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Introduction: Vascular dysfunction, marked by lower endothelial function and increased aortic stiffness, are non-traditional risk factors that precede the development of CVD. However, the age at which these changes in vascular function occur in women and the degree to which reproductive hormones mediate these changes has not been characterized., Methods: Women free from major disease were enrolled across the adult lifespan (aged 18-70, n=140). Endothelial function was assessed as flow-mediated dilation (FMD) of the brachial artery during reactive hyperemia using duplex ultrasound and expressed as percent dilation. Aortic stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). Blood samples were obtained to quantify reproductive hormone concentration. Regression models determined age-related breakpoints and mediating factors between age and vascular outcomes., Results: FMD declined with age with a breakpoint and steeper decline occurring at age 47. Thereafter, age was independently associated with lower FMD (B=-0.13, P<0.001). cfPWV was relatively stable until a breakpoint at age 48, and age was independently associated with higher cfPWV thereafter (B=0.10, P<0.001). Path analysis revealed that the association between age and FMD was partially mediated by follicle stimulating hormone ( ab ind =0.051, P=0.01) and progesterone ( ab ind =0.513, P<0.001) but not estradiol ( ab ind =-0.004, P=0.08). No mediation was present for cfPWV., Conclusions: Age was associated with endothelial dysfunction and aortic stiffness in women beginning at 47 and 48 years, respectively, 3-4 years prior to the average age of menopause. The association between age and endothelial dysfunction was explained in part by elevations in follicle stimulating hormone and progesterone, but not declining estradiol.

Rodent studies demonstrated specialized sodium chloride (NaCl) sensing neurons in the circumventricular organs, which mediate changes in sympathetic nerve activity, arginine vasopressin, thirst, and blood pressure. However, the neural pathways involved in NaCl sensing in the human brain are incompletely understood. The purpose of this pilot study was to determine if acute hypernatremia alters the functional connectivity of NaCl-sensing regions of the brain in healthy young adults. Resting-state fMRI scans were acquired in 13 participants at baseline and during a 30 min hypertonic saline infusion (HSI). We used a seed-based approach to analyze the data, focusing on the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) as regions of interest (ROIs). Blood chemistry and perceived thirst were assessed pre- and post-infusion. As expected, serum sodium increased from pre- to post-infusion in the HSI group. The primary finding of this pilot study was that the functional connectivity between the SFO and a cluster within the OVLT increased from baseline to the late-phase of the HSI. Bidirectional connectivity changes were found with cortical regions, with some regions showing increased connectivity with sodium-sensing regions while others showed decreased connectivity. Furthermore, the functional connectivity between the SFO and the posterior cingulate cortex (a control ROI) did not change from baseline to the late-phase of the HSI. This finding indicates a distinct response within the NaCl sensing network in the human brain specifically related to acute hypernatremia that will need to be replicated in large-scale studies., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The sympathetic nervous system is critical for regulating blood pressure (BP) via the arterial baroreflex and sympathetic transduction in the peripheral vasculature. These mechanisms interact, and both may be altered with aging and impacted by menopause. Although age-related decreases in sympathetic transduction have been demonstrated in women, it remains unclear whether sympathetic baroreflex sensitivity (BRS) is impaired in postmenopausal women (POST). We tested the hypothesis that sympathetic BRS would be enhanced in POST compared with premenopausal women (PRE). We examined beat-by-beat BP and muscle sympathetic nerve activity (MSNA) in 19 PRE (22 ± 2 yr, 22 ± 3 kg/m 2 ) and 12 POST (57 ± 5 yr, 24 ± 2 kg/m 2 ) during 10 min of rest. Spontaneous sympathetic BRS was quantified as the slope of a linear regression between MSNA burst incidence and diastolic BP. Sympathetic transduction to mean arterial pressure (MAP) for the 10 cardiac cycles following spontaneous MSNA bursts was assessed via signal averaging method. Resting MAP was similar (PRE: 82 ± 8 vs. POST: 85 ± 8 mmHg, P = 0.43), whereas resting MSNA was elevated in POST (PRE: 10 ± 6 vs. POST: 45 ± 16 bursts/100 heart beats, P < 0.0001). Spontaneous sympathetic BRS was enhanced in POST (PRE: -2.0 ± 1.2 vs. POST: -5.2 ± 1.9 bursts/beat/mmHg, P < 0.0005). Sympathetic transduction to MAP was attenuated in POST (time: P < 0.001, group: P < 0.001, interaction: P < 0.01). These data suggest that sympathetic BRS may be enhanced in POST. Consistent with recent hypotheses, enhanced sensitivity of the arterial baroreflex's neural arc may signify a compensatory response to reduced efficiency of the peripheral arterial baroreflex arc (i.e., sympathetic transduction) to preserve BP buffering capacity. NEW & NOTEWORTHY Studies examining sympathetic baroreflex function with aging remain equivocal, with some studies showing an increase, decrease, or no change in sympathetic baroreflex sensitivity (BRS) in older adults compared with younger adults. With aging, women experience unique physiological changes due to menopause that influence autonomic function. For the first time, we show that postmenopausal women exhibit a greater sympathetic BRS compared with young premenopausal women.

In urban areas like Chicago, daily life extends above ground level due to the prevalence of high-rise buildings where residents and commuters live and work. This study examines the variation in fine particulate matter (PM 2.5 ) concentrations across building stories. PM 2.5 levels were measured using PurpleAir sensors, installed between 8 April and 7 May 2023, on floors one, four, six, and nine of an office building in Chicago. Additionally, data were collected from a public outdoor PurpleAir sensor on the fourteenth floor of a condominium located 800 m away. The results show that outdoor PM 2.5 concentrations peak at 14 m height, and then decline by 0.11 μg/m 3 per meter elevation, especially noticeable from midnight to 8 a.m. under stable atmospheric conditions. Indoor PM 2.5 concentrations increase steadily by 0.02 μg/m 3 per meter elevation, particularly during peak work hours, likely caused by greater infiltration rates at higher floors. Both outdoor and indoor concentrations peak around noon. We find that indoor and outdoor PM 2.5 are positively correlated, with indoor levels consistently remaining lower than outside levels. These findings align with previous research suggesting decreasing outdoor air pollution concentrations with increasing height. The study informs decision-making by community members and policymakers regarding air pollution exposure in urban settings.

Changes in endothelial function precede the development of cardiovascular disease (CVD). We have previously shown that age-related declines in endothelial function in women are due in part to a reduction in endothelial cell endothelin-B receptor (ET B R) protein expression. However, it is not known if ET B R protein expression changes with aging in men. The purpose of this study was to test the hypothesis that ET B R protein expression is attenuated in older men (OM) compared with younger men (YM). Primary endothelial cells were harvested from the antecubital vein of 14 OM (60 ± 6 yr; 26 ± 3 kg/m 2 ) and 17 YM (24 ± 5 yr; 24 ± 2 kg/m 2 ). Cells were stained with 4',6-diamidino-2-phenylindole, vascular endothelial cadherin, and ET B R. Images were quantified using immunocytochemistry. Endothelial function was assessed using brachial artery flow-mediated dilation (FMD). Systolic BP was similar (OM, 123 ± 11 vs. YM, 122 ± 10 mmHg) whereas diastolic BP was higher in OM (OM, 77 ± 7 vs. YM, 70 ± 6 mmHg; P < 0.01). Total testosterone was lower in OM (OM, 6.28 ± 4.21 vs. YM, 9.10 ± 2.68 ng/mL; P = 0.03). As expected, FMD was lower in OM (OM, 3.85 ± 1.51 vs. YM, 6.40 ± 2.68%; P < 0.01). However, ET B R protein expression was similar between OM and YM (OM, 0.39 ± 0.17 vs. YM, 0.42 ± 0.17 AU; P = 0.66). These data suggest that ET B R protein expression is not altered with age in men. These findings contrast with our previous data in women and further support sex differences in the endothelin system. NEW & NOTEWORTHY Our laboratory has previously shown that age-related declines in endothelial function are associated with a reduction in endothelial cell ET B R protein expression in women. However, it is unclear if endothelial cell ET B R protein expression is reduced with aging in men. This study demonstrates that endothelial cell ET B R protein expression is preserved with aging in men, and provides additional evidence for sex differences in the endothelin system.

In cardiovascular research, sex and gender have not typically been considered in research design and reporting until recently. This has resulted in clinical research findings from which not only all women, but also gender-diverse individuals have been excluded. The resulting dearth of data has led to a lack of sex- and gender-specific clinical guidelines and raises serious questions about evidence-based care. Basic research has also excluded considerations of sex. Including sex and/or gender as research variables not only has the potential to improve the health of society overall now, but it also provides a foundation of knowledge on which to build future advances. The goal of this guidelines article is to provide advice on best practices to include sex and gender considerations in study design, as well as data collection, analysis, and interpretation to optimally establish rigor and reproducibility needed to inform clinical decision-making and improve outcomes. In cardiovascular physiology, incorporating sex and gender is a necessary component when optimally designing and executing research plans. The guidelines serve as the first guidance on how to include sex and gender in cardiovascular research. We provide here a beginning path toward achieving this goal and improve the ability of the research community to interpret results through a sex and gender lens to enable comparison across studies and laboratories, resulting in better health for all.

