Wanpen Vongpatanasin

Myocardial triglycerides and systolic function in humans: in vivo evaluation by localized proton spectroscopy and cardiac imaging.

Recent experimental data suggest that adiposity directly damages the heart by promoting ectopic deposition of triglyceride, a process known as myocardial steatosis. The goal of this study was to develop and validate proton magnetic resonance spectroscopy (1H MRS) as an in vivo tool to measure myocardial lipid content. Complementary studies in rat tissue ex vivo and in 15 healthy humans in vivo provided evidence that 1H MRS constitutes a reproducible technique for the measurement of myocardial triglyceride. In myocardial tissue from Zucker rats, the 1H MRS measurement of triglyceride matched that obtained by biochemical measurement (P < 0.001). In human subjects triglyceride was evident in the hearts of even the very lean individuals and was elevated in overweight and obese subjects. Increased myocardial triglyceride content was accompanied by elevated LV mass and suppressed septal wall thickening as measured by cardiac imaging. Magn Reson Med 49:417–423, 2003.

The Eisenmenger Syndrome in Adults

In 1897, Vicktor Eisenmenger described a patient with cyanosis and dyspnea since infancy who died of massive hemoptysis at 32 years of age. Postmortem examination showed a ventricular septal defect and severe pulmonary vascular disease [1]. In 1958, Paul Wood coined the term Eisenmenger complex to describe pulmonary hypertension at the systemic level due to a high pulmonary vascular resistance, with reversed or bidirectional shunting through a large ventricular septal defect [2]. Subsequently, the term Eisenmenger syndrome has been used to describe pulmonary vascular disease and cyanosis resulting from any systemic-to-pulmonary circulation connection (such as an atrial septal defect, ventricular septal defect, patent ductus arteriosus, or aortopulmonary window). Pathophysiology We reviewed the literature on the pathophysiology, clinical features, natural history, prognosis, and management of the Eisenmenger syndrome in adults. English-language articles from 1966 to the present were identified through a search of the MEDLINE database by using the terms Eisenmenger, congenital heart disease, and pulmonary hypertension. We also included selected cross-referenced articles. Articles on the pathophysiology, clinical presentation, evaluation, natural history, complications, and treatment of the Eisenmenger syndrome in adults were selected, and descriptive and analytical data relevant to the practicing physician were manually extracted. In patients with intracardiac shunting, blood initially shunts from the systemic to the pulmonary circulation (so-called left-to-right shunting) because the resistance in the former is higher. If the defect is large and the left-to-right shunting is sustained (for example, over months to years), exposure of the pulmonary vasculature to systemic arterial pressure or increased blood flow leads to progressive morphologic changes in the microvasculature (Figure 1), including arteriolar medial hypertrophy, intimal proliferation and fibrosis, and capillary and arteriolar occlusion. Eventually, plexiform lesions and necrotizing arteritis occur [3], with resultant obliteration of pulmonary arterioles and capillaries and increased pulmonary vascular resistance. Finally, pulmonary vascular resistance and pulmonary arterial pressure approach systemic vascular resistance and systemic arterial pressure, and the shunt reverses. Figure 1. Pathophysiology of the Eisenmenger syndrome. The pathophysiologic mechanisms responsible for the development of pulmonary microvascular changes in patients with the Eisenmenger syndrome are not completely known. In experimental animals, pulmonary microvascular injury stimulates the production of elastase enzymes and growth factors (that is, insulin-like growth factor I and transforming growth factor), which may cause medial hypertrophy, cellular intimal proliferation, progressive occlusion, and eventual destruction of small arterioles [4-6]. Endothelium-dependent pulmonary arteriolar relaxation is impaired, pulmonary endothelin production is increased, and plasma thromboxane B2 concentrations are elevated in patients with the Eisenmenger syndrome, suggesting that endothelial dysfunction or platelet activation may play a causative role in this condition [7-11]. Clinical Presentation Patients with the Eisenmenger syndrome often have a history of transient pulmonary congestion in infancy as a result of a substantial pulmonary blood flow caused by a large left-to-right intracardiac shunt. Later in infancy or in early childhood, as pulmonary vascular resistance increases, pulmonary blood flow declines, and symptoms of pulmonary congestion abate. When the shunt reverses (that is, when right-to-left shunting occurs), cyanosis and erythrocytosis develop. Less commonly, patients develop the Eisenmenger syndrome in adulthood without obvious symptoms during childhood and seek medical attention because of progressive fatigue, dyspnea, or cyanosis. Eventually, most patients with the Eisenmenger syndrome have one or more of the following conditions: 1) symptoms of a low systemic output [such as dyspnea on exertion, fatigue, or syncope], 2) subtle neurologic abnormalities [such as headache, dizziness, or visual disturbances] due to erythrocytosis and hyperviscosity, or 3) symptoms of congestive heart failure. In addition, arrhythmias and hemoptysis are common, and the former may lead to sudden death. Hemoptysis