Sex Differences in Human Thermoregulation: Relevance for 2020 and Beyond.

The participation of women in physically strenuous athletic and occupational tasks has increased substantially in the past decade. Female sex steroids have influences on thermoregulatory processes that could impact physical performance in the heat. Here, we summarize and evaluate the current literature regarding sex differences in thermoregulation and provide recommendations for heat-illness risk-mitigation strategies.

Influence of recent altitude exposure on sea level sympathetic neural & hemodynamic responses to orthostasis.

Although it has been shown that muscle sympathetic nerve activity increases during high altitude exposure, mechanisms of sympathoexcitation and blood pressure control after return from altitude are not well described. We hypothesized that: (1) living for 12days at 4300m (Pikes Peak, Colorado) would result in increased muscle sympathetic nerve activity 24h after return to sea level; (2) post-Pikes Peak sympathetic neural and hemodynamic responses to orthostasis would be decreased due to a potential 'ceiling effect' on sympathetic activity; and (3) the magnitude of individual increases in sympathetic nerve activity post-Pikes Peak would be inversely related to baseline sympathetic nerve activity before traveling to altitude. Muscle sympathetic nerve activity, heart rate and blood pressure were measured in 9 healthy individuals (24±8years) in supine, 30° and 45° head-up tilt positions. Measurements were conducted twice at sea level, once before (pre-Pikes Peak) a 12day residence at 4300m, and once within 24h of return (post-Pikes Peak). Supine muscle sympathetic nerve activity was higher (post: 27±5 vs pre: 17±6bursts/min) upon return from altitude (p<0.05). Individual values for pre-Pikes Peak sympathetic activity were inversely related to post-altitude sympathoexcitation (r=-0.69, p<0.05). There were no differences in neural or cardiovascular responses to tilt between pre and post- Pikes Peak (p>0.05). We conclude that 12days' residence at 4300m causes a sustained sympathoexcitation which does not impair the ability of muscle sympathetic nerves to respond appropriately to orthostasis.

Quantifying sympathetic neuro-haemodynamic transduction at rest in humans: insights into sex, ageing and blood pressure control.

KEY POINTS: We have developed a simple analytical method for quantifying the transduction of sympathetic activity into vascular tone. This method demonstrates that as women age, the transfer of sympathetic nerve activity into vascular tone is increased, so that for a given level of sympathetic activity there is more vasoconstriction. In men, this measure decreases with age. Test-re-test analysis demonstrated that the new method is a reliable estimate of sympathetic transduction. We conclude that increased sympathetic vascular coupling contributes to the age-related increase in blood pressure that occurs in women only. This measure is a reliable estimate of sympathetic transduction in populations with high sympathetic nerve activity. Thus, it will provide information regarding whether treatment targeting the sympathetic nervous system, which interrupts the transfer of sympathetic nerve activity into vascular tone, will be effective in reducing blood pressure in hypertensive patients. This may provide insight into which populations will respond to certain types of anti-hypertensive medication. ABSTRACT: Sex and age differences in the sympathetic control of resting blood pressure (BP) may be due to differences in the transduction of sympathetic nerve activity (SNA) into vascular tone. Current methods for dynamically quantifying transduction focus on the relationship between SNA and vasoconstriction during a pressor stimulus, which increases BP and may be contra-indicated in patients. We describe a simple analytical method for quantifying transduction under resting conditions. We performed linear regression analysis of binned muscle SNA burst areas against diastolic BP (DBP). We assessed whether the slope of this relationship reflects the transduction of SNA into DBP. To evaluate this, we investigated whether this measure captures differences in transduction in different populations. Specifically, we (1) quantified transduction in young men (YM), young women (YW), older men (OM) and postmenopausal women (PMW); and (2) measured changes in transduction during ß-blockade using propranolol in YW, YM and PMW. YM had a greater transduction vs. OM (0.10 ± 0.01 mmHg (% s)(-1) , n = 23 vs. 0.06 ± 0.01 mmHg (% s)(-1) , n = 18; P = 0.003). Transduction was lowest in YW (0.02 ± 0.01 mmHg (% s)(-1) , n = 23) and increased during ß-blockade (0.11 ± 0.01 mmHg (% s)(-1) ; P < 0.001). Transduction in PMW (0.07 ± 0.01 mmHg (% s)(-1) , n = 23) was greater compared to YW (P = 0.001), and was not altered during ß-blockade (0.06 ± 0.01 mmHg (% s)(-1) ; P = 0.98). Importantly, transduction increased in women with age, but decreased in men. Transduction in women intersected that in men at 55 ± 1.5 years. This measure of transduction captures age- and sex-differences in the sympathetic regulation of DBP and may be valuable in quantifying transduction in disease. In particular, this measure may help target treatment strategies in specific hypertensive subpopulations.

