Cerebrovascular reactivity after cessation of menopausal hormone treatment.

OBJECTIVE: Women who are currently using menopausal hormone therapy (MHT) have higher cerebrovascular reactivity when compared with postmenopausal women who are not taking MHT; however, the effect of cessation of MHT on cerebrovascular reactivity is not known. Given that MHT can have structural and activational effects on vascular function, this study was performed to characterize cerebrovascular reactivity following cessation of MHT in women at low risk for cerebrovascular disease. METHODS: Cerebrovascular reactivity was measured in a subset of women from the Kronos Early Estrogen Prevention Study (KEEPS) 3 years after cessation of the study drug (oral conjugated equine estrogen, transdermal 17ß-estradiol, or placebo [PLA]). RESULTS: Age, body mass index, and blood pressure were comparable among groups. At rest, the middle cerebral artery velocity (MCAv), cerebrovascular conductance index, mean arterial pressure, and cerebral pulsatility index did not differ among groups. Slope-based summary measures of cerebrovascular reactivity did not differ significantly among groups. However, utilizing repeated-measures modeling, there was a significant upward shift in MCAv responses (p = 0.029) in the combined MHT group compared with the PLA group. CONCLUSION: MHT has a marginal sustained effect on cerebrovascular reactivity when measured 3 years after cessation of hormone treatment.

Sex differences in elite swimming with advanced age are less than marathon running.

The sex difference in marathon performance increases with finishing place and age of the runner but whether this occurs among swimmers is unknown. The purpose was to compare sex differences in swimming velocity across world record place (1st-10th), age group (25-89 years), and event distance. We also compared sex differences between freestyle swimming and marathon running. The world's top 10 swimming times of both sexes for World Championship freestyle stroke, backstroke, breaststroke, and butterfly events and the world's top 10 marathon times in 5-year age groups were obtained. Men were faster than women for freestyle (12.4 ± 4.2%), backstroke (12.8 ± 3.0%), and breaststroke (14.5 ± 3.2%), with the greatest sex differences for butterfly (16.7 ± 5.5%). The sex difference in swimming velocity increased across world record place for freestyle (P < 0.001), breaststroke, and butterfly for all age groups and distances (P < 0.001) because of a greater relative drop-off between first and 10th place for women. The sex difference in marathon running increased with the world record place and the sex difference for marathon running was greater than for swimming (P < 0.001). The sex difference in swimming increased with world record place and age, but was less than for marathon running. Collectively, these results suggest more depth in women's swimming than marathon running.

Determination of blood volume by pulse CO-oximetry.

The objective of this study was to determine whether changes in carboxyhaemoglobin (COHb) saturation following carbon monoxide (CO) rebreathing can be accurately detected by pulse CO-oximetry in order to determine blood volume. Noninvasive measurements of carboxyhaemoglobin saturation (SpCO) were continuously monitored by pulse CO-oximetry before, during and following 2 min of CO rebreathing. Reproducibility and accuracy of noninvasive blood volume measurements were determined in 16 healthy non-smoking individuals (15 males, age: 28 ± 2 years, body mass index: 25.4 ± 0.6 kg m(-2)) through comparison with blood volume measurements calculated from invasive measurements of COHb saturation. The coefficient of variation for noninvasive blood volume measurements performed on separate days was 15.1% which decreases to 9.1% when measurements were performed on the same day. Changes in COHb saturation and SpCO following CO rebreathing were strongly correlated (r = 0.90, p < 0.01), resulting in a significant correlation between invasive and noninvasive blood volume measurements (r = 0.83, p = 0.02). Changes in SpCO following CO rebreathing can be accurately detected by pulse CO-oximetry, which could potentially provide a simplified, convenient and reproducible method to rapidly determine blood volume in healthy individuals.

The two-hour marathon: who and when?

