Abstract P156: Estrogen Regulation of Endothelin-B Receptor Mediated Vasodilation

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Katherine Haigh ◽  
Ronald F Feinberg ◽  
Hugh S Taylor ◽  
Megan M Wenner
Keyword(s):  
Postmenopausal Women ◽  
Young Women ◽  
Local Heating ◽  
Receptor Blockade ◽  
Ovarian Hormone ◽  
Hormone Production ◽  
Doppler Flowmetry ◽  
Arterial Blood ◽  
Etb Receptor ◽  
Endothelin B

Our laboratory has recently demonstrated that a loss of endothelin-B (ETB) receptor mediated dilation contributes to impaired vasodilatory function in postmenopausal women. It is unclear if these changes are due to aging, or alterations in ovarian hormones that occur after menopause. The purpose of this study was to test the hypothesis that in a low estradiol state, there is a loss of ETB mediated dilation, and that estradiol administration reverses these responses and mediates dilation. Methods: We tested 8 young women (YW: 24±2 years, 23±1 kg/m 2 , mean arterial BP 84±2mHg) and 6 postmenopausal women (PMW: 56±1 years, 24±1 kg/m 2 , mean arterial BP 94±2mHg). In YW, we suppressed endogenous ovarian hormone production with daily gonadotropin-releasing hormone antagonist (GnRHant; Ganirelix) administration for 10 days, adding estradiol (E2, 0.1 mg/day, Vivelle dot patch) on days 4-10. PMW were tested at baseline and after 1-week E2 administration (0.1 mg/day, Vivelle dot patch). We measured nitric-oxide mediated vasodilation in the cutaneous circulation during local heating (42°C) via laser Doppler flowmetry, followed by microdialysis perfusions of sodium nitroprusside (28mM) with local heating to 43°C to elicit maximal dilation. Cutaneous vascular conductance (CVC) was calculated as cutaneous blood flow/mean arterial blood pressure, and expressed as a percent of maximal dilation. Results: ETB receptor blockade increased vasodilation in YW during hormone suppression with GnRHant (control: 88±3 vs. BQ-788: 94±2 CVC %max, P <0.05). However, ETB receptor blockaded tended to reduce vaodilation during E2 administration (control: 88±3 vs. BQ-788: 82±2 CVC %max, P =0.12). In PMW, ETB receptor blockade had no significant effect on vasodilatory responses (control: 90±4 vs. BQ-788: 95±2 CVC %max, P =0.20). Similarly, ETB receptor blockade did not alter vasodilation after E2 administration (control: 88±7 vs. BQ-788: 88±4 CVC %max). Conclusions: These preliminary data suggest that suppression of endogenous ovarian hormone production alters ETB receptor responses in young women, which is partially mediated by E2. Additional data are needed to determine ETB receptor sensitivity to E2 after menopause.

Insulin sensitivity and big ET-1 conversion to ET-1 after ETA- or ETB-receptor blockade in humans

2002 ◽  
Vol 93 (6) ◽  
pp. 2112-2121 ◽  
Author(s):  
Gunvor Ahlborg ◽  
Jonas Lindström
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Healthy Subjects ◽  
Receptor Blockade ◽  
Receptor Stimulation ◽  
Renal Vasoconstriction ◽  
Arterial Blood ◽  
Etb Receptor

Cardiovascular diseases are characterized by insulin resistance and elevated endothelin (ET)-1 levels. Furthermore, ET-1 induces insulin resistance. To elucidate this mechanism, six healthy subjects were studied during a hyperinsulinemic euglycemic clamp during infusion of (the ET-1 precursor) big ET-1 alone or after ETA- or ETB-receptor blockade. Insulin levels rose after big ET-1 with or without the ETB antagonist BQ-788 ( P < 0.05) but were unchanged after the ETA antagonist BQ-123 + big ET-1. Infused glucose divided by insulin fell after big ET-1 with or without BQ-788 ( P < 0.05). Insulin and infused glucose divided by insulin values were normalized by ETA blockade. Mean arterial blood pressure rose during big ET-1 with or without BQ-788 ( P < 0.001) but was unchanged after BQ-123. Skeletal muscle, splanchnic, and renal blood flow responses to big ET-1 were abolished by BQ-123. ET-1 levels rose after big ET-1 ( P< 0.01) in a similar way after BQ-123 or BQ-788, despite higher elimination capacity after ETA blockade. In conclusion, ET-1-induced reduction in insulin sensitivity and clearance as well as splanchnic and renal vasoconstriction are ETA mediated. ETA-receptor stimulation seems to inhibit the conversion of big ET-1 to ET-1.

