table). There was no significant change in either SBP or DBP in subjects who received placebo. Estradiol levels increased in subjects receiving estrogen, but there was no change in subjects who received placebo.

View this table: [in this window] [in a new window]   Table 1. Hemodynamic and Biochemical Variables at Baseline (Pre) and After (Post) Treatment With Either Estrogen (n=7) or Placebo (n=5)

	Discussion

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The present study demonstrates that 8 weeks of estrogen supplementation attenuates norepinephrine-induced vasoconstriction in the forearm. This effect of estrogen appeared to be specific to the vasoconstrictor norepinephrine, because it did not occur in response to another vasoconstrictor agent, Ang II. Total body norepinephrine spillover decreased significantly after estrogen supplementation, but total body clearance of norepinephrine remained unchanged. Estrogen did not appear to influence regional sympathetic neural outflow, at least in the forearm vascular bed.

Animal studies of the effect of estrogen on norepinephrine-induced vasoconstriction are conflicting, with some reports suggesting an attenuation of such a response and others showing an enhancement in response to estrogen. Shan et al¹⁴ showed that, in male rats, pharmacological doses of estrogen attenuated the pressor responses to norepinephrine and decreased tension generation in tail artery strips. Kondo et al¹⁵ showed that both estradiol and diethylstilbestrol attenuated vascular reactivity in response to norepinephrine in isolated mesenteric arteries. However, in aortic rings from female rats¹⁶ and in mesenteric arteries in male rats,^{17 18} estradiol appeared to enhance vasoconstrictor responses to norepinephrine. Estrogen therapy in postmenopausal women reportedly attenuates responses to mental stress⁹ ; it is likely that such an effect of estrogen is mediated via a decrease in mental stress–induced release of norepinephrine or reduced adrenoceptor responsiveness. Ettinger et al¹⁹ reported that increases in blood pressure and muscle sympathetic nerve activity in response to static exercise were attenuated in women compared with men. However, studies of the effects of estrogen supplementation on norepinephrine-induced vasoconstriction, norepinephrine clearance, or norepinephrine spillover to plasma in humans have not been reported previously .

We have reported previously that estrogen supplementation enhances basal release of nitric oxide in the forearm vasculature.²⁰ Such an effect could attenuate -adrenoceptor–mediated vasoconstriction; in the human coronary circulation, endothelial function has been shown to be a determinant of responses to ₁-adrenoceptor stimulation.²¹ In some previous studies in experimental animals, estrogen has been reported to decrease Ang II–induced vasoconstriction.¹⁶ In humans, hormone replacement therapy is associated with a decrease in serum Ang–converting enzyme activity.²² However, in the present study, estrogen supplementation did not induce any change in Ang II–induced vasoconstriction in the forearm, suggesting that the attenuation of adrenoceptor-mediated vasoconstriction is unlikely to be a nonspecific dampening effect on all vasoconstrictor stimuli. Potential explanations for such an effect on norepinephrine-induced vasoconstriction include decreases in -adrenoceptor numbers⁵ and/or modulation of adrenergically induced accumulation of cAMP.²³ Estrogen supplementation has also been reported to enhance ß-adrenoceptor–mediated vasorelaxation,²⁴ which could result in attenuation of the net vasoconstrictor response observed after infusion of norepinephrine.

Estrogen is reported to inhibit extra-neuronal reuptake of norepinephrine, thus increasing local norepinephrine concentrations.⁶ Such an effect would be expected to increase norepinephrine spillover. In one study, estradiol was reported to decrease norepinephrine levels in the hypothalamus in ovariectomized rats,²⁵ although others have suggested that estrogen enhances hypothalamic norepinephrine release.²⁶ Data in humans on this subject are generally lacking. In the present study, estrogen supplementation had no effect on total body clearance of norepinephrine. Total body spillover was significantly reduced, but forearm spillover remained unchanged. Visceral organs such as the heart, lungs, kidney, liver, and brain contribute to total body spillover,²⁷ and a reduction in sympathetic neural activity in one or more of these organs could account for the fall in total body spillover of norepinephrine.

Increased noradrenergic tone has been implicated in the pathogenesis of hypertension²⁸ and congestive heart failure.²⁹ A recent study has also demonstrated that cardiac sympathetic activity is increased in patients after cardiac arrest resulting from ventricular arrhythmias.³⁰ A decrease in noradrenergic tone may be associated, therefore, with attenuation of hypertension and increased survival from a reduction in cardiac events. Because norepinephrine spillover from individual viscera was not assessed in this study, it is unclear whether the decrease in total body spillover reported reflects a decrease in cardiac norepinephrine spillover.

In the present study, estrogen supplementation induced a fall in both SBP and DBP, but no change occurred in the group that did not receive estrogen. It is possible that either the attenuation of norepinephrine-induced vasoconstriction or the fall in total body norepinephrine spillover, or both phenomena, contributes to the drop in blood pressure observed. In addition, an increase in basal nitric oxide release²⁰ or an enhanced aortic compliance³¹ could contribute to the decrease in blood pressure after estrogen supplementation. Previous studies examining the effect of sex hormones on blood pressure have been conflicting, with some studies showing an increase in blood pressure^{32 33} and others, including the recently concluded Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, showing no change.^{34 35 36} However, some reports have suggested an antihypertensive effect of estrogens.^{37 38 39} Luotola et al⁴⁰ showed that estradiol-17ß decreased the SBP and DBP in normotensive, hypertensive, and borderline hypertensive postmenopausal women. Hassager et al⁴¹ showed that both oral and transdermal treatment with estradiol appear to protect against the age-related increase in DBP observed in early postmenopausal women. Differences in the type of estrogen administered³⁸ or in dose⁴² might help explain some of the discrepancies observed in these studies.

The present study raises several questions that require further examination. Our studies of vascular reactivity were performed in the forearm vasculature: vascular beds differ in their responsiveness to norepinephrine, and the extent to which our findings apply to other vascular beds such as the coronary or renal circulation is unclear. We studied perimenopausal women in whom baseline vasomotor instability might accentuate the influence of an agent such as estrogen, which appears to dampen sympathetic nervous system activity. It would be of interest to repeat our studies in postmenopausal women. It is also unclear whether the effects of estrogen, observed over the 8-week period in the current study, would persist over a longer period of estrogen use. Further, the extent to which other clinical approaches to hormonal therapy, such as transdermal (rather than oral) administration of estrogen or concomitant use of a progestin, would modify our findings is unclear.

In conclusion, the observations reported in the present study of decreases in norepinephrine spillover and in noradrenergic vascular reactivity could explain, at least in part, the survival advantage claimed for estrogen supplementation in postmenopausal women.

	Selected Abbreviations and Acronyms

 

Ang II = angiotensin II DBP = diastolic blood pressure FBF = forearm blood flow NE = norepinephrine SBP = systolic blood pressure

	Acknowledgments

 
This study was funded through a block grant from the National Health and Medical Research Council of Australia and a grant from the Victorian Health Promotion Foundation. Dr Sudhir was funded as a C. J. Martin Fellow by the National Health and Medical Research Council of Australia. We acknowledge the support and advice of Professor John Funder, Director, Baker Medical Research Institute, Melbourne, Australia. We also thank Andrea Turner for performing the catecholamine assays.

Received April 2, 1997; first decision June 29, 1997; accepted July 1, 1997.

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