Sympathetic regulation of blood pressure in normotension and hypertension: when sex matters.

NEW FINDINGS: What is the topic of this review? Hypertension is a major problem in Western society. Risk of hypertension increases with age, especially in women, who have lower risk compared with men until menopause. This review outlines the sex differences in the sympathetic control of blood pressure and how these mechanisms change with age. What advances does it highlight? It has recently been recognized that men and women regulate blood pressure by different physiological mechanisms. This is important for both the understanding and the clinical management of individual patients with hypertension. This review summarizes recent advances in understanding how the regulation of blood pressure in hypertension by the sympathetic nervous system differs between men and women. The sympathetic nervous system has a central role in the regulation of arterial blood pressure (BP) and in the development of hypertension in humans. Recent evidence points to differences between the sexes in the integrative mechanisms by which BP is controlled, suggesting that the development of hypertension may follow distinct pathways in women compared with men. An important aspect of sympathetic control of BP is its substantial interindividual variability. In healthy young men, the variability in sympathetic nerve activity (SNA) is balanced by variability in cardiac output and vascular adrenergic responses, such that BP remains similar, and normal, across a severalfold range of resting SNA values. In young women, variability in resting SNA is similar to that seen in men, but the 'balancing' mechanisms are strikingly different; women exhibit greater ß-adrenergic vasodilatation compared with men, which minimizes the pressor effects of a given level of SNA. Ageing is associated with increased SNA and a loss of the balancing factors seen in younger people, leading to an increased risk of hypertension in older people. Loss of oestrogen with menopause in women appears to be linked mechanistically with the decrease in ß-adrenergic vasodilatation and the increased risk of hypertension in older women. Other important factors contributing to hypertension via sympathetic mechanisms are obesity and arterial stiffening, both of which increase with ageing. We conclude with a discussion of important areas in which more work is needed to understand and manage appropriately the sex-specific mechanisms in the development and maintenance of hypertension.

Quantification of chromatographic effects of vitamin B supplementation in urine and implications for hydration assessment.

Changes in body water elicit reflex adjustments at the kidney, thus maintaining fluid volume homeostasis. These renal adjustments change the concentration and color of urine, variables that can, in turn, be used as biomarkers of hydration status. It has been suggested that vitamin supplementation alters urine color; it is unclear whether any such alteration would confound hydration assessment via colorimetric evaluation. We tested the hypothesis that overnight vitamin B2 and/or B12 supplementation alters urine color as a marker of hydration status. Thirty healthy volunteers were monitored during a 3-day euhydrated baseline, confirmed via first morning nude body mass, urine specific gravity, and urine osmolality. Volunteers then randomly received B2 (n = 10), B12 (n = 10), or B2 + B12 (n = 10) at ∼200 × recommended dietary allowance. Euhydration was verified on trial days (two of the following: body mass ± 1.0% of the mean of visits 1-3, urine specific gravity < 1.02, urine osmolality < 700 mmol/kg). Vitamin purity and urinary B2 concentration ([B2]) and [B12] were quantified via ultraperformance liquid chromatography. Two independent observers assessed urine color using an eight-point standardized color chart. Following supplementation, urinary [B2] was elevated; however, urine color was not different between nonsupplemented and supplemented trials. For example, in the B2 trial, urinary [B2] increased from 8.6 × 10(4) ± 7.7 × 10(4) to 5.7 × 10(6) ± 5.3 × 10(6) nmol/l (P < 0.05), and urine color went from 4 ± 1 to 5 ± 1 (P > 0.05). Both conditions met the euhydrated color classification. We conclude that a large overnight dose of vitamins B2 and B12 does not confound assessment of euhydrated status via urine color.

Sympathetic neural activity to the cardiovascular system: integrator of systemic physiology and interindividual characteristics.

