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

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.

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

Hypertension ◽

10.1161/hyp.70.suppl_1.p156 ◽

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.

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Nitric oxide and attenuated reflex cutaneous vasodilation in aged skin

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00871.2002 ◽

2003 ◽

Vol 284 (5) ◽

pp. H1662-H1667 ◽

Cited By ~ 98

Author(s):

Lacy A. Holowatz ◽

Belinda L. Houghton ◽

Brett J. Wong ◽

Brad W. Wilkins ◽

Aaron W. Harding ◽

...

Keyword(s):

Nitric Oxide ◽

Core Temperature ◽

The Elderly ◽

Doppler Flowmetry ◽

Cutaneous Vasodilation ◽

Forearm Skin ◽

Vascular Responsiveness ◽

Older Subjects ◽

Young Subjects ◽

Reflex Cutaneous Vasodilation

Thermoregulatory cutaneous vasodilation is diminished in the elderly. The goal of this study was to test the hypothesis that a reduction in nitric oxide (NO)-dependent mechanisms contributes to the attenuated reflex cutaneous vasodilation in older subjects. Seven young (23 ± 2 yr) and seven older (71 ± 6 yr) men were instrumented with two microdialysis fibers in the forearm skin. One site served as control (Ringer infusion), and the second site was perfused with 10 mM N G-nitro-l-arginine methyl ester to inhibit NO synthase (NOS) throughout the protocol. Water-perfused suits were used to raise core temperature 1.0°C. Red blood cell (RBC) flux was measured with laser-Doppler flowmetry over each microdialysis fiber. Cutaneous vascular conductance (CVC) was calculated as RBC flux per mean arterial pressure, with values expressed as a percentage of maximal vasodilation (infusion of 28 mM sodium nitroprusside). NOS inhibition reduced CVC from 75 ± 6% maximal CVC (CVCmax) to 53 ± 3% CVCmax in the young subjects and from 64 ± 5% CVCmax to 29 ± 2% CVCmax in the older subjects with a 1.0°C rise in core temperature. Thus the relative NO-dependent portion of cutaneous active vasodilation (AVD) accounted for ∼23% of vasodilation in the young subjects and 60% of the vasodilation in the older subjects at this level of hyperthermia ( P < 0.001). In summary, NO-mediated pathways contributed more to the total vasodilatory response of the older subjects at high core temperatures. This suggests that attenuated cutaneous vasodilation with age may be due to a reduction in, or decreased vascular responsiveness to, the unknown neurotransmitter(s) mediating AVD.

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Thromboxane A2-prostaglandin H2 and renovascular hypertension in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1994.267.5.r1190 ◽

1994 ◽

Vol 267 (5) ◽

pp. R1190-R1197 ◽

Cited By ~ 4

Author(s):

E. H. Boussairi ◽

J. Sacquet ◽

J. Sassard ◽

D. Benzoni

Keyword(s):

Blood Pressure ◽

Renal Artery ◽

Receptor Antagonist ◽

Renovascular Hypertension ◽

Vascular Reactivity ◽

Thromboxane A2 ◽

Malignant Hypertension ◽

Receptor Blockade ◽

Vascular Responsiveness ◽

Goldblatt Hypertension

To evaluate the contribution of thromboxane (Tx) A2-prostaglandin (PG) H2 in two-kidney, one-clip Goldblatt hypertension (GH), 26 GH rats were chronically treated (GHT) with a specific TxA2-PGH2 receptor antagonist, CGS-22652 (30 mg.kg-1.24 h-1 sc); 28 others as well as 17 sham-clipped (SC) rats received vehicle. Twelve GH and 3 GHT rats developed malignant hypertension and died. After 6 wk of treatment, GH rats exhibited higher mean blood pressure (BP; 189 +/- 3 vs. 118 +/- 2 mmHg) and an increased vascular reactivity to the main pressor agents compared with SC rats. Chronic TxA2-PGH2 receptor blockade lowered mean BP in 13 GHT rats (125 +/- 3 mmHg) and decreased their vascular reactivity compared with GH rats. However, 10 GHT rats remained hypertensive (190 +/- 9 mmHg) and differed from the former by an increased vascular reactivity to vasopressin. It is concluded that renal artery clipping induces either benign or malignant hypertension. In benign forms, TxA2-PGH2 blockade normalizes BP through decreasing the vascular responsiveness to the main pressor agents. In malignant forms, it limits the elevation of BP and markedly reduces mortality.