ETB receptor-mediated vasodilation is regulated by estradiol in young women

2021 ◽  
Vol 321 (3) ◽  
pp. H592-H598
Author(s):  
Leena N. Shoemaker ◽  
Katherine M. Haigh ◽  
Andrew V. Kuczmarski ◽  
Shane J. McGinty ◽  
Laura M. Welti ◽  
...  
Keyword(s):  
Young Women ◽  
Gnrh Antagonist ◽  
Endogenous Hormone ◽  
Etb Receptor ◽  
Endothelin B

The endothelin-B (ETB) receptor mediates vasodilation in young women, an effect lost following menopause. It is unclear whether these alterations are due to aging or changes in estradiol (E2). During endogenous hormone suppression (GnRH antagonist), blockade of ETB receptors enhanced cutaneous microvascular vasodilation. However, during E2 administration, blockade of ETB receptors attenuated vasodilation, indicating that the ETB receptor mediates dilation in the presence of E2. In young women, ETB receptors mediate vasodilation in the presence of E2, an effect that is lost when E2 is suppressed.

scholarly journals Lack of limb or sex differences in the cutaneous vascular responses to exogenous norepinephrine

2014 ◽  
Vol 117 (12) ◽  
pp. 1417-1423 ◽  
Author(s):  
Jody L. Greaney ◽  
Anna E. Stanhewicz ◽  
W. Larry Kenney ◽  
Lacy M. Alexander
Keyword(s):  
Sex Differences ◽  
Receptor Antagonist ◽  
Young Women ◽  
Adrenergic Receptor ◽  
Receptor Blockade ◽  
Doppler Flowmetry ◽  
Vascular Responses ◽  
Cutaneous Vasodilation ◽  
Vascular Responsiveness ◽  
Cutaneous Vasoconstriction

The cutaneous circulation is used to examine vascular adrenergic function in clinical populations; however, limited studies have examined whether there are regional limb and sex differences in microvascular adrenergic responsiveness. We hypothesized that cutaneous adrenergic responsiveness would be greater in the leg compared with the arm and that these regional limb differences would be blunted in young women ( protocol 1). We further hypothesized that cutaneous vasoconstriction to exogenous norepinephrine (NE) during β-adrenergic receptor antagonism would be augmented in young women ( protocol 2). In protocol 1, one microdialysis fiber was placed in the skin of the calf and the ventral forearm in 20 healthy young adults (11 men and 9 women). Laser-Doppler flowmetry was used to measure red blood cell flux in response to graded intradermal microdialysis infusions of NE (10−12 to 10−2 M). In protocol 2, three microdialysis fibers were placed in the forearm (6 men and 8 women) for the local perfusion of lactated Ringer (control), 5 mM yohimbine (α-adrenergic receptor antagonist), or 2 mM propranolol (β-adrenergic receptor antagonist) during concurrent infusions of NE (10−12 to 10−2 M). There were no limb or sex differences in cutaneous adrenergic responsiveness (logEC50) to exogenous NE. During α-adrenergic receptor blockade, women had greater exogenous NE-induced cutaneous vasodilation at the lowest doses of NE (10−12 to 10−10 M). Collectively, these data indicate that there are no limb or sex differences in cutaneous adrenergic responsiveness to exogenous NE; however, young women have a greater β-adrenergic receptor-mediated component of the vascular responsiveness to exogenous NE.