The sympathetic nervous system is a ubiquitous, integrating controller of myriad physiological functions. In the present article, we review the physiology of sympathetic neural control of cardiovascular function with a focus on integrative mechanisms in humans. Direct measurement of sympathetic neural activity (SNA) in humans can be accomplished using microneurography, most commonly performed in the peroneal (fibular) nerve. In humans, muscle SNA (MSNA) is composed of vasoconstrictor fibers; its best-recognized characteristic is its participation in transient, moment-to-moment control of arterial blood pressure via the arterial baroreflex. This property of MSNA contributes to its typical "bursting" pattern which is strongly linked to the cardiac cycle. Recent evidence suggests that sympathetic neural mechanisms and the baroreflex have important roles in the long term control of blood pressure as well. One of the striking characteristics of MSNA is its large interindividual variability. However, in young, normotensive humans, higher MSNA is not linked to higher blood pressure due to balancing influences of other cardiovascular variables. In men, an inverse relationship between MSNA and cardiac output is a major factor in this balance, whereas in women, beta-adrenergic vasodilation offsets the vasoconstrictor/pressor effects of higher MSNA. As people get older (and in people with hypertension) higher MSNA is more likely to be linked to higher blood pressure. Skin SNA (SSNA) can also be measured in humans, although interpretation of SSNA signals is complicated by multiple types of neurons involved (vasoconstrictor, vasodilator, sudomotor and pilomotor). In addition to blood pressure regulation, the sympathetic nervous system contributes to cardiovascular regulation during numerous other reflexes, including those involved in exercise, thermoregulation, chemoreflex regulation, and responses to mental stress.

Sympathetic neural regulation of blood pressure: influences of sex and aging.

Sex and age have important influences on sympathetic neural control of blood pressure in humans. Young women are relatively protected against risk of hypertension due to greater peripheral vasodilator influences compared with young men and older people. This protective effect is lost at menopause. Older men and women have higher sympathetic nerve activity and tighter coupling between SNA and blood pressure, contributing to the increased risk of hypertension with aging.

Sex, hormones and neuroeffector mechanisms.

Incidence and rate of cardiovascular disease differ between men and women across the life span. Although hypertension is more prominent in men than women, there is a group of vasomotor disorders [i.e. Raynaud's disease, postural orthostatic tachycardia syndrome and vasomotor symptoms (hot flashes) of menopause and migraine] with a female predominance. Both sex and hormones interact to modulate neuroeffector mechanisms including integrated regulation of the Sry gene and direct effect of sex steroid hormones on synthesis, release and disposition of monoamine neurotransmitters, and distribution and sensitivity of their receptors in brain areas associated with autonomic control. The interaction of the sex chromosomes and steroids also modulates these effector tissues, that is, the heart, vascular smooth muscle and endothelium. Although involvement of central serotonergic centres has been studied in regard to mood disorders such as depression, their contribution to cardiovascular risk is gaining attention. Studies are needed to further evaluate how hormonal treatments and drugs used to modulate adrenergic and serotonergic activity affect progression and risk for cardiovascular disease in men and women.

Relationship between breathing and cardiovascular function at rest: sex-related differences.

AIM: to compare relationships at rest between breathing rate, levels of muscle sympathetic nerve activity, total peripheral resistance and cardiac output among young men and women. METHODS: recordings were made of respiratory movements, sympathetic nerve activity (peroneal microneurography), intra-arterial blood pressure, electrocardiogram, cardiac output (open-circuit acetylene uptake technique) in 19 healthy men (age 27 (+/-) 2years, mean (+/-) SEM) and 17 healthy women (age 25 (+/-) 1years). Total peripheral resistance and stroke volume were calculated. Four minutes epochs of data were analysed. RESULTS: breathing rates and sympathetic activity were similar in men and women but compared to men, women had significantly lower blood pressures, cardiac output and stroke volume. In men breathing rate correlated positively with sympathetic activity (r = 0.58, P < 0.05) but not in women (r = 0.12, P > 0.05). Furthermore, in men, respiratory rate correlated positively with total peripheral resistance (r = 0.65, P < 0.05) and inversely with cardiac output (r =-0.84, P < 0.05) and heart rate (r = -0.60, P < 0.05) but there were no such relationships in women (P > 0.05 for all). CONCLUSIONS: the positive relationship between breathing and sympathetic activity in men, and the inverse coupling of breathing to cardiac output and heart rate suggest that influences of respiration may be important not only for dynamic but also for 'tonic' cardiovascular function. The lack of relationships among these variables in women shows that there are fundamental differences in basic blood pressure regulation between the sexes.

Integrative mechanisms of blood pressure regulation in humans and rats: cross-species similarities.

