Physiological Concentrations of Estradiol Attenuate Endothelin 1–Induced Coronary Vasoconstriction In Vivo

Sudhir, Krishnankutty; Ko, Eitetsu; Zellner, Christian; Wong, Hubert E.; Hutchison, Stuart J.; Chou, Tony M.; Chatterjee, Kanu

doi:10.1161/01.cir.96.10.3626

Cited by 56 publications

(47 citation statements)

References 35 publications

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“…We found that the ET-1-induced constrictive response is unaffected by short-term exposure to physiological (1 × 10 −9 M to 1 × 10 −8 M) and pharmacological (1 × 10 −7 M to 1 × 10 −4 M) concentrations of 17β-estradiol in fresh and organ cultured coronary arteries. This contrasts previous studies which demonstrated physiological concentrations of 17β-estradiol reduced the constrictive response to ET-1 in market-age pigs (Sudhir et al, 1997;Teoh et al, 1999). However, Wynne et al (2004) similarly found that advanced age decreases the inhibitory effect of 17β-estradiol on calcium influx.…”

Section: Discussioncontrasting

confidence: 98%

“…As similarly demonstrated by others using market-age pigs (6 to 12 months) (Barber et al, 1996;Sudhir et al, 1997;Teoh et al, 2000), our study shows that 17β-estradiol can induce the relaxation of a pre-constricted artery. However, the transition of arterial cells to a proliferative phenotype with organ culture (Hill et al, 2001;Hill et al, 2000), attenuated the 17β-estradiol-induced arterial relaxation.…”

Section: Discussionsupporting

confidence: 89%

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The enhanced endothelin-1-induced contraction in cultured coronary arteries from mature female pigs is not antagonized by 17β-estradiol

Tummala

Hill

2007

Vascular Pharmacology

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We have previously reported that organ cultured coronary arteries from market-age pigs (6-9 months of age) exhibit an enhanced contraction to the atherosclerotic-associated peptide, endothelin-1 (ET-1). The objective of this study was to investigate the interaction of 17β-estradiol with ET-1 in organ cultured coronary arteries from older female pigs (3-4 years old). A cumulative-concentration response relationship (1 × 10 −9 M to 3 × 10 −7 M) was generated to ET-1, and the isometric tension measured in fresh and organ cultured (4 days at 37°C) arterial rings that were each pre-incubated for 50 minutes in different concentrations (1 × 10 −9 M to 1 × 10 −5 M) of 17β-estradiol. Compared to freshly used arteries, culturing induced a 2-fold increase in tension development to ET-1 (3 × 10 −7 M). Although 17β-estradiol previously relaxed pre-constricted (with a 60 mM KCl solution) arteries, it did not affect the constrictive response to ET-1. Also, using an ET-1 ELISA we found that 17β-estradiol did not effect ET-1 production in intact arteries. Our results indicate that 17β-estradiol does not attenuate the production and constrictive properties of ET-1 in coronary arteries demonstrating a dedifferentiated cell phenotype.

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Section: Discussioncontrasting

confidence: 98%

Section: Discussionsupporting

confidence: 89%

The enhanced endothelin-1-induced contraction in cultured coronary arteries from mature female pigs is not antagonized by 17β-estradiol

Tummala

Hill

2007

Vascular Pharmacology

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“…1-2 Because ET-1 plays a role in the pathogenesis of DOCA-salt hypertension, [13][14][15][16][17] it is possible that the attenuated development of hypertension in female DOCA-salt rats may be related to a modulation exerted by the gonadal hormones on ET-1 effects on the cardiovascular system. [5][6][7][8][9][10][11] We have recently reported that in DOCA-salt hypertension, male rats display altered vascular and pressor responses to ET-1 and to the ET B agonist IRL-1620 and that these alterations are attenuated in female rats. 3,4 We specu- lated that the differential and gender-related alterations in ET-1-mediated effects in DOCA-salt hypertension may be important in the higher blood pressure levels observed in male DOCA-salt hypertensive rats.…”

Section: Discussionmentioning

confidence: 99%

Ovarian Hormones Modulate Endothelin-1 Vascular Reactivity and mRNA Expression in DOCA-Salt Hypertensive Rats

