Effects of estrogen on nitric oxide biosynthesis and vasorelaxant activity in sheep uterine and renal arteries in vitro

Veille, Jean-Claude; Li, Ping; Eisenach, James C.; Massmann, A.; Figueroa, Jorge

doi:10.1016/s0002-9378(96)70348-4

Cited by 66 publications

(31 citation statements)

References 23 publications

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“…Similarly, the endothelium did not contribute to estrogen-or raloxifene-mediated cerebrovascular relaxation (22,28). Estrogen failed to affect NO release and NO synthase activity in nonpregnant ewe renal arteries (31). Last, acute treatment with raloxifene did not modify endothelial NO-dependent renal artery relaxation responses to acetylcholine (data not shown).…”

Section: Discussionmentioning

confidence: 84%

Raloxifene relaxes rat intrarenal arteries by inhibiting Ca²⁺ influx

Leung

Yao²,

Lau³

et al. 2005

American Journal of Physiology-Renal Physiology

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Raloxifene may confer vascular benefits without causing estrogen-related side effects. However, its action on renal vascular circulation is unknown. This study aimed to examine the sex difference and roles of the endothelium and Ca 2ϩ channels in rat renovascular relaxation to raloxifene. On isolated intralobar renal artery rings mounted in a myograph and contracted by U-46619, concentration-relaxation curves were constructed for raloxifene and contractions to CaCl 2 were studied. Changes in intracellular Ca 2ϩ concentration levels ([Ca 2ϩ ]i) of vascular smooth muscle (VSM) were measured by fura 2 fluorescence. Raloxifene or 17␤-estradiol was equally effective in relaxing renal arteries from both sexes, with raloxifene being more potent than 17␤-estradiol. Endothelial denudation did not affect raloxifene-or 17␤-estradiol-induced relaxation. N G -nitro-L-arginine methyl ester, charybdotoxin plus apamin, indomethacin, or ICI-182, 780 did not modify the effect of raloxifene. Raloxifene caused similar relaxations in rings contracted by U-46619 and high K ϩ . Nifedipine attenuated the potency of raloxifene. Raloxifene reduced CaCl 2-induced contractions. K ϩ (80 mM) stimulated an increase in VSM [Ca 2ϩ ]i, and raloxifene attenuated this effect. Raloxifene-induced reduction of contraction and increase in VSM [Ca 2ϩ ]i were insensitive to ICI-182, 780. In summary, raloxifene causes relaxation in rat renal arteries; this effect is independent of a functional endothelium and is not mediated by ICI 182, 780-sensitive estrogen receptors. Raloxifene inhibited both contractions and VSM [Ca 2ϩ ]i in response to CaCl2, indicating that raloxifene relaxes rat renal arteries primarily through inhibiting Ca 2ϩ influx via Ca 2ϩ channels. There is little sex difference in raloxifeneinduced relaxation.17␤-estradiol; relaxation; rat renal artery SEX-RELATED DIFFERENCES IN the risk for cardiovascular diseases are generally recognized (1). In pooled analysis, observational studies report that hormone replacement therapy (HRT) reduced the primary risk of cardiovascular disease in healthy menopausal women (27). Despite this evidence, the results from recent randomized clinical trials of HRT for primary or secondary prevention of heart disease have found no overall therapeutic benefit (12,20). Instead, HRT resulted in higher incidences of strokes, heart attacks, and thrombosis (20), although the precise mechanism is unknown. Thus conventional HRT is no longer suitable for prevention of cardiovascular disease (19). Therefore, in recent years, a surge of research has focused on more selective agents that retain beneficial properties of estrogen in bone, lipids, and the cardiovascular system but with antiestrogenic activity in the breast and uterus. Such unique compounds are categorized as selective estrogen receptor modulators (SERMs). SERMs manifest selective agonistic or antagonistic activities in a multitude of estrogen target tissues. Although some SERM members have been known for decades, their tissue specificity has only recen...