As our understanding of the importance of individualized medicine continues to grow, the clinical relevance of interindividual variability in hemodynamic variables is receiving increasing attention. However, it is not known whether the rat, which is often used for studies of cardiovascular regulation, exhibits similar interindividual variability. In the present study, we evaluated whether the magnitude of interindividual variability in cardiac output (CO) and total peripheral resistance (TPR) was similar in humans and in rats. We assessed interindividual variability of mean arterial pressure (MAP), CO, and TPR during control conditions in normotensive humans (n = 40) and during normotension and deoxycorticosterone acetate-salt hypertension in Sprague-Dawley rats (n = 16). Humans and rats showed marked interindividual variability in CO and TPR but low variability in MAP. During deoxycorticosterone acetate-salt hypertension, CO was maintained, but TPR was elevated compared with the baseline period. We conclude that the magnitudes of interindividual variability of MAP, CO, and TPR are quantitatively similar in humans and rats, providing support for the relevance of this variability in both species and suggesting that studies in rats could be designed to address questions specific to individualized medicine in hypertension.

Influence of endogenous angiotensin II on control of sympathetic nerve activity in human dehydration.

Arterial blood pressure can often fall too low during dehydration, leading to an increased incidence of orthostatic hypotension and syncope. Systemic sympathoexcitation and increases in volume regulatory hormones such as angiotensin II (AngII) may help to maintain arterial pressure in the face of decreased plasma volume. Our goals in the present study were to quantify muscle sympathetic nerve activity (MSNA) during dehydration (DEH), and to test the hypothesis that endogenous increases in AngII in DEH have a mechanistic role in DEH-associated sympathoexcitation. We studied 17 subjects on two separate study days: DEH induced by 24 h fluid restriction and a euhydrated (EUH) control day. MSNA was measured by microneurography at the peroneal nerve, and arterial blood pressure, electrocardiogram, and central venous pressure were also recorded continuously. Sequential nitroprusside and phenylephrine (modified Oxford test) were used to evaluate baroreflex control of MSNA. Losartan (angiotensin type 1 receptor (AT1) antagonist) was then administered and measurements were repeated. MSNA was elevated during DEH (42 +/- 5 vs. EUH: 32 +/- 4 bursts per 100 heartbeats, P = 0.02). Blockade of AT1 receptors partially reversed this change in MSNA during DEH while having no effect in the control EUH condition. The sensitivity of baroreflex control of MSNA was unchanged during DEH compared to EUH. We conclude that endogenous increases in AngII during DEH contribute to DEH-associated sympathoexcitation.

Autonomic cardiovascular control during a novel pharmacologic alternative to ganglionic blockade.

The purpose of this study was to compare ganglionic blockade with trimethaphan (TMP) and an alternative drug strategy using combined muscarinic antagonist (glycopyrrolate, GLY) and alpha-2 agonist (dexmedetomidine, DEX). Protocol 1: incremental phenylephrine was administered during control and combined GLY-DEX, or control and TMP on two control combined GLY and DEX or TMP infusion on two randomized days. Protocol 2: muscle sympathetic nerve activity (MSNA) and the baroreflex MSNA relationship was determined before and after GLY-DEX. Blood pressure was higher with GLY-DEX (99+/-3 mm Hg) and lower with TMP (78+/-3 mm Hg) relative to control (GLY-DEX: 90+/-2 mm Hg; TMP: 91+/-2 mm Hg; P<0.05). Incremental phenylephrine increased pressure during GLY-DEX (P<0.01 vs control) and TMP (P<0.01 vs control) to a similar degree. Both GLY-DEX and TMP infusion inhibited norepinephrine release (P<0.01 vs control). GLY-DEX inhibited baseline MSNA (P<0.05) and baroreflex changes in MSNA (P<0.01). We conclude that the GLY-DEX alternative drug strategy can be used as a reasonable alternative to pharmacologic ganglionic blockade to examine autonomic cardiovascular control.

Relationship between muscle sympathetic nerve activity and systemic hemodynamics during nitric oxide synthase inhibition in humans.