Endothelin-1 (ET-1) contributes to vascular dysfunction in postmenopausal women (PMW). Although aerobic exercise is beneficial in reducing ET-1-mediated vasoconstrictor tone in men, it is unknown whether this favorable vascular effect occurs in women. We tested the hypothesis that aerobic exercise training reduces ET-1-mediated vasoconstriction in PMW. We further hypothesized that reductions in ET-1 vasoconstrictor tone underly exercise-induced improvements in endothelium-dependent vasodilatation in PMW. Forearm blood flow (FBF) responses to intra-arterial infusion of selective ET A receptor blockade (BQ-123, 100 nmol/min for 60 min) and acetylcholine (4.0, 8.0, and 16.0 μg/100 mL tissue/min) in the absence and presence of ET A receptor blockade were determined before and after a 12-wk aerobic exercise training intervention in 18 healthy, sedentary PMW (58 ± 4 yr). Women exercised an average of 4.9 ± 0.7 day/wk for 51 ± 7 min/day at 71 ± 3% of maximal heart rate. Before exercise, BQ-123 significantly increased FBF (∼25%) in sedentary PMW; however, this effect was abolished following the exercise intervention. FBF responses to acetylcholine were also significantly higher after exercise training (from 4.2 ± 1.2 to 14.0 ± 3.8 mL/100 mL tissue/min) versus before (from 4.1 ± 1.0 to 11.4 ± 3.3 mL/100 mL tissue/min; ∼25% increase; P < 0.05). Before exercise training, coinfusion of BQ-123 with acetylcholine enhanced (∼25%; P < 0.05) the vasodilator response (from 4.4 ± 1.1 to 13.9 ± 4.2 mL/100 mL tissue/min) compared with acetylcholine alone; after exercise training, the presence of BQ-123 did not significantly affect the vasodilator response to acetylcholine. Aerobic exercise training reduces ET-1-mediated vasoconstriction in PMW. Furthermore, decreased ET-1-mediated vasoconstriction is an important mechanism underlying aerobic exercise-induced improvement in endothelium-dependent vasodilation in PMW. NEW & NOTEWORTHY Endothelin-1 (ET-1) contributes to declines in endothelial function in postmenopausal women. To our knowledge, we show for the first time that aerobic exercise reduces ET-1-mediated vasoconstriction in previously sedentary postmenopausal women. Moreover, aerobic exercise improved endothelial-dependent dilation due in part to the reductions in ET-1-mediated vasoconstriction.

Introduction: Postmenopausal women (PMW) display exaggerated increases in blood pressure (BP) during exercise, yet the mechanism(s) involved remain unclear. Moreover, research on the impact of menopausal changes in estradiol on cardiovascular control during exercise are limited. Herein, we tested the hypothesis that sympathetic responses during exercise are augmented in PMWcompared with young women (YW), and estradiol administration attenuates these responses., Methods: Muscle sympathetic nerve activity (MSNA) and mean arterial pressure (MAP) were measured in 13 PMW (58 ± 1 yr) and 17 YW (22 ± 1 yr) during 2 min of isometric handgrip. Separately, MSNA and BP responses were measured during isometric handgrip in six PMW (53 ± 1 yr) before and after 1 month of transdermal estradiol (100 μg·d-1). A period of postexercise ischemia (PEI) to isolate muscle metaboreflex activation followed all handgrip bouts., Results: Resting MAP was similar between PMW and YW, whereas MSNA was greater in PMW (23 ± 3 vs 8 ± 1 bursts per minute; P < 0.05). During handgrip, the increases in MSNA (PMW Δ16 ± 2 vs YW Δ6 ± 1 bursts per minute; P < 0.05) and MAP (PMW Δ18 ± 2 vs YW Δ12 ± 2 mm Hg; P < 0.05) were greater in PMW and remained augmented during PEI. Estradiol administration decreased resting MAP but not MSNA in PMW. Moreover, MSNA (PMW (-E2) Δ27 ± 8 bursts per minute versus PMW (+E2) Δ12 ± 5 bursts per minute; P < 0.05) and MAP (Δ31 ± 8 mm Hg vs Δ20 ± 6 mm Hg; P < 0.05) responses during handgrip were attenuated in PMW after estradiol administration. Likewise, MAP responses during PEI were lower after estradiol., Conclusions: These data suggest that PMW exhibit an exaggerated MSNA and BP response to isometric exercise, due in part to heightened metaboreflex activation. Furthermore, estradiol administration attenuated BP and MSNA responses to exercise in PMW., (Copyright © 2021 by the American College of Sports Medicine.)

The mechanisms for the benefits of Angiotensin Receptor Neprilysin Inhibition (ARNi) in heart failure patients with reduced ejection fraction (HFrEF) are likely beyond blood pressure reduction. Measures of vascular function such as arterial stiffness and endothelial function are strong prognostic markers of cardiovascular outcomes in HFrEF, yet the impact of ARNi on vascular health remains to be explored. We hypothesized that arterial stiffness and endothelial function would improve after 12 weeks of ARNi in HFrEF. We tested 10 stable HFrEF patients at baseline and following 12 weeks of ARNi [64 ± 9 years, Men/Women: 9/1, left ventricular ejection fraction (EF): 28 ± 6%] as well as 10 stable HFrEF patients that remained on conventional treatment (CON: 60 ± 7 years, Men/Women: 6/4, EF: 31 ± 5%; all p = NS). Arterial stiffness was assessed via carotid-femoral pulse wave velocity (PWV) and endothelial function was assessed via brachial artery flow-mediated dilation (FMD). PWV decreased after 12 weeks of ARNi (9.0 ± 2.1 vs. 7.1 ± 1.2 m/s; p < 0.01) but not in CON (7.0 ± 2.4 vs. 7.5 ± 2.3 m/s; p = 0.35), an effect that remained when controlling for reductions in mean arterial pressure (p < 0.01). FMD increased after 12 weeks of ARNi (2.2 ± 1.9 vs. 5.5 ± 2.1%; p < 0.001) but not in CON (4.8 ± 3.8 vs. 5.4 ± 3.4%; p = 0.34). Baseline PWV (p = 0.06) and FMD (p = 0.07) were not different between groups. These preliminary data suggest that 12 weeks of ARNi therapy may reduce arterial stiffness and improve endothelial function in HFrEF. Thus, the findings from this pilot study suggest that the benefits of ARNi are beyond blood pressure reduction and include improvements in vascular function., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Neurons in the organum vasculosum of the lamina terminalis (OVLT) sense extracellular NaCl and angiotensin II concentrations to regulate body fluid homeostasis and arterial blood pressure. Lesion of the anteroventral third ventricular region or OVLT attenuates multiple forms of neurogenic hypertension. However, the extent by which OVLT neurons directly regulate sympathetic nerve activity to produce hypertension is not known. Therefore, the present study tested this hypothesis by using a multi-faceted approach including optogenetics, single-unit and multifiber nerve recordings, and chemogenetics. First, optogenetic activation of OVLT neurons in conscious Sprague-Dawley rats (250-400 g) produced frequency-dependent increases in arterial blood pressure and heart rate. These responses were not altered by the vasopressin receptor antagonist (β-mercapto-β,β-cyclopentamethylenepropionyl1,O-me-Tyr2,Arg8)-vasopressin but eliminated by the ganglionic blocker chlorisondamine. Second, optogenetic activation of OVLT neurons significantly elevated renal, splanchnic, and lumbar sympathetic nerve activity. Third, single-unit recordings revealed optogenetic activation of the OVLT significantly increased the discharge of bulbospinal, sympathetic neurons in the rostral ventrolateral medulla. Lastly, chronic chemogenetic activation of OVLT neurons for 7 days significantly increased 24-hour fluid intake and mean arterial blood pressure. When the 24-hour fluid intake was clamped at baseline intakes, chemogenetic activation of OVLT neurons still produced a similar increase in arterial blood pressure. Neurogenic pressor activity assessed by the ganglionic blocker chlorisondamine was greater at 7 days of OVLT activation versus baseline. Collectively, these findings indicate that acute or chronic activation of OVLT neurons produces a sympathetically mediated hypertension.

Black women (BLW) have a higher prevalence of cardiovascular disease (CVD) morbidity and mortality compared with White women (WHW). A racial disparity in CVD risk has been identified early in life as young adult BLW demonstrate attenuated vascular function compared with WHW. Previous studies comparing vascular function between premenopausal WHW and BLW have been limited to the early follicular (EF) phase of the menstrual cycle, which may not reflect their vascular function during other menstrual phases. Therefore, we evaluated peripheral microvascular function in premenopausal WHW and BLW using passive leg movement (PLM) during three menstrual phases: EF, ovulation (OV), and mid-luteal (ML). We hypothesized that microvascular function would be augmented during the OV and ML phases compared with the EF phase in both groups, but would be attenuated in BLW compared with WHW at all three phases. PLM was performed on 26 apparently healthy premenopausal women not using hormonal contraceptives: 15 WHW (23 ± 3 yr), 11 BLW (24 ± 5 yr). There was a main effect of race on the overall change in leg blood flow (ΔLBF) ( P = 0.01) and leg blood flow area under the curve (LBF AUC) ( P = 0.02), such that LBF was lower in BLW. However, there was no effect of phase on ΔLBF ( P = 0.69) or LBF AUC ( P = 0.65), nor an interaction between race and phase on ΔLBF ( P = 0.37) or LBF AUC ( P = 0.75). Despite peripheral microvascular function being unchanged across the menstrual cycle, a racial disparity was apparent as microvascular function was attenuated in BLW compared with WHW across the menstrual cycle. NEW & NOTEWORTHY This is the first study to compare peripheral microvascular function between young, otherwise healthy Black women and White women at multiple phases of the menstrual cycle. Our novel findings demonstrate a significant effect of race on peripheral microvascular function such that Black women exhibit significant attenuations in microvascular function across the menstrual cycle compared with White women.