scholarly journals Sex differences in forearm vasoconstrictor response to voluntary apnea

2014 ◽  
Vol 306 (3) ◽  
pp. H309-H316 ◽  
Author(s):  
Hardikkumar M. Patel ◽  
Matthew J. Heffernan ◽  
Amanda J. Ross ◽  
Matthew D. Muller
Keyword(s):  
Sex Differences ◽  
Postmenopausal Women ◽  
Young Women ◽  
Young Men ◽  
Breath Hold ◽  
Doppler Flowmetry ◽  
Men And Women ◽  
Female Sex Hormones ◽  
Vasoconstrictor Response ◽  
Obstructive Sleep

Clinical evidence indicates that obstructive sleep apnea is more common and more severe in men compared with women. Sex differences in the vasoconstrictor response to hypoxemia-induced sympathetic activation might contribute to this clinical observation. In the current laboratory study, we determined sex differences in the acute physiological responses to maximal voluntary end-expiratory apnea (MVEEA) during wakefulness in healthy young men and women (26 ± 1 yr) as well as healthy older men and women (64 ± 2 yr). Mean arterial pressure (MAP), heart rate (HR), brachial artery blood flow velocity (BBFV, Doppler ultrasound), and cutaneous vascular conductance (CVC, laser Doppler flowmetry) were measured, and changes in physiological parameters from baseline were compared between groups. The breath-hold duration and oxygen-saturation nadir were similar between groups. In response to MVEEA, young women had significantly less forearm vasoconstriction compared with young men (ΔBBFV: 2 ± 7 vs. −25 ± 6% and ΔCVC: −5 ± 4 vs. −31 ± 4%), whereas ΔMAP (12 ± 2 vs. 16 ± 3 mmHg) and ΔHR (4 ± 2 vs. 6 ± 3 bpm) were comparable between groups. The attenuated forearm vasoconstriction in young women was not observed in postmenopausal women (ΔBBFV −21 ± 5%). We concluded that young women have blunted forearm vasoconstriction in response to MVEEA compared with young men, and this effect is not evident in older postmenopausal women. These data suggest that female sex hormones dampen neurogenic vasoconstriction in response to apnea-induced hypoxemia.

Regional hemodynamics during postexercise hypotension. II. Cutaneous circulation

2004 ◽  
Vol 97 (6) ◽  
pp. 2071-2076 ◽  
Author(s):  
Brad W. Wilkins ◽  
Christopher T. Minson ◽  
John R. Halliwill
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Local Heating ◽  
Exercise Bout ◽  
Internal Temperature ◽  
Vascular Conductance ◽  
Doppler Flowmetry ◽  
Arterial Blood ◽  
Postexercise Hypotension ◽  
Cutaneous Circulation

After an acute bout of exercise, there is an unexplained elevation in systemic vascular conductance that is not completely offset by an increase in cardiac output, resulting in a postexercise hypotension. The contributions of the splanchnic and renal circulations are examined in a companion paper (Pricher MP, Holowatz LA, Williams JT, Lockwood JM, and Halliwill JR. J Appl Physiol 97: 2065–2070, 2004). The purpose of this study was to determine the contribution of the cutaneous circulation in postexercise hypotension under thermoneutral conditions (∼23°C). Arterial blood pressure was measured via an automated sphygmomanometer, internal temperature was measured via an ingestible pill, and skin temperature was measured with eight thermocouples. Red blood cell flux (laser-Doppler flowmetry) was monitored at four skin sites (chest, forearm, thigh, and leg), and cutaneous vascular conductance (CVC) was calculated (red blood cell flux/mean arterial pressure) and scaled as percent maximal CVC (local heating to 43°C). Ten subjects [6 men and 4 women; age 23 ± 1 yr; peak O2 uptake (V̇o2 peak) 45.8 ± 2.0 ml·kg−1·min−1] volunteered for this study. After supine rest (30 min), subjects exercised on a bicycle ergometer for 1 h at 60% of their V̇o2 peak and were then positioned supine for 90 min. Exercise elicited a postexercise hypotension reaching a nadir at 46.0 ± 4.5 min postexercise (77 ± 1 vs. 82 ± 2 mmHg preexercise; P < 0.05). Internal temperature increased (38.0 ± 0.1 vs. 36.7 ± 0.1°C preexercise; P < 0.05), remaining elevated at 90 min postexercise (36.9 ± 0.1°C vs. preexercise; P < 0.05). CVC at all four skin sites was elevated by the exercise bout ( P < 0.05), returning to preexercise values within 50 min postexercise ( P > 0.05). Therefore, although transient changes in CVC occur postexercise, they do not appear to play an obligatory role in mediating postexercise hypotension under thermoneutral conditions.