Large interindividual differences exist in resting sympathetic nerve activity (SNA) among normotensive humans with similar arterial pressure (AP). We recently showed inverse relationships of resting SNA with cardiac output (CO) and vascular adrenergic responsiveness that appear to balance the influence of differences in SNA on blood pressure. In the present study, we tested whether nitric oxide (NO)-mediated vasodilation has a role in this balance by evaluating hemodynamic responses to systemic NO synthase (NOS) inhibition in individuals with low and high resting muscle SNA (MSNA). We measured MSNA via peroneal microneurography, CO via acetylene uptake and AP directly, at baseline and during increasing systemic doses of the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA). Baseline MSNA ranged from 9 to 38 bursts/min (13 to 68 bursts/100 heartbeats). L-NMMA caused dose-dependent increases in AP and total peripheral resistance and reflex decreases in CO and MSNA. Increases in AP with L-NMMA were greater in individuals with high baseline MSNA (PANOVA<0.05). For example, after 8.5 mg/kg of L-NMMA, in the low MSNA subgroup (n=6, 28+/-4 bursts/100 heartbeats), AP increased 9+/-1 mmHg, whereas in the high-MSNA subgroup (n=6, 58+/-3 bursts/100 heartbeats), AP increased 15+/-2 mmHg (P<0.01). The high-MSNA subgroup had lower baseline CO and smaller decreases in CO with L-NMMA, but changes in total peripheral resistance were not different between groups. We conclude that differences in CO among individuals with varying sympathetic traffic have important hemodynamic implications during disruption of NO-mediated vasodilation.

Vascular adrenergic responsiveness is inversely related to tonic activity of sympathetic vasoconstrictor nerves in humans.

In humans, sympathetic nerve activity (SNA) at rest can vary several-fold among normotensive individuals with similar blood pressures. We recently showed that a balance exists between SNA and cardiac output, which may contribute to the maintenance of normal blood pressures over the range of resting SNA levels. In the present studies, we assessed whether variability in vascular adrenergic responsiveness has a role in this balance. We tested the hypothesis that forearm vascular responses to noradrenaline (NA) and tyramine (TYR) are related to SNA such that individuals with lower resting SNA have greater adrenergic responsiveness, and vice-versa. We measured multifibre muscle SNA (MSNA; microneurography), arterial pressure (brachial catheter) and forearm blood flow (plethysmography) in 19 healthy subjects at baseline and during intrabrachial infusions of NA and TYR. Resting MSNA ranged from 6 to 34 bursts min(-1), and was inversely related to vasoconstrictor responsiveness to both NA (r = 0.61, P = 0.01) and TYR (r = 0.52, P = 0.02), such that subjects with lower resting MSNA were more responsive to NA and TYR. We conclude that interindividual variability in vascular adrenergic responsiveness contributes to the balance of factors that maintain normal blood pressure in individuals with differing levels of sympathetic neural activity. Further understanding of this balance may have important implications for our understanding of the pathophysiology of hypertension.

Interactions of plasma osmolality with arterial and central venous pressures in control of sympathetic activity and heart rate in humans.

Plasma osmolality alters control of sympathetic activity and heart rate in animal models; however, it is unknown whether physiological increases in plasma osmolality have such influences in humans and what effect concurrent changes in central venous and/or arterial pressures may have. We tested whether physiological increases in plasma osmolality (similar to those during exercise dehydration) alter control of muscle sympathetic nerve activity (MSNA) and heart rate (HR) in humans. We studied 17 healthy young adults (7 women, 10 men) at baseline and during arterial pressure (AP) transients induced by sequential injections of nitroprusside and phenylephrine, under three conditions: control (C), after 1 ml/kg intravenous hypertonic saline (HT1), and after 2 ml/kg hypertonic saline (HT2). We continuously measured HR, AP, central venous pressure (CVP; peripherally inserted central catheter) and MSNA (peroneal microneurography) in all conditions. Plasma osmolality increased from 287 +/- 1 mosmol/kg in C to 290 +/- 1 mosmol/kg in HT1 (P < 0.05) but did not increase further in HT2 (291 +/- 1 mosmol/kg; P > 0.05 vs. C). Mean AP and CVP were similar between C and HT1, but both increased slightly in HT2. HR increased slightly but significantly during both HT1 and HT2 vs. C (P < 0.05). Sensitivity of baroreflex control of MSNA was significantly increased vs. C in HT1 [-7.59 +/- 0.97 (HT1) vs. -5.85 +/- 0.63 (C) arbitrary units (au).beat(-1).mmHg(-1); P < 0.01] but was not different in HT2 (-6.55 +/- 0.94 au.beat(-1).mmHg(-1)). We conclude that physiological changes in plasma osmolality significantly alter control of MSNA and HR in humans, and that this influence can be modified by CVP and AP.

Balance between cardiac output and sympathetic nerve activity in resting humans: role in arterial pressure regulation.