is caused by pulmonary infarction; rupture of a pulmonary artery dilated by aneurysm or a thin-walled pulmonary arteriole; or bleeding diathesis, which often manifests initially as mucosal (that is, epistaxis or gingival) bleeding. Cerebrovascular accidents frequently occur as a result of hyperviscosity, paradoxical embolism, or a cerebral abscess. Physical Examination Physical examination of the patient with the Eisenmenger syndrome reveals central cyanosis and clubbing of the nail bed. If systemic vascular resistance falls, as may occur with hot weather, exercise, fever, or systemic infection, the magnitude of right-to-left shunting and cyanosis increases. Patients with a patent ductus arteriosus may have normal, pink nail beds on the right hand and cyanosis and clubbing of the nail beds on the left hand and both feet (so-called differential cyanosis). This occurs because venous blood shunts through the ductus and enters the aorta distal to the right subclavian artery. The jugular venous pressure may be normal or elevated, with a prominent V wave if tricuspid regurgitation is present. The arterial pulse is usually diminished or normal [2]. Signs of pulmonary hypertension, including a right parasternal heave, a palpable pulmonary valve closure, a right-sided fourth heart sound, and a loud pulmonic component of the second heart sound, are uniformly present. The second heart sound may be single (such as with ventricular septal defect) or widely split (such as with atrial septal defect). A high-pitched, diastolic, decrescendo murmur of pulmonic regurgitation (Graham Steell murmur) is often audible, and a holosystolic murmur of tricuspid regurgitation may occur when right heart failure intervenes. In many patients, a pulmonary ejection click and soft systolic ejection murmur are audible and are attributable to dilation of the main pulmonary artery. Murmurs usually associated with ventricular septal defect or patent ductus arteriosus are absent. The lung fields are clear, and peripheral edema is absent unless right ventricular systolic dysfunction ensues. Noninvasive and Invasive Evaluation In patients with the Eisenmenger syndrome, 12-lead electrocardiography shows right atrial enlargement and right ventricular or biventricular hypertrophy. Atrial arrhythmias are often present, especially in patients with atrial septal defects. Chest radiography usually reveals prominent, dilated central pulmonary arteries with a reduction in the size and number of peripheral vessels. Calcification of the pulmonary arteries or ductus arteriosus, signifying atherosclerosis, may be visualized. Patients with the Eisenmenger syndrome who have ventricular septal defect or patent ductus arteriosus usually have a normal or minimally increased cardiothoracic ratio, whereas most patients with the syndrome who have atrial septal defect have cardiomegaly [12] with dilation attributed to right ventricular enlargement caused by previously increased flow [2]. Two-dimensional echocardiography is helpful in visualizing intracardiac defects and identifying associated cardiac or valvular abnormalities. Color flow Doppler imaging usually can detect intracardiac shunting. However, because the pulmonary and systemic arterial pressures are similar in patients with the Eisenmenger syndrome, the pressure gradient and flow across the intracardiac defect may be small and therefore difficult to visualize by color flow Doppler imaging [13]. In such patients, contrast echocardiography should be performed. An intravenously injected contrast agent (such as agitated normal saline, indocyanine green, or hydrogen peroxide) quickly appears in the left heart chambers when a right-to-left intracardiac shunt is present; the magnitude of intracardiac right-to-left shunting can be assessed qualitatively as small, moderate, or large but cannot be quantitated precisely [14, 15]. Transesophageal echocardiography can be performed safely in patients with the Eisenmenger syndrome and is superior to the transthoracic approach for detecting atrial septal abnormalities or patent ductus arteriosus [13, 16]. It is valuable for evaluating patients with unexplained pulmonary hypertension. Transesophageal echocardiography should be performed in patients with the Eisenmenger syndrome who are being considered for lung transplantation because it provides additional diagnostic information (such as the presence of additional unsuspected intracardiac defects, unrecognized intracardiac shunts, or proximal pulmonary artery thrombus) that may alter surgical intervention in approximately 25% of patients [16, 17]. Magnetic resonance imaging can identify intracardiac defects and patent ductus arteriosus and is particularly useful in patients with previous cardiac surgery in whom echocardiographic evaluation is technically difficult [18-21]. Although this test provides excellent visualization of the pulmonary and systemic arterial systems and cardiac chambers, it is limited in its ability to identify structural valvular abnormalities. Cine magnetic resonance imaging can detect right-to-left or bidirectional intracardiac shunting but has not yet proven useful in assessing the magnitude of shunting. In patients suspected of having the Eisenmenger syndrome, cardiac catheterization should be performed to detect, localize, and quantitate intracardiac shunting and to determine the severity of pulmonary vascular disease [15]. The assessment of pulmonary vascular resistance before and after administration of a pulmonary arteriolar vasodilator (that is, 100% oxygen o