There are clear differences between men and women, and differences among races, in the incidence and prevalence of hypertension. Furthermore, there is extensive inter-individual variability among humans in the extent to which sodium ingestion alters blood pressure. Orthostatic intolerance and orthostatic hypotension are more common in women; these are often treated with a high salt diet, which has variable efficacy in increasing blood volume and blood pressure. Conversely, people with certain forms of hypertension are often counseled to decrease their sodium intake. Non-Hispanic Black men and women have higher rates of hypertension compared to non-Hispanic White men and women and other racial/ethnic groups. In aggregate, Black women appear to have better orthostatic tolerance than White women. In the present paper, we summarize and evaluate the current evidence for mechanisms of blood pressure regulation in men and women, as well as differences between Black and White groups, with a focus on cardiovascular responses to salt and differences among these groups. We also provide a brief review of factors that are not traditionally considered to be "biological" - such as socio-economic disparities resulting from historic and contemporary inequity across racial groups. These non-biological factors have direct and substantial influences on cardiovascular mechanisms, as well as implications for the influences of salt and sodium intake on blood pressure and cardiovascular health. We conclude that both biological and socio-economic factors provide critical modulating influences when considering the impacts of sodium on cardiovascular health as functions of race and sex., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The endothelin-B (ET B ) receptor is a key regulator of vascular endothelial function in women. We have previously shown that the ET B receptor mediates vasodilation in young women, an effect that is lost after menopause. However, the direct impact of changes in estradiol (E 2 ) on ET B receptor function in women remains unclear. Therefore, the purpose of this study was to test the hypothesis that E 2 exposure modulates ET B receptor-mediated dilation in young women. Fifteen young women (24 ± 4 yr, 24 ± 3 kg/m 2 ) completed the study. Endogenous sex hormone production was suppressed with daily administration of a gonadotropin-releasing hormone antagonist (GnRHant; Ganirelix) for 10 days; E 2 (0.1 mg/day, Vivelle-Dot patch) was added back on days 4-10 . We measured vasodilation in the cutaneous microcirculation (microvascular endothelial function) via local heating (42°C) on day 4 (GnRHant) and day 10 (GnRHant + E 2 ) using laser Doppler flowmetry coupled with intradermal microdialysis during perfusions of lactated Ringer's (control) and ET B receptor antagonist (BQ-788, 300 nM). During GnRHant, vasodilatory responses to local heating were enhanced with ET B receptor blockade (control: 83 ± 9 vs. BQ-788: 90 ± 5%CVC max , P = 0.004). E 2 administration improved vasodilation in the control site (GnRHant: 83 ± 9 vs. GnRHant + E 2 : 89 ± 8%CVC max , P = 0.036). Furthermore, cutaneous vasodilatory responses during ET B receptor blockade were blunted after E 2 administration (control: 89 ± 8 vs. BQ-788: 84 ± 8%CVC max , P = 0.047). These data demonstrate that ovarian hormones, specifically E 2 , modulate ET B receptor function and contribute to the regulation of microvascular endothelial function in young women. NEW & NOTEWORTHY 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.

Aging is a primary risk factor for cardiovascular disease (CVD), which is the leading cause of death in developed countries. Globally, the population of adults over the age of 60 is expected to double by the year 2050. CVD prevalence and mortality rates differ between men and women as they age in part due to sex-specific mechanisms impacting the biological processes of aging. Measures of vascular function offer key insights into cardiovascular health. Changes in vascular function precede changes in CVD prevalence rates in men and women and with aging. A key mechanism underlying these changes in vascular function is the endothelin (ET) system. Studies have demonstrated sex and sex hormone effects on endothelin-1 (ET-1), and its receptors ETA and ETB. However, with aging there is a dysregulation of this system resulting in an imbalance between vasodilation and vasoconstriction. Thus, ET-1 may play a role in the sex differences observed with vascular aging. While most research has been conducted in pre-clinical animal models, we describe more recent translational data in humans showing that the ET system is an important regulator of vascular dysfunction with aging and acts through sex-specific ET receptor mechanisms. In this review, we present translational evidence (cell, tissue, animal, and human) that the ET system is a key mechanism regulating sex-specific changes in vascular function with aging, along with therapeutic interventions to reduce ET-mediated vascular dysfunction associated with aging. More knowledge on the factors responsible for the sex differences with vascular aging allow for optimized therapeutic strategies to attenuate CVD risk in the expanding aging population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kuczmarski, Welti, Moreau and Wenner.)

Older adults have reduced fluid intake and impaired body fluid and electrolyte regulation. Older female adults exhibit exaggerated exercise blood pressure (BP) responses, which is associated with an increased risk of adverse cardiovascular events. However, it is unclear if dysregulated body fluid homeostasis contributes to altered exercise BP responses in older female adults. We tested the hypothesis that short-term water deprivation (WD) increases exercise BP responses in older female adults. Fifteen female adults (eight young [25 ± 6 years] and seven older [65 ± 6 years]) completed two experimental conditions in random crossover fashion; a euhydration control condition and a stepwise reduction in water intake over three days concluding with a 16-hr WD period. During both trials, beat-to-beat BP (photoplethysmography) and heart rate (electrocardiogram) were continuously assessed during rest, handgrip exercise (30% MVC), and post-exercise ischemia (metaboreflex isolation). At screening, older compared to young female adults had greater systolic and diastolic BP (p ≤ .02). Accelerometer-assessed habitual physical activity was not different between groups (p = .65). Following WD, 24-hr urine flow rate decreased, whereas thirst, urine specific gravity, and plasma osmolality increased (condition: p < .05 for all), but these WD-induced changes were not different between age groups (interaction: p ≥ .31 for all). Resting systolic and diastolic BP values were higher in older compared to young adults (p < .01 for both), but were not different between experimental conditions (p ≥ .20). In contrast to our hypothesis, WD was associated with attenuated systolic BP responses during handgrip exercise (post hoc: p < .01) and post-exercise ischemia (post hoc: p = .03) in older, but not young, female adults. These data suggest that reduced water intake-induced challenges to body fluid homeostasis do not contribute to exaggerated exercise BP responses in post-menopausal female adults., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

The endothelin system plays an important role in mediating vascular function. The endothelin-B receptor (ET B R) on endothelial cells mediates vasodilation via nitric oxide production. The vasodilatory effect of the ET B R is lost following menopause and may contribute to impaired vascular endothelial function in postmenopausal women (PMW). However, it is unclear if these functional changes are due to changes in ET B R expression on the endothelium. Therefore, the purpose of this study was to test the hypothesis that endothelial cell ET B R expression is lower in PMW compared with young women (YW). Primary endothelial cells were harvested from the antecubital vein of healthy PMW ( n = 15, 60 ± 6 yr) and YW ( n = 15, 22 ± 2 yr). Cells were identified as endothelial cells by staining for vascular endothelial cadherin, and nuclear integrity was assessed using 4',6-diamidino-2-phenylindole (DAPI). Within those cells, ET B R was quantified using immunocytochemistry; fluorescence intensity was measured in 30 cells and averaged for each participant. Endothelial function was assessed using brachial artery flow-mediated dilation (FMD). Endothelial cell ET B R expression was lower in PMW [0.46 ± 0.11 arbitrary units (AU)] compared with YW (0.58 ± 0.14 AU; P = 0.02). Furthermore, significant correlations between ET B R expression and FMD ( r = 0.47, P < 0.01), total cholesterol ( r = -0.38, P = 0.04), and LDL cholesterol ( r = -0.39, P = 0.03) were observed. These data demonstrate that endothelial cell ET B R expression is attenuated in PMW. These novel findings provide additional insight into the mechanisms underlying vascular endothelial dysfunction in PMW. NEW & NOTEWORTHY Our study provides novel data demonstrating attenuated endothelial ET B R expression in postmenopausal women. Furthermore, our data extend current knowledge by demonstrating a positive relation between ET B R expression and brachial artery flow-mediated dilation. These findings provide additional mechanistic insight into vascular endothelial dysfunction in postmenopausal women.

Renovascular hypertension is characterized by activation of the renin-angiotensin-aldosterone system, blunted natriuretic responses, and elevated sympathetic nerve activity. Excess dietary salt intake exaggerates arterial blood pressure (ABP) in multiple models of experimental hypertension. The present study tested whether a high-salt diet exaggerated ABP and vascular dysfunction in a 2-kidney, 1-clip (2K1C) murine model. Male C57BL/6J mice (8-12 wk) were randomly assigned, and fed a 0.1% or 4.0% NaCl diet, and instrumented with telemetry units to measure ABP. Then, the 2K1C model was produced by placing a cuff around the right renal artery. Systolic, diastolic, and mean ABP were significantly higher in mice fed 4.0% vs. 0.1% NaCl at 1 wk but not after 3 wk. Interestingly, 2K1C hypertension progressively increased arterial pulse pressure in both groups; however, the magnitude was significantly greater in mice fed 4.0% vs. 0.1% NaCl at 3 wk. Moreover, pulse wave velocity was significantly greater in 2K1C mice fed 4.0% vs. 0.1% NaCl diet or sham-operated mice fed either diet. Histological assessment of aortas indicated no structural differences among groups. Finally, endothelium-dependent vasodilation was significantly and selectively attenuated in the aorta but not mesenteric arteries of 2K1C mice fed 4.0% NaCl vs. 0.1% NaCl or sham-operated control mice. The findings suggest that dietary salt loading transiently exaggerates 2K1C renovascular hypertension but promotes chronic aortic stiffness and selective aortic vascular dysfunction. NEW & NOTEWORTHY High dietary salt exaggerates hypertension in multiple experimental models. Here we demonstrate that a high-salt diet produces a greater increase in arterial blood pressure at 1 wk after induction of 2-kidney, 1-clip (2K1C) hypertension but not at 3 wk. Interestingly, 2K1C mice fed a high-salt diet displayed an exaggerated pulse pressure, elevated pulse wave velocity, and reduced endothelium-dependent vasodilation of the aorta but not mesenteric arteries. These findings suggest that dietary salt may interact with underlying cardiovascular disease to promote selective vascular dysfunction and aortic stiffness.