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Section: Discussionmentioning

confidence: 84%

Raloxifene relaxes rat intrarenal arteries by inhibiting Ca²⁺ influx

Leung

Yao²,

Lau³

et al. 2005

American Journal of Physiology-Renal Physiology

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“…5B). Administration of estrogen to OVX sheep caused a significant enhancement of bradykinin-induced vasodilation of uterine but not renal arteries (52). After chronic infusion of estrogen in OVX sheep, the relative uterine vascular responses significantly exceeded systemic hemodynamic changes (35).…”

Section: Discussionmentioning

confidence: 93%

Estrogen replacement enhances EDHF-mediated vasodilation of mesenteric and uterine resistance arteries: role of endothelial cell Ca²⁺

Burger

Kuzina

Osol

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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Burger NZ, Kuzina OY, Osol G, Gokina NI. Estrogen replacement enhances EDHF-mediated vasodilation of mesenteric and uterine resistance arteries: role of endothelial cell Ca 2ϩ . Am J Physiol Endocrinol Metab 296: E503-E512, 2009. First published January 6, 2009 doi:10.1152/ajpendo.90517.2008.-Endothelium-derived hyperpolarizing factor (EDHF) plays an important role in the regulation of vascular microcirculatory tone. This study explores the role of estrogen in controlling EDHF-mediated vasodilation of uterine resistance arteries of the rat and also analyzes the contribution of endothelial cell (EC) Ca 2ϩ signaling to this process. A parallel study was also performed with mesenteric arteries to provide comparison with a nonreproductive vasculature. Mature female rats underwent ovariectomy, with one half receiving 17␤-estradiol replacement (OVXϩE) and the other half serving as estrogen-deficient controls (OVX). Uterine or mesenteric resistance arteries were harvested, cannulated, and pressurized. Nitric oxide and prostacyclin production were inhibited with 200 M N G -nitro-L-arginine and 10 M indomethacin, respectively. ACh effectively dilated the arteries preconstricted with phenylephrine but failed to induce dilation of vessels preconstricted with high-K ϩ solution. ACh EC50 values were decreased by estrogen replacement by five-and twofold in uterine and mesenteric arteries, respectively. As evidenced by fura-2-based measurements of EC cytoplasmic Ca 2ϩ concentration ([Ca 2ϩ ]i), estrogen replacement was associated with increased basal and ACh-stimulated EC [Ca 2ϩ ]i rise in uterine, but not mesenteric, vessels. These data demonstrate that EDHF contributes to endothelium-dependent vasodilation of uterine and mesenteric resistance arteries and that estrogen controls EDHFrelated mechanism(s) more efficiently in reproductive vs. nonreproductive vessels. Enhanced endothelial Ca 2ϩ signaling may be an important underlying mechanism in estrogenic modulation of EDHFmediated vasodilation in small resistance uterine arteries. endothelium-derived hyperpolarizing factor; acetylcholine; fura-2; high potassium THE VASCULAR ENDOTHELIUM plays an important role in the control of blood vessel tone through release of relaxing and contracting factors in response to mechanical or agonist-

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“…Others have reported that pregnancy is characterized by upregulated UA endothelial eNOS expression (28,29,47) and specific activity (27,31,46). Estrogen also upregulates UA endothelial eNOS expression (35,36,40) and activity (41). Our previous report (28) of a lack of change in UA eNOS protein levels from day 110 to 142 of ovine pregnancy demonstrates eNOS actually is elevated in the second trimester and must fall somewhat during Values are means Ϯ SE of external diameters (in mm); n ϭ 6 sheep from the luteal phase, 6 sheep from the follicular phase, 6 midpregnant sheep (82 Ϯ 1 days), and 6 late pregnant sheep (127 Ϯ 3 days).…”

Section: Discussionmentioning

confidence: 98%

Endothelial vasodilator production by uterine and systemic arteries. IX. eNOS gradients in cycling and pregnant ewes