High-Density Lipoprotein Promotes Endothelial Cell Migration and Reendothelialization via Scavenger Receptor-B Type I

Vascular disease risk is inversely related to circulating levels of high-density lipoprotein (HDL) cholesterol. However, the mechanisms by which HDL provides vascular protection are unclear. The disruption of endothelial monolayer integrity is an important contributing factor in multiple vascular disorders, and vascular lesion severity is tempered by enhanced endothelial repair. Here, we show that HDL stimulates endothelial cell migration in vitro in a nitric oxide-independent manner via scavenger receptor B type I (SR-BI)-mediated activation of Rac GTPase. This process does not require HDL cargo molecules, and it is dependent on the activation of Src kinases, phosphatidylinositol 3-kinase, and p44/42 mitogen-activated protein kinases. Rapid initial stimulation of lamellipodia formation by HDL via SR-BI, Src kinases, and Rac is also demonstrable. Paralleling the in vitro findings, carotid artery reendothelialization after perivascular electric injury is blunted in apolipoprotein A-I−/− mice, and reconstitution of apolipoprotein A-I expression rescues normal reendothelialization. Furthermore, reendothelialization is impaired in SR-BI−/− mice. Thus, HDL stimulates endothelial cell migration via SR-BI-initiated signaling, and these mechanisms promote endothelial monolayer integrity in vivo.

Transdermal Estrogen Replacement Therapy Decreases Sympathetic Activity in Postmenopausal Women

Background—Menopause heralds a dramatic increase in incident hypertension, suggesting a protective effect of estrogen on blood pressure (BP). In female rats, estrogen has been shown to decrease sympathetic nerve discharge (SND) and BP. SND, however, has not been recorded during estrogen replacement therapy (ERT) in humans. Methods and Results—In 12 normotensive postmenopausal women, we conducted a randomized crossover placebo-controlled study to test whether chronic ERT caused a sustained decrease in SND and BP. Twenty-four-hour ambulatory BP, SND, and arterial baroreflex sensitivity were measured before and after 8 weeks of transdermal estradiol (200 &mgr;g/d), oral conjugated estrogens (0.625 mg/d), or placebo. To test the acute effects of estrogen on SND, additional studies were performed in the same women receiving intravenous conjugated estrogens or sublingual estradiol. After 8 weeks of transdermal ERT, the basal rate of SND decreased by 30% (from 40±4 to 27±4 bursts per minute, P =0.0001) and ambulatory diastolic BP fell by 5±2 mm Hg (P =0.0003). In contrast, SND and BP were unaffected either by 8 weeks of oral ERT or by acute estrogen administration. Neither transdermal nor oral ERT had any effects on baroreflex sensitivity. Conclusions—In normotensive postmenopausal women, chronic transdermal ERT decreases SND without augmenting arterial baroreflexes and causes a small but statistically significant decrease in ambulatory BP. Sympathetic inhibition is evident only with chronic rather than acute estrogen administration, implying a genomic mechanism of action. Because the effects of transdermal ERT are larger than those of oral ERT, the route of administration may be an important consideration in optimizing the beneficial effects of ERT on BP and overall cardiovascular health.

Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women

OBJECTIVES We investigated whether the route of estrogen replacement therapy (ET) is the major determinant of C-reactive protein (CRP) in postmenopausal women. BACKGROUND Recent studies demonstrated that oral ET causes a sustained increase in CRP, implicating a proinflammatory effect. Because CRP is synthesized in the liver, we hypothesized that estrogen-induced CRP elevation is related to first-pass hepatic metabolism. METHODS In 21 postmenopausal women, we conducted a randomized, crossover, placebo-controlled study to compare the effects of transdermal versus oral ET on CRP and inflammatory cytokines. We measured CRP, interleukin (IL)-1-beta, IL-6, and tumor necrosis factor-alpha before and after eight weeks of transdermal estradiol (E(2)) (100 microg/day), oral conjugated estrogen (CEE) (0.625 mg/day), or placebo. Insulin-like growth factor-1 (IGF-1), a hepatic-derived anabolic peptide, was also measured. RESULTS Transdermal E(2) had no effect on CRP or IGF-1 levels. In contrast, eight weeks of oral conjugated estrogens caused a more than twofold increase in CRP and a significant reduction in IGF-1 (p < 0.01) in the same women. The magnitude of increase in CRP was inversely correlated to the decrease in IGF-1 (r = -0.49, p = 0.008). Neither transdermal E(2) nor oral CEE had any effects on the plasma concentrations of cytokines that promote CRP synthesis. CONCLUSIONS In postmenopausal women, oral but not transdermal ET increased CRP by a first-pass hepatic effect. An increase in CRP levels is accompanied by a reduction in IGF-1, an anti-inflammatory growth factor. Because CRP is a powerful predictor of an adverse prognosis in otherwise healthy postmenopausal women, the route of administration may be an important consideration in minimizing the adverse effects of ET on cardiovascular outcomes.

Cocaine Stimulates the Human Cardiovascular System via a Central Mechanism of Action

BACKGROUND Cocaine is thought to stimulate the cardiovascular system by blocking peripheral norepinephrine reuptake. This study was designed to test the novel hypotheses that cocaine also stimulates the human cardiovascular system by (1) increasing central sympathetic outflow, or (2) decreasing parasympathetic control of heart rate. METHODS AND RESULTS In 14 healthy cocaine-naive humans, we measured blood pressure, heart rate, and skin sympathetic nerve activity (SNA) with intraneural microelectrodes before, during, and for 90 minutes after intranasal cocaine (2 mg/kg, n=7) or lidocaine (2 mg/kg, n=7). Intranasal cocaine caused an initial but transient 3. 3-fold increase in skin SNA during the period of intranasal administration followed by a sustained 2.4-fold increase lasting for up to 90 minutes after cocaine. Unlike cocaine, intranasal lidocaine caused only a small transient increase in skin SNA due to local nasal irritation. The cocaine-induced increase in SNA was accompanied by decreased skin blood flow, increased skin vascular resistance, and increased heart rate. In 11 additional subjects, we showed that the cocaine-induced increase in heart rate was eliminated by beta-adrenergic receptor blockade (propranolol) but unaffected by muscarinic receptor blockade (atropine), indicating sympathetic mediation. CONCLUSIONS These studies provide direct microneurographic evidence in humans that intranasal cocaine stimulates central sympathetic outflow. This central sympathetic activation appears to be targeted not only to the cutaneous circulation promoting peripheral vasoconstriction but also to the heart promoting tachycardia.

Overweight and Sympathetic Overactivity in Black Americans

A large body of clinical investigation implicates an important role for the sympathetic nervous system in linking obesity with hypertension. However, the experimental support for this hypothesis is derived from strictly white cohorts. The goal of this study was to determine whether being overweight begets sympathetic overactivity in black Americans, the ethnic minority at highest risk for hypertension. We recorded postganglionic sympathetic nerve discharge with microelectrodes in muscle nerve fascicles of the peroneal nerve in 92 normotensive young adult black men and women within a wide range of body mass index. The same experiments were performed in a control group of 45 normotensive white men and women of similar ages and body mass indices. The major new findings are 2-fold. First, in young, normotensive, overtly healthy black women, being overweight begets sympathetic overactivity (r =0.45, P =0.0009), a putative intermediate phenotype for incident hypertension. Second, in black men, sympathetic nerve discharge is dissociated from body mass index (r =0.03, P =NS). This dissociation is explained in part by a 20% to 40% higher rate of sympathetic nerve discharge in lean black men compared with lean white men and lean black and white women (28±3 versus 18±2, 21±2, and 17±2 bursts/min, respectively;P <0.05). Sympathetic nerve discharge in lean black men is comparable to that of overweight black men and women as well as white men and women. These data provide the first microneurographic evidence for tonic central sympathetic overactivity in blacks, both adiposity-related sympathetic overactivity in black women and adiposity-independent sympathetic overactivity in black men.