Chronic hormone replacement therapy does not alter resting or maximal skin blood flow

1998 ◽  
Vol 85 (2) ◽  
pp. 505-510 ◽  
Author(s):  
E. M. Brooks-Asplund ◽  
W. L. Kenney
Keyword(s):  
Blood Flow ◽  
Replacement Therapy ◽  
Postmenopausal Women ◽  
Skin Blood Flow ◽  
Local Heating ◽  
Hormone Replacement ◽  
Venous Occlusion ◽  
Body Core Temperature ◽  
Vascular Conductance ◽  
Doppler Flowmetry

Postmenopausal women on estrogen replacement therapy (ERT) regulate body core temperature at a lower baseline level at rest in a thermoneutral environment. We conducted a series of studies to test whether, in a thermoneutral environment, chronic (≥2 yr) oral ERT significantly alters baseline skin blood flow (SkBF) and cutaneous vascular conductance (CVC) and whether ERT alters maximal CVC (CVCmax) and SkBF in postmenopausal women. In the first set of studies, forearm blood flow (FBF) was measured by venous-occlusion plethysmography in 24 postmenopausal women: 8 not taking exogenous hormone therapy (No HRT group), 8 on ERT, and 8 receiving combination of estrogen and progesterone therapy, at rest and during prolonged (1 h) local heating of the forearm at 42°C. Mean arterial pressure (MAP) was measured by brachial auscultation before each set of FBF measurements to calculate forearm vascular conductance (FVC = FBF/MAP). SkBF was measured by laser-Doppler flowmetry (LDF), and CVC was calculated as LDF/MAP and standardized as %CVCmax. Baseline FVC, %CVCmax, and maximal FVC were not significantly different among the three groups of women. In the second set of experiments, LDF in ERT and No HRT groups was measured at rest in both thermoneutral and warm environments. %CVCmax was again not significantly different between ERT and No HRT groups at thermoneutral ambient temperatures and increased similarly in the warm environment. Therefore, chronic exogenous ERT does not appear to influence either baseline or maximal SkBF.

scholarly journals ETBreceptor contribution to vascular dysfunction in postmenopausal women

2017 ◽  
Vol 313 (1) ◽  
pp. R51-R57 ◽  
Author(s):  
Megan M. Wenner ◽  
Kelly N. Sebzda ◽  
Andrew V. Kuczmarski ◽  
Ryan T. Pohlig ◽  
David G. Edwards
Keyword(s):  
Receptor Antagonist ◽  
Postmenopausal Women ◽  
Vascular Dysfunction ◽  
Local Heating ◽  
Doppler Flowmetry ◽  
Cutaneous Vasodilation ◽  
Age Related ◽  
Measured Flow ◽  
Vasodilatory Function ◽  
Cutaneous Vascular Conductance