Joyce

Phernetton

Shaw

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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The follicular phase (FOL) and pregnancy exhibit increases in uterine blood flow (UBF), estrogen levels, and uterine artery (UA) endothelial nitric oxide synthase (eNOS) expression. UA branching within the mesometrium increases the total vascular cross-sectional area, which reduces the vascular perfusion pressure gradient, thus locally decreasing the blood flow velocity. Shear stress (SS) activates eNOS and may be associated with UBF elevations during FOL and pregnancy. We hypothesized that regional differences in eNOS responses are observed with both decreases in vessel diameter and during the ovarian cycle and pregnancy. Endothelial isolated proteins were collected from renal (RA) and internal iliac arteries (II) as well as from primary (UA 1°), secondary (UA 2°), and tertiary (UA 3°) UA branches of nonpregnant luteal phase (LUT; n ϭ 6) and FOL (n ϭ 6) as well as midpregnant (MP; 82 Ϯ 1 days gestation, n ϭ 6) and late pregnant (LP; 127 Ϯ 3 days gestation, n ϭ 6) ewes (term ϭ 145 Ϯ 3 days gestation) for Western blot analysis. LUT RA, II, and UA 1°eNOS levels were similar. There was a 60.7 Ϯ 9.8% reduction in eNOS expression in UA 2°and UA 3°. A similar decreasing eNOS regional expression gradient was observed in LP ewes. No eNOS regional expression gradient was observed in FOL or MP ewes because eNOS increased in UA 2°and UA 3°. In UA 2°and UA 3°, MP Ͼ LP ϭ FOL Ͼ LUT. Thus, with increasing UBF, FOL and pregnancy rises in SS may regulate eNOS protein expression in smaller diameter UAs. A decrease in LUT and LP UA 2°and UA 3°endothelial eNOS suggest a possible negative feedback mechanism due to downregulation of eNOS if SS is normalized. uterus; shear stress; endothelial nitric oxide synthase; ovarian; estrogen; progesterone UTERINE ARTERY (UA), but not systemic (renal) artery (RA) endothelial, endothelial nitric oxide (NO) synthase (eNOS) protein (29, 40) and mRNA (29) are elevated during the follicular phase of the ovarian cycle, in which the endogenous estrogen-to-progesterone ratio and uterine blood flow (UBF) are elevated (9, 11, 26). A low basal UBF level and a low estrogen-toprogesterone ratio characterize the luteal phase. Similar increases in eNOS protein levels were noted during the follicular phase of the menstrual cycle in women (31). Furthermore, these alterations in eNOS levels in the UA endothelium can be mimicked by exogenous administration of 17␤-estradiol and/or progesterone (35,36,40). [27][28][29]37,47) and its physiological second messenger cGMP (17,27,37) are increased during pregnancy. UA, but not systemic artery endothelial, eNOS protein (28,29,31,47) and mRNA (1, 29) expression and activity (27,31,46) also are elevated by pregnancy. UA eNOS protein levels are unchanged during late gestation, from day 110 to 142 of ovine pregnancy (28), although nitrite or nitrate (NO x ) levels increase with advancing gestational ages during the third trimester (29). The timing of either the gestational increase in UA eNOS expression or the circulating NO x levels during the second trimester of pregnanc...

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Effects of estrogen on nitric oxide biosynthesis and vasorelaxant activity in sheep uterine and renal arteries in vitro

Cited by 66 publications

References 23 publications

Raloxifene relaxes rat intrarenal arteries by inhibiting Ca²⁺ influx

Raloxifene relaxes rat intrarenal arteries by inhibiting Ca²⁺ influx

Estrogen replacement enhances EDHF-mediated vasodilation of mesenteric and uterine resistance arteries: role of endothelial cell Ca²⁺

Endothelial vasodilator production by uterine and systemic arteries. IX. eNOS gradients in cycling and pregnant ewes

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Effects of estrogen on nitric oxide biosynthesis and vasorelaxant activity in sheep uterine and renal arteries in vitro

Cited by 66 publications

References 23 publications

Raloxifene relaxes rat intrarenal arteries by inhibiting Ca2+ influx

Raloxifene relaxes rat intrarenal arteries by inhibiting Ca2+ influx

Estrogen replacement enhances EDHF-mediated vasodilation of mesenteric and uterine resistance arteries: role of endothelial cell Ca2+

Endothelial vasodilator production by uterine and systemic arteries. IX. eNOS gradients in cycling and pregnant ewes

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Product

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Raloxifene relaxes rat intrarenal arteries by inhibiting Ca²⁺ influx

Raloxifene relaxes rat intrarenal arteries by inhibiting Ca²⁺ influx

Estrogen replacement enhances EDHF-mediated vasodilation of mesenteric and uterine resistance arteries: role of endothelial cell Ca²⁺