Background: High sodium (Na+) intake augments blood pressure variability (BPV) in normotensive rodents, without changes in resting blood pressure (BP). Augmented BPV is associated with end-organ damage and cardiovascular morbidity. It is unknown if changes in dietary Na+ influence BPV in humans. We tested the hypothesis that high Na+ feeding would augment BPV in healthy adults., Methods: Twenty-one participants (10 F/11 M; 26 ± 5 years; BP: 113 ± 11/62 ± 7 mm Hg) underwent a randomized, controlled feeding study that consisted of 10 days of low (2.6 g/day), medium (6.0 g/day), and high (18.0 g/day) salt diets. On the ninth day of each diet, 24-h urine samples were collected and BPV was calculated from 24-h ambulatory BP monitoring. On the tenth day, in-laboratory beat-to-beat BPV was calculated during 10 min of rest. Serum electrolytes were assessed. We calculated average real variability (ARV) and standard deviation (SD) as metrics of BPV. As a secondary analysis, we calculated central BPV from the 24-h ambulatory BP monitoring., Results: 24-h urinary Na+ excretion (low = 41 ± 24, medium = 97 ± 43, high = 265 ± 92 mmol/24 h, P < 0.01) and serum Na+ (low = 140.0 ± 2.1, medium = 140.7 ± 2.7, high = 141.7 ± 2.5 mmol/l, P = 0.009) increased with greater salt intake. 24-h ambulatory ARV (systolic BP ARV: low = 9.5 ± 1.7, medium = 9.5 ± 1.2, high = 10.0 ± 1.9 mm Hg, P = 0.37) and beat-to-beat ARV (systolic BP ARV: low = 2.1 ± 0.6, medium = 2.0 ± 0.4, high = 2.2 ± 0.8 mm Hg, P = 0.46) were not different. 24-h ambulatory SD (systolic BP: P = 0.29) and beat-to-beat SD (systolic BP: P = 0.47) were not different. There was a trend for a main effect of the diet (P = 0.08) for 24-h ambulatory central systolic BPV., Conclusions: Ten days of high sodium feeding does not augment peripheral BPV in healthy, adults., Clinical Trials Registration: NCT02881515., (© American Journal of Hypertension, Ltd 2020. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The organum vasculosum of the lamina terminalis (OVLT) contains NaCl-sensitive neurons to regulate thirst, neuroendocrine function, and autonomic outflow. The OVLT also expresses the angiotensin II (AngII) type1 receptor, and AngII increases Fos expression in OVLT neurons. The present study tested whether individual OVLT neurons sensed both NaCl and AngII to regulate thirst and body fluid homeostasis. A multifaceted approach, including in vitro whole-cell patch recordings, in vivo single-unit recordings, and optogenetic manipulation of OVLT neurons, was used in adult, male Sprague Dawley rats. First, acute intravenous infusion of hypertonic NaCl or AngII produced anatomically distinct patterns of Fos-positive nuclei in the OVLT largely restricted to the dorsal cap versus vascular core, respectively. However, in vitro patch-clamp recordings indicate 66% (23 of 35) of OVLT neurons were excited by bath application of both hypertonic NaCl and AngII. Similarly, in vivo single-unit recordings revealed that 52% (23 of 44) of OVLT neurons displayed an increased discharge to intracarotid injection of both hypertonic NaCl and AngII. In marked contrast to Fos immunoreactivity, neuroanatomical mapping of Neurobiotin-filled cells from both in vitro and in vivo recordings revealed that NaCl- and AngII-responsive neurons were distributed throughout the OVLT. Next, optogenetic excitation of OVLT neurons stimulated thirst but not salt appetite. Conversely, optogenetic inhibition of OVLT neurons attenuated thirst stimulated by hypernatremia or elevated AngII but not hypovolemia. Collectively, these findings provide the first identification of individual OVLT neurons that respond to both elevated NaCl and AngII concentrations to regulate thirst and body fluid homeostasis. SIGNIFICANCE STATEMENT Body fluid homeostasis requires the integration of neurohumoral signals to coordinate behavior, neuroendocrine function, and autonomic function. Extracellular NaCl concentrations and the peptide hormone angiotensin II (AngII) are two major neurohumoral signals that regulate body fluid homeostasis. Herein, we present the first compelling evidence that individual neurons located in the organum vasculosum of the lamina terminalis detect both NaCl and AngII. Furthermore, optogenetic interrogations demonstrate that these neurons play a pivotal role in the regulation of thirst stimulated by NaCl and AngII. These novel observations lay the foundation for future investigations for how such inputs as well as others converge onto unique organum vasculosum of the lamina terminalis neurons to coordinate body fluid homeostasis and contribute to disorders of fluid balance., (Copyright © 2020 the authors.)

High dietary salt increases arterial blood pressure variability (BPV) in salt-resistant, normotensive rodents and is thought to result from elevated plasma [Na + ] sensitizing central sympathetic networks. Our purpose was to test the hypothesis that water deprivation (WD)-induced elevations in serum [Na + ] augment BPV via changes in baroreflex function and sympathetic vascular transduction in humans. In a randomized crossover fashion, 35 adults [17 female/18 male, age: 25 ± 4 yr, systolic/diastolic blood pressure (BP): 107 ± 11/60 ± 7 mmHg, body mass index: 23 ± 3 kg/m 2 ] completed two hydration protocols: a euhydration control condition (CON) and a stepwise reduction in water intake over 3 days, concluding with 16 h of WD. We assessed blood and urine electrolyte concentrations and osmolality, resting muscle sympathetic nerve activity (MSNA; peroneal microneurography; 18 paired recordings), beat-to-beat BP (photoplethysmography), common femoral artery blood flow (Doppler ultrasound), and heart rate (single-lead ECG). A subset of participants ( n = 25) underwent ambulatory BP monitoring during day 3 of each protocol. We calculated average real variability as an index of BPV. WD increased serum [Na + ] (141.0 ± 2.3 vs. 142.1 ± 1.7 mmol/L, P < 0.01) and plasma osmolality (288 ± 4 vs. 292 ± 5 mosmol/kg H 2 O, P < 0.01). However, WD did not increase beat-to-beat (1.9 ± 0.4 vs. 1.8 ± 0.4 mmHg, P = 0.24) or ambulatory daytime (9.6 ± 2.1 vs. 9.4 ± 3.3 mmHg, P = 0.76) systolic BPV. Additionally, sympathetic baroreflex sensitivity ( P = 0.20) and sympathetic vascular transduction were not different after WD ( P = 0.17 for peak Δmean BP following spontaneous MSNA bursts). These findings suggest that, despite modestly increasing serum [Na + ], WD does not affect BPV, arterial baroreflex function, or sympathetic vascular transduction in healthy young adults.

Excess dietary salt intake excites central sympathetic networks, which may be related to plasma hypernatremia. Plasma hypernatremia also occurs following water deprivation (WD). The purpose of this study was to test the hypothesis that WD induces hypernatremia and consequently augments sympathetic and pressor responses to sympathoexcitatory stimuli in rats and humans. Sympathetic nerve activity (SNA) and arterial blood pressure (ABP) responses to sciatic afferent nerve stimulation (2-20 Hz) and chemical stimulation of the rostral ventrolateral medulla (RVLM) were assessed in rats after 48 h of WD and compared with normally hydrated control rats (CON). In a parallel randomized-crossover human experiment ( n = 13 healthy young adults), sympathetic (microneurography) and pressor (photoplethysmography) responses to static exercise were compared between 16-h WD and CON conditions. In rats, plasma [Na + ] was significantly higher in WD versus CON [136 ± 2 vs. 144 ± 2 (SD) mM, P < 0.01], but sciatic afferent nerve stimulation produced similar increases in renal SNA [5 Hz, 174 ± 34 vs. 169 ± 49% (SD), n = 6-8] and mean ABP [5 Hz, 21 ± 6 vs. 18 ± 7 (SD mmHg, n = 6-8]. RVLM injection of l-glutamate also produced similar increases in SNA and ABP in WD versus CON rats. In humans, WD increased serum [Na + ] [140.6 ± 2.1 vs. 142.1 ± 1.9 mM (SD), P = 0.02] but did not augment sympathetic [muscle SNA: change from baseline (Δ) 6 ± 7 vs. 5 ± 7 (SD) bursts/min, P = 0.83] or mean ABP [Δ 12 ± 5 vs. 11 ± 8 (SD) mmHg, P = 0.73; WD vs. CON for all results] responses during the final minute of exercise. These findings suggest that despite eliciting relative hypernatremia, WD does not augment sympathetic or pressor responses to sciatic afferent stimulation in rats or to static exercise in humans. NEW & NOTEWORTHY Excess dietary salt intake excites central sympathetic networks, which may be related to plasma hypernatremia. Plasma hypernatremia also occurs following water deprivation (WD). We sought to determine whether plasma hypernatremia/hyperosmolality induced by WD augments sympathetic and pressor responses to sympathoexcitatory stimuli. Our findings suggest that WD does not augment sympathetic or pressor responses to sciatic afferent nerve stimulation in rats or to static exercise in humans.