Endothelin-1 (ET-1) contributes to age-related endothelial dysfunction in men via the ETAreceptor. However, there are sex differences in the ET-1 system, and ETBreceptors are modulated by sex hormones. The purpose of this study was to test the hypothesis that ETBreceptors contribute to impaired vasodilatory function in postmenopausal women (PMW). We measured flow-mediated dilation (FMD) using ultrasound, and cutaneous nitric oxide-mediated vasodilation during local heating (42°C) via laser Doppler flowmetry in 18 young women (YW; 22 ± 1 yr) and 16 PMW (56 ± 1 yr). Cutaneous microdialysis perfusions of lactated Ringer (control), an ETBreceptor antagonist (BQ-788, 300 nM), and an ETAreceptor antagonist (BQ-123, 500 nM), were done through separate fibers, followed by perfusions of sodium nitroprusside (28 mM) and local heating to 43°C (max). Cutaneous vascular conductance (CVC) was calculated as cutaneous blood flow/mean arterial pressure and expressed as a percent of maximal dilation. FMD (YW: 7.5 ± 0.5 vs. PMW: 5.6 ± 0.6%) and cutaneous vasodilation (YW: 93 ± 2 vs. PMW: 83 ± 4%CVCmax) were lower in PMW (both P < 0.05). Blockade of ETBreceptors decreased cutaneous vasodilation in YW (87 ± 2%CVCmax; P < 0.05 vs. control) but increased vasodilation in PMW (93 ± 1%CVCmax; P < 0.05 vs. control). ETAreceptor blockade had minimal effect in YW (92 ± 1%CVCmax) but increased cutaneous vasodilation in PMW (91 ± 2%CVCmax; P < 0.05 vs. control). In conclusion, ETBreceptors mediate vasodilation in YW, but this effect is lost after menopause. Impaired vasodilatory function in PMW is due in part to a loss of ETB-mediated dilation.

scholarly journals AT II Receptor Blockade and Renal Denervation: Different Interventions with Comparable Renal Effects?

2021 ◽  
pp. 1-11
Author(s):  
Kristina Rodionova ◽  
Martin Hindermann ◽  
Karl Hilgers ◽  
Christian Ott ◽  
Roland E. Schmieder ◽  
...  
Keyword(s):  
Body Weight ◽  
Volume Expansion ◽  
Neural Control ◽  
Renal Denervation ◽  
Urine Volume ◽  
Receptor Blockade ◽  
Ang Ii ◽  
Water Excretion ◽  
Arterial Blood ◽  
Renal Sympathetic

<b><i>Background:</i></b> Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX). <b><i>Methods:</i></b> Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied. <b><i>Results:</i></b> CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF. <b><i>Conclusion:</i></b> The prominent function of increased RSNA – retaining salt and water – could no longer be observed after renal Ang II receptor blockade in CHF rats.

scholarly journals Endothelin ETB Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders

2021 ◽  
Vol 22 (9) ◽  
pp. 4333
Author(s):  
Yutaka Koyama
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neurotrophic Factors ◽  
Drug Target ◽  
Therapeutic Strategy ◽  
Reactive Astrocytes ◽  
Brain Disorders ◽  
Etb Receptor ◽  
Target Molecules ◽  
Endothelin B

In brain disorders, reactive astrocytes, which are characterized by hypertrophy of the cell body and proliferative properties, are commonly observed. As reactive astrocytes are involved in the pathogenesis of several brain disorders, the control of astrocytic function has been proposed as a therapeutic strategy, and target molecules to effectively control astrocytic functions have been investigated. The production of brain endothelin-1 (ET-1), which increases in brain disorders, is involved in the pathophysiological response of the nervous system. Endothelin B (ETB) receptors are highly expressed in reactive astrocytes and are upregulated by brain injury. Activation of astrocyte ETB receptors promotes the induction of reactive astrocytes. In addition, the production of various astrocyte-derived factors, including neurotrophic factors and vascular permeability regulators, is regulated by ETB receptors. In animal models of Alzheimer’s disease, brain ischemia, neuropathic pain, and traumatic brain injury, ETB-receptor-mediated regulation of astrocytic activation has been reported to improve brain disorders. Therefore, the astrocytic ETB receptor is expected to be a promising drug target to improve several brain disorders. This article reviews the roles of ETB receptors in astrocytic activation and discusses its possible applications in the treatment of brain disorders.

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