Whoever breaks 2 h will likely have outstanding running economy and small body size along with exposure to high altitude and significant physical activity early in life. However, neither of these factors nor any specific suite of genotypes appear to be obligatory for a time this fast. Current trends suggest that an East African will be the first to break 2 h. However periods of regional dominance in distance running are not unique to the East Africans: athletes from Finland, Eastern Europe, Australia, and New Zealand have all had extended periods of success at a range of distances. From a physiological perspective, more information is clearly needed on the relationship between VO(2max) and running economy and the influence of running economy and body size on thermoregulation and fuel use.

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.

Disparity in regional and systemic circulatory capacities: do they affect the regulation of the circulation?

In this review we integrate ideas about regional and systemic circulatory capacities and the balance between skeletal muscle blood flow and cardiac output during heavy exercise in humans. In the first part of the review we discuss issues related to the pumping capacity of the heart and the vasodilator capacity of skeletal muscle. The issue is that skeletal muscle has a vast capacity to vasodilate during exercise [approximately 300 mL (100 g)(-1) min(-1)], but the pumping capacity of the human heart is limited to 20-25 L min(-1) in untrained subjects and approximately 35 L min(-1) in elite endurance athletes. This means that when more than 7-10 kg of muscle is active during heavy exercise, perfusion of the contracting muscles must be limited or mean arterial pressure will fall. In the second part of the review we emphasize that there is an interplay between sympathetic vasoconstriction and metabolic vasodilation that limits blood flow to contracting muscles to maintain mean arterial pressure. Vasoconstriction in larger vessels continues while constriction in smaller vessels is blunted permitting total muscle blood flow to be limited but distributed more optimally. This interplay between sympathetic constriction and metabolic dilation during heavy whole-body exercise is likely responsible for the very high levels of oxygen extraction seen in contracting skeletal muscle. It also explains why infusing vasodilators in the contracting muscles does not increase oxygen uptake in the muscle. Finally, when approximately 80% of cardiac output is directed towards contracting skeletal muscle modest vasoconstriction in the active muscles can evoke marked changes in arterial pressure.

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.

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.

Gait and balance of transfemoral amputees using passive mechanical and microprocessor-controlled prosthetic knees.

BACKGROUND: Microprocessor-controlled knee joints appeared on the market a decade ago. These joints are more sophisticated and more expensive than mechanical ones. The literature is contradictory regarding changes in gait and balance when using these sophisticated devices. METHODS: This study employed a crossover design to assess the comparative performance of a passive mechanical knee prosthesis compared to a microprocessor-controlled knee joint in 15 subjects with an above-knee amputation. Objective measurements of gait and balance were obtained. RESULTS: Subjects demonstrated significantly improved gait characteristics after receiving the microprocessor-controlled prosthetic knee joint (p<0.01). Improvements in gait were a transition from a hyperextended knee to a flexed knee during loading response which resulted in a change from an internal knee flexor moment to a knee extensor moment. The participants' balance also improved (p<0.01). All conditions of the Sensory Organization Test (SOT) demonstrated improvements in equilibrium score. The composite score also increased. CONCLUSIONS: Transfemoral amputees using a microprocessor-controlled knee have significant improvements in gait and balance.

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.

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.

Glucose-induced suppression of endogenous glucose production: dynamic response to differing glucose profiles.

To determine whether, in the presence of constant insulin concentrations, a change in glucose concentrations results in a reciprocal change in endogenous glucose production (EGP), glucagon ( approximately 130 ng/l) and insulin ( approximately 65 pmol/l) were maintained at constant "basal" concentrations while glucose was clamped at approximately 5.3 mM (euglycemia), approximately 7.0 mM (sustained hyperglycemia; n = 10), or varied to create a "postprandial" profile (profile; n = 11). EGP fell slowly over the 6 h of the euglycemia study. In contrast, an increase in glucose to 7.13 +/- 0.3 mmol/l resulted in prompt and sustained suppression of EGP to 9.65 +/- 1.21 micromol x kg-1 x min-1. On the profile study day, glucose increased to a peak of 11.2 +/- 0.5 mmol/l, and EGP decreased to a nadir of 6.79 +/- 2.54 micromol x kg-1 x min-1 by 60 min. Thereafter, the fall in glucose was accompanied by a reciprocal rise in EGP to rates that did not differ from those observed on the euglycemic study day (11.31 +/- 2.45 vs. 12.11 +/- 3.21 micromol x kg-1 x min-1). Although the pattern of change of glucose differed markedly on the sustained hyperglycemia and profile study days, by design the area above basal did not. This resulted in equivalent suppression of EGP below basal (-1,952 +/- 204 vs. -1,922 +/- 246 mmol. kg-1. 6 h-1). These data demonstrate that, in the presence of a constant basal insulin concentration, changes in glucose within the physiological range rapidly and reciprocally regulate EGP.