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Vascular responses after alpha adrenergic receptor blockade

Journal of Clinical Investigation ◽

10.1172/jci105699 ◽

1968 ◽

Vol 47 (1) ◽

pp. 1-9 ◽

Cited By ~ 33

Author(s):

Francois M. Abboud ◽

Phillip G. Schmid ◽

John W. Eckstein

Keyword(s):

Adrenergic Receptor ◽

Receptor Blockade ◽

Vascular Responses ◽

Alpha Adrenergic Receptor ◽

Adrenergic Receptor Blockade

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Sex differences to myocardial ischemia and β-adrenergic receptor blockade in conscious rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01241.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. H1523-H1529 ◽

Cited By ~ 15

Author(s):

Heidi L. Lujan ◽

Stephen E. DiCarlo

Keyword(s):

Sex Differences ◽

Ventricular Tachycardia ◽

Coronary Artery ◽

Arterial Pressure ◽

Adrenergic Receptor ◽

Gonadal Hormones ◽

Sustained Ventricular Tachycardia ◽

Receptor Blockade ◽

Conscious Rats ◽

Adrenergic Receptor Blockade

We recently documented sex differences in the susceptibility to reperfusion-induced sustained ventricular tachycardia and β-adrenergic receptor blockade in conscious rats. However, the effect of sex on ischemia-induced ventricular arrhythmias and β-adrenergic receptor blockade is underinvestigated. Therefore, we tested the hypothesis that gonadal hormones influence the ventricular arrhythmia threshold (VAT) induced by coronary artery occlusion as well as the response to β-adrenergic receptor blockade. The VAT was defined as the time from coronary occlusion to sustained ventricular tachycardia resulting in a reduction in arterial pressure. Male and female intact and gonadectomized (GnX) rats were instrumented with a radiotelemetry device for recording arterial pressure, temperature, and ECG, as well as a Doppler ultrasonic flow probe to measure cardiac output and a snare around the left main coronary artery. The VAT was determined in conscious rats by pulling on the snare. The VAT was significantly longer in intact females (5.56 ± 0.19) vs. intact males (4.31 ± 0.14 min). This sex difference was abolished by GnX. Specifically, GnX decreased the VAT in females (4.55 ± 0.22) and increased the VAT in males (5.14 ± 0.30 min). Thus male sex hormones increase and female sex hormones decrease the susceptibility to ischemia-induced sustained ventricular tachycardia. β-Adrenergic receptor blockade increased the VAT in intact males and GnX females only. Thus gonadal hormones influence the response to β-adrenergic receptor blockade. Uncovering major differences between males and females in the pathophysiology of the cardiovascular system may result in sex-specific optimization of patient treatments.

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Vascular responses after alpha adrenergic receptor blockade

Journal of Clinical Investigation ◽

10.1172/jci105700 ◽

1968 ◽

Vol 47 (1) ◽

pp. 10-19 ◽

Cited By ~ 10

Author(s):

Francois M. Abboud ◽

John W. Eckstein

Keyword(s):

Adrenergic Receptor ◽

Receptor Blockade ◽

Vascular Responses ◽

Alpha Adrenergic Receptor ◽

Adrenergic Receptor Blockade

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Sex differences in forearm vasoconstrictor response to voluntary apnea

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00746.2013 ◽

2014 ◽

Vol 306 (3) ◽

pp. H309-H316 ◽

Cited By ~ 15

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.

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ETBreceptor contribution to vascular dysfunction in postmenopausal women

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00410.2016 ◽

2017 ◽

Vol 313 (1) ◽

pp. R51-R57 ◽

Cited By ~ 12

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.

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