Megan M. Wenner

High Dietary Sodium Intake Impairs Endothelium-Dependent Dilation in Healthy Salt-Resistant Humans

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.

Blood pressure and water regulation: understanding sex hormone effects within and between men and women

Abstract  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.

Androgens influence microvascular dilation in PCOS through ET-A and ET-B receptors

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 testosterones 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.

Endothelin B receptor contribution to peripheral microvascular function in women with polycystic ovary syndrome.

Non‐Technical Summary  Although the core feature in polycystic ovary syndrome (PCOS) is a hormonal imbalance, this syndrome is associated with obesity, insulin resistance, hypertension and endothelial dysfunction. This constellation of factors leads to greater risks for infertility, diabetes and cardiovascular disease. In this study we examine two important receptors involved in endothelial function, ET‐A and ET‐B, using the skin microcirculation to examine small blood vessel responses. We demonstrate that the ET‐B receptor is likely to play an important role in the pathophysiology of cardiovascular disease in women with PCOS.

Progesterone enhances adrenergic control of skin blood flow in women with high but not low orthostatic tolerance

Non‐technical summary Women experience orthostatic intolerance (the inability to maintain blood pressure during postural changes) more frequently than men. This difference between men and women may in part be related to how oestradiol and progesterone influence dilatation and constriction of blood vessels. We show that progesterone enhances vasoconstriction in women who have a higher tolerance to orthostatic stress, but not in women with low tolerance. The increase in vasoconstriction with progesterone administration in women with high tolerance appears to be mediated by prostaglandins (hormone‐like substances that assist in maintaining bodily functions). These results show that progesterone alters blood vessel constriction and can help us understand blood pressure regulation in women.

Cerebrospinal Fluid Hypernatremia Elevates Sympathetic Nerve Activity and Blood Pressure via the Rostral Ventrolateral Medulla

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.

Mechanisms contributing to low orthostatic tolerance in women: the influence of oestradiol

•  The maintenance of blood pressure upon standing is accomplished through an integration of physiological systems. The inability to maintain blood pressure upon standing is called orthostatic intolerance and occurs more frequently in women than in men. •  Given that ovarian hormones fluctuate throughout the menstrual cycle, it is difficult to isolate the effects of oestradiol on cardiovascular control systems in humans. •  We utilize a novel study design in which we suppress endogenous ovarian hormones, then add back oestradiol to isolate its effects on blood pressure‐regulating systems. •  We show that women with low orthostatic tolerance have a lower vasoconstrictor response to gravitational stress and lower stroke volume in comparison to women with normal/high orthostatic tolerance. Oestradiol further suppresses the vasoconstrictor response to gravitational stress in women with low orthostatic tolerance; heart rate increases more to compensate for this impairment. •  These results help us to better understand why women are more susceptible to orthostatic intolerance and how oestradiol affects the regulation of blood pressure.

Sympathetic reactivity in young women with a family history of hypertension

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.

Exaggerated increases in blood pressure during isometric muscle contraction in hypertension: Role for purinergic receptors

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.

ETB receptor contribution to vascular dysfunction in postmenopausal women

Endothelin-1 (ET-1) contributes to age-related endothelial dysfunction in men via the ETA receptor. However, there are sex differences in the ET-1 system, and ETB receptors are modulated by sex hormones. The purpose of this study was to test the hypothesis that ETB 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 ETB receptor antagonist (BQ-788, 300 nM), and an ETA 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%CVCmax) were lower in PMW (both P < 0.05). Blockade of ETB receptors 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). ETA receptor 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, ETB 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 ETB-mediated dilation.