Sympathetic vasodilation in human muscle.

The idea that there might be sympathetic vasodilator nerves to skeletal muscle is an old concept that fits with the archaic 'fight or flight' model of the sympathetic nervous system. Clear evidence for vasodilator nerves to skeletal muscle began to emerge in animals during the 1930s, when stimulation of selected brainstem areas was shown to evoke hypertension, tachycardia and skeletal muscle vasodilation (i.e. the 'defense reaction'). By the 1940s and 1950s this idea was well established and it was shown in animals that the sympathetic dilator nerves to muscles were cholinergic. During this time, circumstantial evidence began to suggest the existence of sympathetic cholinergic vasodilator fibres in human skeletal muscle. In this context, the well- known forearm vasodilator response to mental stress was shown to be atropine-sensitive, and absent after surgical sympathectomy. However, while there was clear histological evidence for sympathetic cholinergic dilator fibres in animal muscle, such evidence was not seen in humans. Additionally, attempts to record from sympathetic dilator fibres human muscle have never demonstrated clear evidence for dilator nerve traffic, and many 'sympathetic dilator' responses are still present after local anaesthetic nerve block. More recently, the skeletal muscle dilator response to sympathoexcitatory manoeuvres in both humans and animals appears to be nitric oxide (NO)-dependent. While there are clearly atropine-sensitive and NO-dependent dilator nerves to skeletal muscles in animals, our current thinking is that most 'sympathetic dilator' responses in human muscle are due to adrenaline or local cholinergic mechanisms acting to stimulate NO release from the vascular endothelium.

Cutaneous vascular function during acute hyperglycemia in healthy young adults.

Although it is well established that severe chronic hyperglycemia is associated with microvascular disease, it is not known whether transient hyperglycemia similar to that observed with impaired glucose tolerance or early Type 2 diabetes contributes to this pathology by altering microvascular function. To test the hypothesis that acute hyperglycemia decreases microvascular vasodilator responsiveness in human skin, we measured the cutaneous vasodilator response to local warming. This response can be divided into two phases, an initial peak that relies predominantly on local sensory nerves and a second slower phase that is largely dependent on endothelial nitric oxide. We reasoned that a change in one or both phases would indicate a change in the corresponding mechanism(s) with hyperglycemia. Twenty-eight healthy volunteers (14 women, 14 men) were randomly divided into three groups, corresponding to 6 h of euglycemia (n = 8), 6 h when glucose was clamped at approximately 7 mmol/l (n = 10), or 6 h when glucose was varied to mimic a postprandial pattern (i.e., peak glucose approximately 11.1 mmol/l) commonly observed in individuals with impaired glucose tolerance (n = 10). Insulin concentrations in all instances were maintained at approximately 65 pmol/l by means of continuous infusions of somatostatin and insulin. Glucagon and growth hormone were also continuously infused to maintain their basal concentrations. Despite substantial differences in both the level and pattern of glucose concentrations, neither maximum cutaneous vasodilation nor the pattern of the vasodilator response to local warming differed over the 6 h of study. We conclude that acute hyperglycemia similar to levels commonly observed in people with either early Type 2 diabetes or impaired glucose tolerance does not alter the vasodilator response to local warming of the skin in humans.