Previous studies have demonstrated an inverse relation between resting muscle sympathetic nerve activity (MSNA) and vasoconstrictor responsiveness (i.e., sympathetic transduction), such that those with high resting MSNA have low vascular responsiveness, and vice versa. The purpose of this investigation was to determine whether biological sex influences the balance between resting MSNA and beat-to-beat sympathetic transduction. We measured blood pressure (BP) and MSNA during supine rest in 54 healthy young adults (27 females: 23 ± 4 yr, 107 ± 8/63 ± 8 mmHg; 27 males: 25 ± 3 yr, 115 ± 11/64 ± 7 mmHg; means ± SD). We quantified beat-to-beat fluctuations in mean arterial pressure (MAP, mmHg) and limb vascular conductance (LVC, %) for 10 cardiac cycles after each MSNA burst using signal averaging, an index of sympathetic vascular transduction. In females, there was no correlation between resting MSNA (burst incidence; burst/100 heartbeats) and peak ΔMAP ( r  = -0.10, P = 0.62) or peak ΔLVC ( r  = -0.12, P = 0.63). In males, MSNA was related to peak ΔMAP ( r  = -0.50, P = 0.01) and peak ΔLVC ( r  = 0.49, P = 0.03); those with higher resting MSNA had blunted increases in MAP and reductions in LVC in response to a burst of MSNA. In a sub-analysis, we performed a median split between high- versus low-MSNA status on ΔMAP and ΔLVC within each sex and found that only males demonstrated a significant difference in ΔMAP and ΔLVC between high- versus low-MSNA groups. These findings support an inverse relation between resting MSNA and sympathetic vascular transduction in males only and advance our understanding on the influence of biological sex on sympathetic nervous system-mediated alterations in beat-to-beat BP regulation.

A positive family history of hypertension (+FH) is a risk factor for the future development of hypertension. Hypertension is associated with reductions in baroreflex sensitivity (BRS). Therefore, we hypothesized that young women with a +FH [ n = 12, 22 ± 1 yr, body mass index (BMI) 21 ± 1 kg/m 2 , mean arterial pressure (MAP) 79 ± 1 mmHg] would have lower BRS compared with young women without a family history of hypertension (-FH) ( n = 13, 22 ± 1 yr, BMI 21 ± 1 kg/m 2 , MAP 77 ± 2 mmHg, all P > 0.05 between groups). Continuous measurements of muscle sympathetic nerve activity, blood pressure, and electrocardiogram derived R-R interval were recorded at rest and during a Valsalva maneuver. Both cardiovagal BRS and vascular sympathetic BRS were assessed. Resting cardiovagal BRS was reduced in the +FH women (all sequences: -FH 32.3 ± 3.7 vs. +FH 20.2 ± 2.9 ms/mmHg, P = 0.02). Cardiovagal BRS during phase IV (-FH 16.5 ± 2.7 vs. +FH 7.6 ± 1.3 ms/mmHg, P < 0.01) but not phase II (-FH 5.5 ± 0.9 vs. +FH 5.0 ± 0.8 ms/mmHg, P = 0.67) of the Valsalva maneuver was also lower in the +FH women. Vascular sympathetic BRS at rest (-FH -2.38 ± 0.7 vs. +FH -2.33 ± 0.3 bursts· min -1 ·mmHg -1 , P = 0.58) and during the Valsalva (-FH -0.74 ± 0.23 vs. +FH -0.66 ± 0.18 bursts·15 s -1 ·mmHg -1 , P = 0.79) were not different between groups. These data suggest that healthy young women with a positive family history of hypertension have reduced cardiovagal BRS. This may be one mechanism contributing to the increased incidence of hypertension in this population later in life. NEW & NOTEWORTHY Having a family history of hypertension increases the risk of developing future hypertension. Reductions in baroreflex function have been demonstrated in hypertension and are an important marker for future cardiovascular disease. We show that young women with a family history of hypertension have lower cardiovagal baroreflex sensitivity. This alteration in autonomic function may be one mechanism contributing to the future incidence of hypertension in this patient population.

The American Heart Association recommends no more than 1500 mg of sodium/day as ideal. Some cohort studies suggest low-sodium intake is associated with increased cardiovascular mortality. Extremely low-sodium diets (≤500 mg/d) elicit activation of the renin-angiotensin-aldosterone system and stimulate sympathetic outflow. The effects of an American Heart Association-recommended diet on sympathetic regulation of the vasculature are unclear. Therefore, we assessed whether a 1000 mg/d diet alters sympathetic outflow and sympathetic vascular transduction compared with the more commonly recommended 2300 mg/d. We hypothesized that sodium reduction from 2300 to 1000 mg/d would not affect resting sympathetic outflow but would reduce sympathetic transduction in healthy young adults. Seventeen participants (age: 26±2 years, 9F/8M) completed 10-day 2300 and 1000 mg/d sodium diets in this randomized controlled feeding study (crossover). We measured resting renin activity, angiotensin II, aldosterone, blood pressure, muscle sympathetic nerve activity, and norepinephrine. We quantified beat-by-beat changes in mean arterial pressure and leg vascular conductance (femoral artery ultrasound) following spontaneous sympathetic bursts to assess sympathetic vascular transduction. Reducing sodium to 1000 mg/d increased renin activity, angiotensin II, and aldosterone ( P<0.01 for all) but did not alter mean arterial pressure (78±2 versus 77±2 mm Hg, P=0.56), muscle sympathetic nerve activity (13.9±1.3 versus 13.9±0.8 bursts/min, P=0.98), or plasma/urine norepinephrine. Sympathetic vascular transduction decreased ( P<0.01). These data suggest that reducing sodium from 2300 to 1000 mg/d stimulates the renin-angiotensin-aldosterone system, does not increase resting basal sympathetic outflow, and reduces sympathetic vascular transduction in normotensive adults.

Diseases of the cardiovascular system are the leading cause of morbidity and mortality in men and women in developed countries, and cardiovascular disease (CVD) is becoming more prevalent in developing countries. The prevalence of atherosclerotic CVD in men is greater than in women until menopause, when the prevalence of CVD increases in women until it exceeds that of men. Endothelial function is a barometer of vascular health and a predictor of atherosclerosis that may provide insights into sex differences in CVD as well as how and why the CVD risk drastically changes with menopause. Studies of sex differences in endothelial function are conflicting, with some studies showing earlier decrements in endothelial function in men compared with women, whereas others show similar age-related declines between the sexes. Because the increase in CVD risk coincides with menopause, it is generally thought that female hormones, estrogens in particular, are cardioprotective. Moreover, it is often proposed that androgens are detrimental. In truth, the relationships are more complex. This review first addresses female and male sex hormones and their receptors and how these interact with the cardiovascular system, particularly the endothelium, in healthy young women and men. Second, we address sex differences in sex steroid receptor-independent mechanisms controlling endothelial function, focusing on vascular endothelin and the renin-angiotensin systems, in healthy young women and men. Finally, we discuss sex differences in age-associated endothelial dysfunction, focusing on the role of attenuated circulating sex hormones in these effects.

Objective: We recently demonstrated ETB R mediate vasodilation in young but not postmenopausal women; it is unclear if this is related to age or a decline in ovarian hormones. The purpose of this study was to test the hypothesis that ETB R responses are modulated by ovarian hormones., Methods: We measured cutaneous vasodilatory responses in 12 young women (22 ± 1 years, 23 ± 1 kg/m 2 ) during the ML (days 20-25) and EF (days 2-5) phases of the menstrual cycle. Cutaneous microdialysis perfusions of lactated Ringer (control), ETB R antagonist (BQ-788, 300 nmol/L), and ETA R antagonist (BQ-123, 500 nmol/L) were performed, followed by local heating to 42°C., Results: Serum estradiol (ML: 118 ± 16 vs EF: 44 ± 9 pg/mL, P < 0.05) and progesterone (ML: 8.3 ± 1.0 vs EF: 0.7 ± 0.2 ng/mL, P < 0.05) were higher during ML vs EF phase. ETB R blockade decreased vasodilation during ML (control: 91 ± 2 vs BQ-788: 83 ± 2%CVCmax, P < 0.05) but not EF (control: 89 ± 2 vs BQ-788: 89 ± 1%CVCmax). ETA R blockade also decreased vasodilation during ML (control: 91 ± 2 vs BQ-123: 87 ± 2%CVCmax, P < 0.05) but not EF (control: 89 ± 2 vs BQ-123: 92 ± 2%CVCmax)., Conclusions: These data suggest that fluctuations in ovarian hormones modulate ETB R and ETA R responses in young women., (© 2018 John Wiley & Sons Ltd.)

High dietary sodium intake has been linked to alterations in neurally mediated cardiovascular function, but the effects of high sodium on cardiovagal baroreflex sensitivity (cBRS) in healthy adults are unknown. The purpose of this study was to determine whether high dietary sodium alters cBRS and heart rate variability (HRV) and whether acute intravenous sodium loading similarly alters cBRS and HRV. High dietary sodium (300 mmol/day, 7 days) was compared with low dietary sodium (20 mmol/day, 7 days; randomized) in 14 participants (38 ± 4 yr old, 23 ± 1 kg/m 2 body mass index, 7 women). Acute sodium loading was achieved via a 23-min intravenous hypertonic saline infusion (HSI) in 14 participants (22 ± 1 yr old, 23 ± 1 kg/m 2 body mass index, 7 women). During both protocols, participants were supine for 5 min during measurement of beat-to-beat blood pressure (photoplethysmography) and R-R interval (ECG). cBRS was evaluated using the sequence method. Root mean square of successive differences in R-R interval (RMSSD) was used as an index of HRV. Serum sodium (137.4 ± 0.7 vs. 139.9 ± 0.5 meq/l, P < 0.05), plasma osmolality (285 ± 1 vs. 289 ± 1 mosmol/kgH 2 O, P < 0.05), cBRS (18 ± 2 vs. 26 ± 3 ms/mmHg, P < 0.05), and RMSSD (62 ± 6 vs. 79 ± 10 ms, P < 0.05) were increased following high-sodium diet intake compared with low-sodium diet intake. HSI increased serum sodium (138.1 ± 0.4 vs. 141.1 ± 0.5 meq/l, P < 0.05) and plasma osmolality (286 ± 1 vs. 290 ± 1 mosmol/kgH 2 O, P < 0.05) but did not change cBRS (26 ± 5 vs. 25 ± 3 ms/mmHg, P = 0.73) and RMSSD (63 ± 9 vs. 63 ± 8 ms, P = 0.99). These data suggest that alterations in dietary sodium intake alter cBRS and HRV but that acute intravenous sodium loading does not alter these indexes of autonomic cardiovascular regulation.