et al. 2001

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Abstract-We previously demonstrated a differential activation of the endothelin-1 (ET-1) pathway in male and female deoxycorticosterone (DOCA)-salt hypertensive rats, with the male rats exhibiting marked alterations in vascular and pressor responses to ET-1 and Suc-[Glu, 9 Ala 11,15 ]-ET-1(8-21) (IRL-1620), an ET B agonist. Mechanisms underlying these gender differences are unclear, and we hypothesized that the ovarian hormones attenuate vascular ET B responses in female DOCA-salt rats. Female Wistar rats were randomized in 3 groups: sham-operated, ovariectomized (OVX), and OVX plus hormone replacement with estradiol (E) or estradiol/progesterone (EP). Two weeks later, rats were uninephrectomized and further randomized in DOCA-salt (subcutaneous injections of desoxycorticosterone and drinking water containing NaCl/KCl) and control normotensive (subcutaneous injections of vehicle and tap water). Blood pressure was evaluated both by direct and standard tail-cuff methods. Responses to IRL-1620 were evaluated in vivo/in situ in the mesenteric microcirculation. mRNA expression of ET-1 and ET A/B receptors was evaluated in mesenteric arteries by reverse transcription-polymerase chain reaction and expressed relative to GAPDH. OVX-DOCA rats developed a more severe form of hypertension than did DOCA rats. Treatment with E or EP restored blood pressure to levels observed in DOCA rats. In the mesentery, IRL-1620 induced vasodilatation in control rats, a mild vasoconstriction in DOCA rats, and marked vasoconstriction in OVX-DOCA rats. Both E and EP decreased IRL-1620 -induced vasoconstriction in the DOCA group. In the normotensive group, OVX did not change blood pressure or IRL-1620 -induced vasodilation. Removal of the ovaries increased ET-1 mRNA in arteries from DOCA and control rats, although treatment with E or EP reversed these changes. Vascular ET B receptor mRNA levels were greatly enhanced in OVX-DOCA but not OVX-control rats. Hormone replacement with E or EP restored ET B receptor expression in the DOCA group. A greater blood pressure-lowering effect of bosentan (ET A /ET B blocker) was observed in OVX-DOCA rats. The observation that OVX worsens hypertension as well as the altered ET B receptor-mediated responses and the effects of bosentan in female DOCA rats supports our suggestion that the ovarian hormones modulate ET-1/ET B receptor vascular responses/expression in DOCA-salt hypertension. Key Words: deoxycorticosterone Ⅲ vasoconstriction Ⅲ endothelin Ⅲ estrogen Ⅲ receptors, endothelin I n deoxycorticosterone (DOCA)-salt hypertension and other experimental models of hypertension, male rats develop an earlier and more severe form of hypertension than do female rats. 1-2 We have recently suggested that differential activation of endothelin-1 (ET-1) pathways, expressed by a functional upregulation of ET B receptors, may play a role in the higher blood pressure (BP) levels observed in male DOCA-salt hypertensive rats. [3][4] We observed that mesenteric arterioles from male but not female DOCA-salt rats display incre...

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“…Our own work using a rat model of menopause (12-mo-old ovariectomized Sprague-Dawley rats) found increased mesenteric artery reactivity to big ET-1 (an ET-1 precursor) compared with young cycling females, which was ameliorated in the "menopausal" animals receiving chronic estrogen treatment (55). A study by Sudhir et al (93) showed an attenuation of ET-1 responses in coronary arteries following acute intracoronary injection of a physiologically relevant dose of estrogen, suggesting the possibility of rapid nongenomic estrogen effect. These in vivo findings clearly show a key role for estrogen in protecting the cardiovascular system from ET-1-mediated pathological change, which may be lost during menopause.…”

Section: Sex Hormones and Endothelinmentioning

confidence: 97%

Endothelin in the female vasculature: a role in aging?

Lekontseva

Chakrabarti

Davidge

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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vascular diseases are the leading cause of morbidity and mortality in the world. Aging is associated with an increased incidence of cardiovascular disease. Premenopausal women are relatively protected from vascular alterations compared with age-matched men, likely due to higher levels of the female sex hormones. However, these vasoprotective effects in women are attenuated after menopause. Thus, the vascular system in aging women is affected by both the aging process as well as loss of hormonal protection, positioning women of this age group at a high risk for cardiovascular diseases such as hypertension, myocardial infarction, and stroke. The endothelin system in general and endothelin-1 (ET-1) in particular plays an important role in the pathogenesis of vascular dysfunction associated with aging. Evidence suggests that the female sex steroids can interfere with the vascular expression and actions of ET-1 via several mechanisms, which may further contribute to pathological processes in the vasculature of aging women. In this review, we have summarized hormone-dependent vascular pathways whereby ET-1 may mediate the deleterious effects of aging in postmenopausal females.ET-1; menopause; estrogen; vasoconstriction; inflammation AGING OF THE VASCULAR SYSTEM is a complex process characterized by sustained proinflammatory and proconstrictor changes in the vascular microenvironment. The resulting structural and functional alterations in systemic vasculature lead to increased risk of cardiovascular diseases such as hypertension, myocardial infarction, and stroke in the aging population (12,18,51,70). In the absence of chronic preexisting conditions, such as diabetes, premenopausal women express a favorable cardiovascular phenotype compared with age-matched men, largely due to the vasoprotective role of ovarian steroids such as estrogen (92). An alteration in circulating sex hormones at menopause, such as the decrease in estrogens and a relative excess of androgens, is associated with the conversion from a low-to high-risk cardiovascular profile (19,56). Although the mechanisms underlying the pathogenesis of vascular dysfunction in postmenopausal women are not completely understood, it is believed to result from a complex interplay between the aging process and the decline in ovarian hormones like estrogen.Endothelin has emerged as one of the key mediators of vascular dysfunction and remodeling in aging. Interestingly, there is evidence that female sex steroids (in particular, estrogen) can regulate the endothelin system at various levels from gene transcription and posttranslational modification of the peptide to expression of its vascular receptors and postreceptor signaling events. This review will summarize current knowledge on the impact of aging and female sex hormones on the endothelin system, as well as outline directions where further research is needed. A better understanding of the role of endothelin in the pathogenesis of vascular dysfunction in postmenopausal women may lead to the development of novel sex-...

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Physiological Concentrations of Estradiol Attenuate Endothelin 1–Induced Coronary Vasoconstriction In Vivo

Cited by 56 publications

References 35 publications

The enhanced endothelin-1-induced contraction in cultured coronary arteries from mature female pigs is not antagonized by 17β-estradiol

The enhanced endothelin-1-induced contraction in cultured coronary arteries from mature female pigs is not antagonized by 17β-estradiol

Ovarian Hormones Modulate Endothelin-1 Vascular Reactivity and mRNA Expression in DOCA-Salt Hypertensive Rats

Endothelin in the female vasculature: a role in aging?

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