Effect of Estrogen Replacement on Vasoconstrictor Responses in Rat Mesenteric Arteries

Abstract

Abstract-Recent studies have shown that estrogen can increase endothelial nitric oxide synthase expression and/or activity and that nitric oxide may play a role in attenuating vasoconstrictor responses. Yet there are still controversies in this field. Our hypothesis was that the role of nitric oxide in modulating vasoconstrictor responses in estrogen-replaced animals depends on the agonist. The aim of the study was to determine the effect of long-term estrogen replacement on vascular reactivity of resistance-sized mesenteric arteries in ovariectomized rats with the use of a variety of vasoconstrictors. Female Sprague-Dawley rats were ovariectomized at 11 weeks of age. 17␤-estradiol pellets (0.5 mg/pellet) were implanted in the estrogen-replaced group (nϭ9) for 4 weeks; placebo pellets were used in the ovariectomized group (nϭ10). Resistance-sized mesenteric arteries were dissected and mounted onto a dual-chamber arteriograph system. Estradiol replacement did not alter the response of mesenteric arteries to either arginine vasopressin or the thromboxane mimetic U46619. Inhibition of nitric oxide synthase with N G -monomethyl-L-arginine (100 mol/L) did not modulate these vasoconstrictor responses in either group of rats. In contrast, the dose-response curve of the adrenergic agonist phenylephrine was significantly attenuated for the estradiol-replaced rats compared with the ovariectomized group (EC 50 ϭ0.90Ϯ0.17 vs 0.44Ϯ0.08 mol/L, PϽ0.05). After incubation with N G -monomethyl-Larginine, the EC 50 of phenylephrine significantly decreased in both groups, but a significant difference remained between the 2 groups (EC 50 ϭ0.41Ϯ0.08 vs 0.28Ϯ0.02 mol/L, PϽ0.05). Importantly, Western immunoblotting demonstrated that the expression of ␣ 1 -adrenergic receptors was significantly suppressed by estradiol replacement. We conclude that estrogen may have a specific effect on adrenergic vasoconstriction by modulating its receptors. (Hypertension. 1999;34:1117-1122.) Key Words: steroids Ⅲ nitric oxide Ⅲ receptors, adrenergic, alpha Ⅲ vasopressin Ⅲ thromboxanes E pidemiological studies have shown that the incidence of cardiovascular disease in premenopausal women is lower than that in men and postmenopausal women. 1,2 This is believed to be due to the protective effect of circulating estrogen because estrogen replacement therapy significantly reduces the incidence of cardiovascular disorders in postmenopausal women. 3,4 The vascular wall has been shown to contain specific high-affinity receptors for estrogen both in humans 5,6 and in animals, 7-9 providing strong biological evidence that the cardiovascular system is one of the targets of estrogen. However, the exact mechanisms of the protective effect of estrogen are still unknown.Estrogen treatment in animal models increases systemic and uterine blood flow 10 -13 and attenuates the pressor response to phenylephrine (PE) in mesenteric 14 and aortic arteries. 15 Many of these studies have implicated nitric oxide (NO) as the mediator of the altered vascular response resulting from...

Postexercise α-adrenergic receptor hyporesponsiveness in hypertensive rats is due to nitric oxide

“…This is suggested because postmenopausal women, on estrogen replacement therapy, have a lower incidence of cardiovascular disorders than age-matched men (1). These data document that female sex hormones provide beneficial cardiovascular effects that may be mediated by altering vascular reactivity (57). Thus the effects of sex and the interactions of sex with exercise on vascular responses may be mediated by circulating sex hormones, especially estrogen.…”

Effects of estrogens and selective estrogen receptor modulators on vascular reactivity in the perfused mesenteric vascular bed

“…Estrogens may enhance vascular ␣-adrenergic receptor affinity (4,7). Other studies have shown that ␣-adrenergic receptor expression decreased with estrogen treatment in ovariectomized rats (44). The different effects described in these studies may be due to technical differences, such as different formulations of estrogens or different routes of administration.…”

Gender-dependent modulation of α1-adrenergic responses in rat mesenteric arteries

“…Maximal contractile responses expressed as a percentage of resting diameter were also not significantly different between stimuli and genders. However, net mesenteric artery contractile responses may be modulated by both endothelium and vascular smooth muscle-derived vasoactive factors (2,9,19,22,24). Therefore, we considered the possibility that these modulatory influences could be gender dependent and, because different G protein-coupled contractile agonists may variably stimulate smooth muscle and endothelium-dependent pathways, agonist specific.…”

“…However, when considering responsiveness to a vasoconstrictor, the relative importance of this modulatory pathway can be expected to vary with respect to both stimulus and blood vessel type and is dependent on the relative complement of agonist receptors on endothelium versus smooth muscle (20,24). Similarly, the production of vasoactive arachidonic acid metabolites by endothelium or vascular smooth muscle can be expected to vary depending on stimulus, vascular bed, and possibly gender.…”