Purpose: African American individuals are more prone to salt-sensitive hypertension than Caucasian individuals. Small changes in serum sodium (Na + ) result in increased blood pressure (BP). However, it remains unclear if there are racial differences in BP responsiveness to increases in serum Na + . Therefore, the purpose of this investigation was to determine if African American adults have altered BP responsiveness to acute changes in serum Na + compared to Caucasian adults. Methods: We measured beat-by-beat BP, serum Na + , plasma renin activity (PRA), angiotensin II (Ang II), and aldosterone (Aldo) during a 60-min 3% NaCl infusion (hypertonic saline infusion, HSI) in 39 participants (19 African Americans, age: 23 ± 1, 20 Caucasians, age: 25 ± 1). Data reported as African American vs. Caucasian cohort, mean ± SEM. Results: Baseline BP and serum Na + were similar between groups and increased during HSI in both African American and Caucasian participants ( p < 0.01). However, the peak change in serum Na + was greater in African American participants (Δ5.8 ± 0.34 vs. Δ4.85 ± 0.38 mmol/L, p = 0.03). There was a significant group effect ( p = 0.02) and an interaction between race and serum Na + on systolic BP ( p = 0.02). Larger categorical changes in serum Na + corresponded to changes in systolic BP ( p < 0.01) and African American participants demonstrated greater systolic BP responses for a given categorical serum Na + increase ( p < 0.01). Baseline Aldo was lower in African American adults (7.2 ± 0.6 vs. 12.0 ± 1.9 ng/dL, p = 0.03), there was a trend for lower baseline PRA (0.59 ± 0.9 vs. 1.28 ± 0.34 ng/mL/h, p = 0.07), and baseline Ang II was not different (14.2 ± 1.8 vs. 18.5 ± 1.4 pg/mL, p = 0.17). PRA and Aldo decreased during the HSI ( p ≤ 0.01), with a greater decline in PRA (Δ-0.31 ± 0.07 vs. Δ-0.85 ± 0.25 ng/mL/h, p < 0.01) and Aldo (Δ-2.5 ± 0.5 vs. Δ-5.0 ± 1.1 ng/dL, p < 0.01) in Caucasian participants. However, the racial difference in PRA ( p = 0.57) and Aldo ( p = 0.59) reduction were no longer significant following baseline covariate analysis. Conclusion: African American individuals demonstrate augmented serum Na + to an acute hypertonic saline load and greater systolic BP responsiveness to a given serum Na + . The altered BP response may be attributable to lower basal PRA and Aldo and a subsequently blunted RAAS response during the HSI.

Background: The compensatory reserve measurement (CRM) has been established to accurately measure the body's total integrated capacity to compensate for physiologic states of reduced central blood volume and predict hemodynamic decompensation associated with inadequate tissue oxygenation. We previously demonstrated that African American (AA) women have a higher tolerance to reductions in central blood volume. Therefore, we tested the hypothesis that the CRM would identify racial differences during simulated hemorrhage, before the onset of traditional signs/symptoms., Methods: We performed a retrospective analysis during simulated hemorrhage using lower-body negative pressure (LBNP) in 23 AA (22 ± 1 years; 24 ± 1 kg/m) and 31 white women (WW) (20 ± 1 years; 23 ± 1 kg/m). Beat-by-beat blood pressure (BP) and heart rate (HR) were recorded during progressive lower body negative pressure to presyncope. The BP waveforms were analyzed using a machine-learning algorithm to derive the CRM at each lower body negative pressure stage., Results: Resting mean arterial BP (AA, 78 ± 3 mm Hg vs. WW, 74 ± 2 mm Hg) and HR (AA, 68 ± 2 bpm vs. WW, 65 ± 2 bpm) were similar between groups. The CRM progressively decreased during LBNP in both groups; however, the rate of decline in the CRM was less (p < 0.05) in AA. The CRM was 4% higher in AA at -15 mm Hg LBNP and progressively increased to 21% higher at -50 mm Hg LBNP (p < 0.05). However, changes in BP and HR were not different between groups., Conclusion: These data support the notion that the greater tolerance to simulated hemorrhage induced by LBNP in AA women can be explained by their greater capacity to protect the reserve to compensate for progressive central hypovolemia compared with WW, independent of standard vital signs., Level of Evidence: Diagnostic test, level II.

Elevated plasma osmolality (pOsm) has been shown to increase resting sympathetic nerve activity in animals and humans. The present study tested the hypothesis that increases in pOsm and serum sodium (sNa + ) concentration would exaggerate muscle sympathetic nerve activity (MSNA) and blood pressure (BP) responses to handgrip (HG) exercise and postexercise ischemia (PEI). BP and MSNA were measured during HG followed by PEI before and after a 23-min hypertonic saline infusion (HSI-3% NaCl). Eighteen participants (age 23 ± 1 yr; BMI 24 ± 1 kg/m 2 ) completed the protocol; pOsm and sNa + increased from pre- to post-HSI (285 ± 1 to 291 ± 1 mosmol/kg H 2 O; 138.2 ± 0.3 to 141.3 ± 0.4 mM; P < 0.05 for both). Resting mean BP (90 ± 2 vs. 92 ± 1 mmHg) and MSNA (11 ± 2 vs. 15 ± 2 bursts/min) were increased pre- to post-HSI ( P < 0.05 for both). Mean BP responses to HG (106 ± 2 vs. 111 ± 2 mmHg, P < 0.05) and PEI (102 ± 2 vs. 107 ± 2 mmHg, P < 0.05) were higher post-HSI. Similarly, MSNA during HG (20 ± 2 vs. 29 ± 2 bursts/min, P < 0.05) and PEI (19 ± 2 vs. 24 ± 3 bursts/min, P < 0.05) were greater post-HSI. In addition, the change in MSNA was greater post-HSI during HG (Δ9 ± 2 vs. Δ13 ± 3 bursts/min, P < 0.05). A second set of participants ( n = 13, age 23 ± 1 yr; BMI 24 ± 1 kg/m 2 ) completed a time control (TC) protocol consisting of quiet rest instead of an infusion. The TC condition yielded no change in resting sNa + , pOsm, mean BP, or MSNA (all P > 0.05); responses to HG and PEI were not different pre- to post-quiet rest ( P > 0.05). In summary, acutely increasing pOsm and sNa + exaggerates BP and MSNA responses during HG exercise and PEI. NEW & NOTEWORTHY Elevated plasma osmolality has been shown to increase resting sympathetic activity and blood pressure. This study provides evidence that acute elevations in plasma osmolality and serum sodium exaggerated muscle sympathetic nerve activity and blood pressure responses during exercise pressor reflex activation in healthy young adults.

Blood pressure responses to dietary sodium vary widely person-to-person. Salt sensitive rodent models display altered autonomic function, a trait thought to contribute to poor cardiovascular health. Thus, we hypothesized that increased salt sensitivity (SS) in normotensive humans would be associated with increased muscle sympathetic nerve activity (MSNA), decreased high frequency heart rate variability (HF-HRV), and decreased baroreflex sensitivity. Healthy normotensive men and women completed 1week of high (300mmol·day -1 ) and 1week of low (20mmol·day -1 ) dietary sodium (random order) with 24h mean arterial pressure (MAP) assessed on the last day of each diet to assess SS. Participants returned to the lab under habitual sodium conditions for testing. Forty-two participants are presented in this analysis, 19 of which successful MSNA recordings were obtained (n=42: age 39±2yrs., BMI 24.3±0.5kg·(m 2 ) -1 , MAP 83±1mmHg, habitual urine sodium 93±7mmol·24h -1 ; n=19: MSNA burst frequency 20±2 bursts·min -1 ). The variables of interest were linearly regressed over the magnitude of SS. Higher SS was associated with increased MSNA (burst frequency: r=0.469, p=0.041), decreased HF-HRV (r=-0.349, p=0.046), and increased LF/HF-HRV (r=0.363, p=0.034). SS was not associated with sympathetic or cardiac baroreflex sensitivity (p>0.05). Multiple regression analysis accounting for age found that age, not SS, independently predicted HF-HRV (age adjusted no longer significant; p=0.369) and LF/HF-HRV (age adjusted p=0.273). These data suggest that age-related salt sensitivity of blood pressure in response to dietary sodium is associated with altered resting autonomic cardiovascular function., (Copyright © 2017 Elsevier B.V. All rights reserved.)