Large, reproducible interindividual differences exist in resting sympathetic nerve activity among normotensive humans with similar arterial pressures, resulting in a lack of correlation between muscle sympathetic nerve activity (MSNA) and arterial pressure among individuals. Although it is known that the arterial pressure is the main short-term determinant of MSNA in humans via the arterial baroreflex, the lack of correlation among individuals suggests that the level of arterial pressure is not the only important input in regulation of MSNA in humans. We studied the relationship between cardiac output (CO) and baroreflex control of sympathetic activity by measuring MSNA (peroneal microneurography), arterial pressure (arterial catheter), CO (acetylene uptake technique) and heart rate (HR; electrocardiogram) in 17 healthy young men during 20 min of supine rest. Across individuals, MSNA did not correlate with mean or diastolic blood pressure (r<0.01 for both), but displayed a significant negative correlation with CO (r=-0.71, P=0.001). To assess whether CO is related to arterial baroreflex control of MSNA, we constructed a baroreflex threshold diagram for each individual by plotting the percentage occurrence of a sympathetic burst against diastolic pressure. The mid-point of the diagram (T50) at which 50% of cardiac cycles are associated with bursts, was inversely related to CO (r=-0.75, P<0.001) and stroke volume (SV) (r=-0.57, P=0.015). We conclude that dynamic inputs from CO and SV are important in regulation of baroreflex control of MSNA in healthy, normotensive humans. This results in a balance between CO and sympathetically mediated vasoconstriction that may contribute importantly to normal regulation of arterial pressure in humans.

Baroreflex control of muscle sympathetic nerve activity in postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is characterized by excessive tachycardia during orthostasis. To test the hypothesis that patients with POTS have decreased sympathetic neural responses to baroreflex stimuli, we measured heart rate (HR) and muscle sympathetic nerve activity (MSNA) responses to three baroreflex stimuli including vasoactive drug boluses (modified Oxford technique), Valsalva maneuver, and head-up tilt (HUT) in POTS patients and healthy control subjects. The MSNA response to the Valsalva maneuver was significantly greater in the POTS group (controls, 26 +/- 7 vs. POTS, 48 +/- 6% of baseline MSNA/mmHg; P = 0.03). POTS patients also had an exaggerated MSNA response to 30 degrees HUT (controls, 123 +/- 24 vs. POTS, 208 +/- 30% of baseline MSNA; P = 0.03) and tended to have an exaggerated response to 45 degrees HUT (controls, 137 +/- 27 vs. POTS, 248 +/- 58% of baseline MSNA; P = 0.10). Sympathetic baroreflex sensitivity calculated during administration of the vasoactive drug boluses also tended to be greater in the POTS patients; however, this did not reach statistical significance (P = 0.15). Baseline MSNA values during supine rest were not different between the groups (controls, 23 +/- 4 vs. POTS, 16 +/- 5 bursts/100 heartbeats; P = 0.30); however, resting HR was significantly higher in the POTS group (controls, 58 +/- 3 vs. POTS, 82 +/- 4 beats/min; P = 0.0001). Our results suggest that POTS patients have exaggerated MSNA responses to baroreflex challenges compared with healthy control subjects, although resting supine MSNA values did not differ between the groups.

Influence of increased central venous pressure on baroreflex control of sympathetic activity in humans.

Volume expansion often ameliorates symptoms of orthostatic intolerance; however, the influence of this increased volume on integrated baroreflex control of vascular sympathetic activity is unknown. We tested whether acute increases in central venous pressure (CVP) diminished subsequent responsiveness of muscle sympathetic nerve activity (MSNA) to rapid changes in arterial pressure. We studied healthy humans under three separate conditions: control, acute 10 degrees head-down tilt (HDT), and saline infusion (SAL). In each condition, heart rate, arterial pressure, CVP, and peroneal MSNA were measured during 5 min of rest and then during rapid changes in arterial pressure induced by sequential boluses of nitroprusside and phenylephrine (modified Oxford technique). Sensitivities of integrated baroreflex control of MSNA and heart rate were assessed as the slopes of the linear portions of the MSNA-diastolic blood pressure and R-R interval-systolic pressure relations, respectively. CVP increased approximately 2 mmHg in both SAL and HDT conditions. Resting heart rate and mean arterial pressure were not different among trials. Sensitivity of baroreflex control of MSNA was decreased in both SAL and HDT condition, respectively: -3.1 +/- 0.6 and -3.3 +/- 1.0 versus -5.0 +/- 0.6 units.beat(-1).mmHg(-1) (P < 0.05 for SAL and HDT vs. control). Sensitivity of baroreflex control of the heart was not different among conditions. Our results indicate that small increases in CVP decrease the sensitivity of integrated baroreflex control of sympathetic nerve activity in healthy humans.