New Findings: What is the central question of this study? Alterations in blood pressure control at exercise onset are apparent in older adults with established cardiovascular disease. It is currently not known whether these alterations are evident in young adults with a family history of hypertension. What is the main finding and its importance? We demonstrate that young women with a family history of hypertension display a larger change in blood pressure within the first 10 s of isometric exercise. These data suggest altered blood pressure control in young women with a family history of hypertension. Hypertensive adults demonstrate atypical increases in blood pressure (BP) and muscle sympathetic nerve activity (MSNA) at the immediate onset of static muscle contraction. However, it is unknown whether these abnormal responses occur in young, otherwise healthy adults at risk for developing future disease, such as those with a family history of hypertension (+FH). We tested the hypothesis that +FH young women have exaggerated increases in BP and MSNA at the onset of static muscle contraction compared with those without a family history of hypertension (-FH). We retrospectively examined beat-by-beat BP and MSNA during the initial 30 s of isometric handgrip exercise (30% of maximal voluntary contraction) in 16 +FH (22 ± 2 years old, 22 ± 3 kg m -2 ) and 16 -FH (22 ± 3 years old, 22 ± 3 kg m -2 ) women. Resting mean arterial pressure (+FH 80 ± 11 mmHg versus -FH 84 ± 13 mmHg), MSNA burst frequency (+FH 7 ± 3 bursts min -1 versus -FH 9 ± 5 bursts min -1 ) and burst incidence [+FH 12 ± 4 bursts (100 heart beats) -1 versus -FH 12 ± 8 bursts (100 heart beats) -1 ] were similar between groups (all P > 0.05). Within the first 10 s of exercise, changes in mean arterial pressure (+FH Δ8 ± 6 mmHg versus -FH Δ3 ± 2 mmHg, P < 0.05) and heart rate (+FH Δ8 ± 5 beats min -1 versus -FH Δ4 ± 4 beats min -1 , P < 0.05) were greater in +FH women. Absolute MSNA burst frequency during the first 30 s of exercise was not different between groups (-FH 7 ± 5 bursts min -1 versus +FH 9 ± 3 bursts min -1 ). Cardiovascular and sympathetic responses during the cold pressor test were not different between groups. These data demonstrate that young women at risk for developing cardiovascular disease exhibit greater changes in BP at the onset of static muscle contraction., (© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.)

Endothelin-1 (ET-1) contributes to age-related endothelial dysfunction in men via the ET A receptor. However, there are sex differences in the ET-1 system, and ET B receptors are modulated by sex hormones. The purpose of this study was to test the hypothesis that ET B receptors 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 ET B receptor antagonist (BQ-788, 300 nM), and an ET A receptor 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%CVC max ) were lower in PMW (both P < 0.05). Blockade of ET B receptors decreased cutaneous vasodilation in YW (87 ± 2%CVC max ; P < 0.05 vs. control) but increased vasodilation in PMW (93 ± 1%CVC max ; P < 0.05 vs. control). ET A receptor blockade had minimal effect in YW (92 ± 1%CVC max ) but increased cutaneous vasodilation in PMW (91 ± 2%CVC max ; P < 0.05 vs. control). In conclusion, ET B receptors mediate vasodilation in YW, but this effect is lost after menopause. Impaired vasodilatory function in PMW is due in part to a loss of ET B -mediated dilation., (Copyright © 2017 the American Physiological Society.)

Distension of peripheral veins in humans elicits a pressor and sympathoexcitatory response that is mediated through group III/IV skeletal muscle afferents. There is some evidence that autonomic reflexes mediated by these sensory fibers are blunted with increasing age, yet to date the venous distension reflex has only been studied in young adults. Therefore, we tested the hypothesis that the venous distension reflex would be attenuated in middle-aged compared with young adults. Nineteen young (14 men/5 women, 25 ± 1 yr) and 13 middle-aged (9 men/4 women, 50 ± 2 yr) healthy normotensive participants underwent venous distension via saline infusion through a retrograde intravenous catheter in an antecubital vein during limb occlusion. Beat-by-beat blood pressure, muscle sympathetic nerve activity (MSNA), and model flow-derived cardiac output (Q), and total peripheral resistance (TPR) were recorded throughout the trial. Mean arterial pressure (MAP) increased during the venous distension in both young (baseline 83 ± 2, peak 94 ± 3 mmHg; P < 0.05) and middle-aged adults (baseline 88 ± 2, peak 103 ± 3 mmHg; P < 0.05). MSNA also increased in both groups [young: baseline 886 ± 143, peak 1,961 ± 242 arbitrary units (AU)/min; middle-aged: baseline 1,164 ± 225, peak 2,515 ± 404 AU/min; both P < 0.05]. TPR (P < 0.001), but not Q (P = 0.76), increased during the trial. However, the observed increases in blood pressure, MSNA, and TPR were similar between young and middle-aged adults. Additionally, no correlation was found between age and the response to venous distension (all P > 0.05). These findings suggest that peripheral venous distension elicits a pressor and sympathetic response in middle-aged adults similar to the response observed in young adults., (Copyright © 2016 the American Physiological Society.)

Elevated NaCl concentrations of the cerebrospinal fluid increase sympathetic nerve activity (SNA) in salt-sensitive hypertension. Neurons of the rostral ventrolateral medulla (RVLM) play a pivotal role in the regulation of SNA and receive mono- or polysynaptic inputs from several hypothalamic structures responsive to hypernatremia. Therefore, the present study investigated the contribution of RVLM neurons to the SNA and pressor response to cerebrospinal fluid hypernatremia. Lateral ventricle infusion of 0.15 mol/L, 0.6 mol/L, and 1.0 mol/L NaCl (5 µL/10 minutes) produced concentration-dependent increases in lumbar SNA, adrenal SNA, and arterial blood pressure, despite no change in splanchnic SNA and a decrease in renal SNA. Ganglionic blockade with chlorisondamine or acute lesion of the lamina terminalis blocked or significantly attenuated these responses, respectively. RVLM microinjection of the gamma-aminobutyric acid (GABAA) agonist muscimol abolished the sympathoexcitatory response to intracerebroventricular infusion of 1 mol/L NaCl. Furthermore, blockade of ionotropic glutamate, but not angiotensin II type 1, receptors significantly attenuated the increase in lumbar SNA, adrenal SNA, and arterial blood pressure. Finally, single-unit recordings of spinally projecting RVLM neurons revealed 3 distinct populations based on discharge responses to intracerebroventricular infusion of 1 mol/L NaCl: type I excited (46%; 11/24), type II inhibited (37%; 9/24), and type III no change (17%; 4/24). All neurons with slow conduction velocities were type I cells. Collectively, these findings suggest that acute increases in cerebrospinal fluid NaCl concentrations selectively activate a discrete population of RVLM neurons through glutamate receptor activation to increase SNA and arterial blood pressure., (© 2015 American Heart Association, Inc.)

Objective: E2 enhances vasodilation in healthy women, but vascular effects of the phytoestrogen GEN are still under investigation. IR compromises microvascular function. We therefore examined the interaction of E2 , GEN, and IR on microvascular vasodilatory responsiveness., Methods: We hypothesized that E2 and GEN increase microvascular vasodilation in healthy women (control, n = 8, 23 ± 2 year, BMI: 25.9 ± 2.9 kg/m2) but not in women with IR (n = 7, 20 ± 1 year, BMI: 27.3 ± 3.0 kg/m2). We used the cutaneous circulation as a model of microvascular vasodilatory function. We determined CVC with laser Doppler flowmetry and beat-to-beat blood pressure during local cutaneous heating (42 °C) with E2 or GEN microdialysis perfusions. Because heat-induced vasodilation is primarily an NO-mediated response, we examined microvascular vasodilation with and without L-NMMA., Results: In C, E2 enhanced CVC (94.4 ± 2.6% vs. saline 81.6 ± 4.2% CVCmax , p < 0.05), which was reversed with L-NMMA (80.9 ± 7.8% CVCmax , p < 0.05), but GEN did not affect vasodilation. Neither E2 nor GEN altered CVC in IR, although L-NMMA attenuated CVC during GEN., Conclusions: Our study does not support improved microvascular responsiveness during GEN exposure in healthy young women, and demonstrates that neither E2 nor GEN improves microvascular vasodilatory responsiveness in women with IR., (© 2015 John Wiley & Sons Ltd.)

Young adults with a family history of hypertension (+FH) have increased risk of developing hypertension. Furthermore, the blood pressure (BP) response to sympathoexcitatory stimuli in young adults can predict the future development of hypertension. Therefore, we hypothesized young women with a +FH would have exaggerated cardiovascular and sympathetic reactivity compared with young women without a family history of hypertension (-FH). Beat-by-beat mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA) were measured in 14 women +FH (22 ± 1 yr, 21 ± 1 kg/m(2), MAP 80 ± 2 mmHg) and 15 women -FH (22 ± 1 yr, 22 ± 1 kg/m(2), MAP 78 ± 2 mmHg) during acute sympathoexcitatory maneuvers: cold pressor test, 2 min of isometric handgrip (HG) exercise at 30% of maximal voluntary contraction, and 3 min of postexercise ischemia (PEI; isolated activation of the skeletal muscle metaboreflex). During cold pressor test, the increase in BP was greater in women +FH (ΔMAP: +FH 16 ± 2 vs. -FH 11 ± 1 mmHg, P < 0.05), which was accompanied by an exaggerated increase in MSNA (ΔMSNA: +FH 17 ± 2 vs. -FH 8 ± 2 burst/min, P < 0.05). The increase in BP was greater in +FH during the last minute of HG (ΔMAP: +FH 23 ± 3 vs. -FH 12 ± 1 mmHg, P < 0.05) and during PEI (ΔMAP: +FH 17 ± 3 vs. -FH 9 ± 2 mmHg, P < 0.05). Similarly, the increase in MSNA was greater in +FH during both HG (ΔMSNA: +FH 12 ± 2 vs. -FH 6 ± 2 burst/min, P < 0.05) and PEI (ΔMSNA: +FH 16 ± 2 vs. -FH 4 ± 2 burst/min, P < 0.05). These data demonstrate that +FH women have greater BP and sympathetic reactivity compared with -FH women., (Copyright © 2015 the American Physiological Society.)

Physical activity is a cornerstone therapy for the primary prevention and treatment of hypertension, which is becoming increasingly prevalent in modern societies. During exercise, heart rate and blood pressure (BP) increase in order to acutely meet the metabolic demands of the working skeletal muscle. In hypertensive adults, isometric exercise-induced increases in BP are excessive, potentially increasing the risk of an acute cardiovascular event during or after physical activity. Recently, the skeletal muscle metaboreflex has emerged as a significant contributor to the development of aberrant cardiovascular control during isometric exercise in this clinical population. Our laboratory has conducted a series of studies characterizing the skeletal muscle metaboreflex in hypertensive humans. We and others have demonstrated that hypertension is characterized by greater increases in muscle sympathetic nerve activity and BP during selective activation of the metaboreflex during post-exercise muscle ischemia compared to the increases noted in healthy age-matched normotensive adults, suggesting that the skeletal muscle metaboreflex is exaggerated in human hypertension. The focus of this review is the skeletal muscle metaboreflex (i.e., the metabolic component of the exercise pressor reflex) in hypertension, with particular emphasis on the potential role of purinergic receptors in mediating the exaggerated responses to muscle metaboreflex activation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Hyperandrogenism and vascular dysfunction often coexist in women with polycystic ovary syndrome (PCOS). We hypothesized that testosterone compromises cutaneous microvascular dilation in women with PCOS via the endothelin-1 ET-B subtype receptor. To control and isolate testosterone's effects on microvascular dilation, we administered a gonadotropin-releasing hormone antagonist (GnRHant) for 11 days in obese, otherwise healthy women [controls, 22.0 (4) yr, 36.0 (3.2) kg/m(2)] or women with PCOS [23 (4) yr, 35.4 (1.3) kg/m(2)], adding testosterone (T; 2.5 mg/day) on days 8-11. Using laser Doppler flowmetry and cutaneous microdialysis, we measured changes in skin microcirculatory responsiveness (ΔCVC) to local heating while perfusing ET-A (BQ-123) and ET-B (BQ-788) receptor antagonists under three experimental conditions: baseline (BL; prehormone intervention), GnRHant (day 4 of administration), and T administration. At BL, ET-A receptor inhibition enhanced heat-induced vasodilation in both groups [ΔCVC control 2.03 (0.65), PCOS 2.10 (0.25), AU/mmHg, P < 0.05]; ET-B receptor inhibition reduced vasodilation in controls only [ΔCVC 0.98 (0.39), 1.41 (0.45) AU/mmHg for controls, PCOS] compared with saline [ΔCVC controls 1.27 (0.48), PCOS 1.31 (0.13) AU/mmHg]. GnRHant enhanced vasodilation in PCOS [saline ΔCVC 1.69 (0.23) AU/mmHg vs. BL, P < 0.05] and abolished the ET-A effect in both groups, a response reasserted with T in controls. ET-B receptor inhibition reduced heat-induced vasodilation in both groups during GnRHant and T [ΔCVC, controls: 0.95 (0.21) vs. 0.51 (13); PCOS: 1.27 (0.23) vs. 0.84 (0.27); for GnRHant vs. T, P < 0.05]. These data demonstrate that androgen suppression improves microvascular dilation in PCOS via ET-A and ET-B receptors.

The impact of 17β-oestradiol (E2) exposure on autonomic control of orthostasis in young women is unclear. We tested the hypothesis that autonomic cardiovascular regulation is more sensitive to E2 exposure in women with low orthostatic tolerance. Women underwent an initial maximal lower body negative pressure (LBNP) test to place them into a low (LT, n = 7, 22 ± 1 years old, body mass index 22 ± 1 kg m(-2)) or a high orthostatic tolerance group (HT, n = 7, 22 ± 1 years old, body mass index 24 ± 1 kg m(-2)). We then suppressed endogenous reproductive hormone production using a gonadotrophin-releasing hormone antagonist (GnRHant) for 10 days, with E2 administration during the last 7 days of GnRHant. We measured R-R interval and beat-by-beat blood pressure during the modified Oxford protocol, and changes in heart rate, blood pressure and forearm vascular resistance (FVR) during submaximal LBNP. During submaximal LBNP, FVR increased in HT (ANOVA P < 0.05) but not in LT (ANOVA P > 0.05), and stroke volume was lower in LT relative to HT at all levels of LBNP (P < 0.05). Compared with GnRHant, E2 administration shifted FVR lower in LT (ANOVA P < 0.05), with no effect in HT. Administration of E2 increased baroreflex control of heart rate (derived from the modified Oxford protocol) in LT (GnRHant 10.7 ± 2.5 ms mmHg(-1) vs. E2 16.1 ± 2.4 ms mmHg(-1), P < 0.05) but not in HT (GnRHant 13.4 ± 1.9 ms mmHg(-1) vs. E2 15.3 ± 2.4 ms mmHg(-1), n.s.). In conclusion, blunted peripheral vasoconstriction and lower stroke volume contribute to compromised orthostatic tolerance in women; this inability to vasoconstrict is further exacerbated by exposure to E2. Furthermore, E2 administration increases baroreflex-mediated heart rate responses to orthostasis in low orthostatic tolerant women, which is likely to be a compensatory mechanism for the blunted peripheral vascular resistance and lower central volume.

Background: Excess dietary sodium has been linked to the development of hypertension and other cardiovascular diseases. In humans, the effects of sodium consumption on endothelial function have not been separated from the effects on blood pressure. The present study was designed to determine if dietary sodium intake affected endothelium-dependent dilation (EDD) independently of changes in blood pressure., Method: Fourteen healthy salt-resistant adults were studied (9M, 5F; age 33 ± 2.4 years) in a controlled feeding study. After a baseline run-in diet, participants were randomized to a 7-day high-sodium (300-350 mmol/day) and 7-day low-sodium (20 mmol/day) diet. Salt resistance, defined as a 5 mmHg or less change in a 24-h mean arterial pressure, was individually assessed while on the low-sodium and high-sodium diets and confirmed in the participants undergoing study (low-sodium: 85 ± 1 mmHg; high-sodium: 85 ± 2 mmHg). EDD was determined in each participant via brachial artery flow-mediated dilation on the last day of each diet., Results: Sodium excretion increased during the high-sodium diet (P < 0.01). EDD was reduced on the high-sodium diet (low: 10.3 ± 0.9%, high: 7.3 ± 0.7%; P < 0.05). The high-sodium diet significantly suppressed plasma renin activity (PRA), plasma angiotensin II, and aldosterone (P < 0.05)., Conclusion: These data demonstrate that excess salt intake in humans impairs endothelium-dependent dilation independently of changes in blood pressure.

Cardiovascular disease remains the leading cause of death for both men and women. Hypertension is less prevalent in young women compared with young men, but menopausal women are at greater risk for hypertension compared with men of similar age. Despite these risks, women do not consistently receive first line treatment for the early stages of hypertension, and the greater morbidity in menopause reflects this neglect. This review focuses on ovarian hormone effects on the cardiovascular and water regulatory systems that are associated with blood pressure control in women. The study of ovarian hormones within young women is complex because these hormones fluctuate across the menstrual cycle, and these fluctuations can complicate conclusions regarding sex differences. To better isolate the effects of oestrogen and progesterone on the cardiovascular and water regulation systems, we developed a model to transiently suppress reproductive function followed by controlled hormone administration. Sex differences in autonomic regulation of blood pressure appear related to ovarian hormone exposure, and these hormonal differences contribute to sex differences in hypertension and orthostatic tolerance. Oestrogen and progesterone exposure are also associated with plasma volume expansion, and a leftward shift in the osmotic operating point for body fluid regulation. In young, healthy women, the shift in osmoregulation appears to have only a minor effect on overall body water balance. Our overarching conclusion is that ovarian hormone exposure is the important underlying factor contributing to differences in blood pressure and water regulation between women and men, and within women throughout the lifespan.

Although dose-response curves are commonly used to describe in vivo cutaneous α-adrenergic responses, modeling parameters and analyses methods are not consistent across studies. The goal of the present investigation was to compare three analysis methods for in vivo cutaneous vasoconstriction studies using one reference data set. Eight women (22 ± 1 yr, 24 ± 1 kg/m(2)) were instrumented with three cutaneous microdialysis probes for progressive norepinephrine (NE) infusions (1 × 10(-8), 1 × 10(-6), 1 × 10(-5), 1 × 10(-4), and 1 × 10(-3) logM). NE was infused alone, co-infused with NG-monomethyl-l-arginine (l-NMMA, 10 mM) or Ketorolac tromethamine (KETO, 10 mM). For each probe, dose-response curves were generated using three commonly reported analyses methods: 1) nonlinear modeling without data manipulation, 2) nonlinear modeling with data normalization and constraints, and 3) percent change from baseline without modeling. Not all data conformed to sigmoidal dose-response curves using analysis 1, whereas all subjects' curves were modeled using analysis 2. When analyzing only curves that fit the sigmoidal model, NE + KETO induced a leftward shift in ED(50) compared with NE alone with analyses 1 and 2 (F test, P < 0.05) but only tended to shift the response leftward with analysis 3 (repeated-measures ANOVA, P = 0.08). Neither maximal vasoconstrictor capacity (E(max)) in analysis 1 nor %change CVC change from baseline in analysis 3 were altered by blocking agents. In conclusion, although the overall detection of curve shifts and interpretation was similar between the two modeling methods of curve fitting, analysis 2 produced more sigmoidal curves.