Relationship Between Sympathetic Baroreflex Sensitivity and Arterial Stiffness in Elderly Men and Women

Previous human studies have shown that large-artery stiffness contributes to an age-related decrease in cardiovagal baroreflex sensitivity. Whether this is also true with sympathetic baroreflex sensitivity is unknown. We tested the hypothesis that sympathetic baroreflex sensitivity is associated with the stiffness of baroreceptor segments (the carotid artery and the aorta) in elderly individuals and that sex affects this relationship. Sympathetic baroreflex sensitivity was assessed from the spontaneous changes in beat-by-beat diastolic pressure and corresponding muscle sympathetic nerve activity (microneurography) during supine rest in 30 men (mean±SEM: 69±1 years) and 31 women (68±1 years). Carotid artery stiffness (B-mode ultrasonography) and aortic stiffness (MRI) were also determined. We found that elderly women had lower sympathetic baroreflex sensitivity than elderly men (−2.33±0.25 versus −3.32±0.25 bursts · 100 beats−1 · mm Hg−1; P=0.007). &bgr;-Stiffness indices of the carotid artery and the aorta were greater in elderly women than in men (6.68±0.48 versus 5.10±0.50 and 4.03±0.47 versus 2.68±0.42; both P<0.050). Sympathetic baroreflex sensitivity was inversely correlated with carotid artery stiffness in both men and women (r=0.49 and 0.50; both P<0.05), whereas this relation was shifted in parallel upward (toward a reduced sensitivity) in women with no changes in the slope (0.26 versus 0.24 arbitrary units). Sympathetic baroreflex sensitivity and aortic stiffness showed similar trends. Thus, barosensory artery stiffness seems to be one independent determinant of sympathetic baroreflex sensitivity in elderly men and women. The lower sympathetic baroreflex sensitivity in elderly women may predispose them to an increased prevalence of hypertension.

Mechanism of Cocaine-Induced Hyperthermia in Humans

Context The cause of hyperthermia in cocaine abuse is not well understood. Both excess heat generation and defective heat dissipation are potential causes of fatal hyperthermia. Contribution Nasal administration of cocaine causes greater increase in core body temperature, decrease in heat perception, and greater impairment of sweating and skin blood flow compared with nasal lidocaine administration. Implications Excessive heat production, impaired heat dissipation, and alteration of behavioral responses to increased body temperature may lead to fatal hyperthermia in cocaine abusers. The Editors Cocaine abuse is a major cause of life-threatening cardiovascular emergencies, including hypertensive crisis, acute myocardial infarction, and ventricular arrhythmias. The lethal effect of cocaine is unique among those of other illicit drugs because it is related not only to dose but also to cocaines propensity to cause hyperthermia. Although fatal cocaine overdose typically is associated with high blood cocaine levels (3 to 6 mg/L) (1), cocaine-related deaths can also occur when hyperthermia is present at blood levels 10 to 20 times lower (2). The intrinsic thermogenic property of cocaine underlies recent epidemiologic data indicating that mortality rates for cocaine overdose increase substantially in hot weather (3). This temperature-dependent increase in mortality rates is specific to cocaine and is not seen with opiates or other illicit drugs. These clinical observations are bolstered by experiments in dogs demonstrating that cocaine-induced death can be eliminated by multiple strategies that prevent hyperthermia (4). In humans, however, the underlying mechanisms mediating cocaine-induced hyperthermia are poorly understood. The hyperthermic properties of cocaine have been attributed largely to a hypermetabolic state (agitation with increased locomotor activity) that increases heat production (5). Indeed, cocaine-induced hyperthermia has been likened to two other syndromes, neuroleptic malignant syndrome and malignant hyperthermia, that are characterized by hyperpyrexia, delirium, tachycardia, and elevated blood pressure (6, 7). In both of those syndromes, excessive heat production due to involuntary muscle contraction is sufficient to raise body temperature even in a cool environment (for example, an operating room). In contrast, cocaine-induced hyperthermia is seen primarily in the setting of high ambient temperatures. We therefore hypothesized that, in addition to increased heat production, impaired heat dissipation is another important mechanism contributing to the hyperthermic properties of cocaine. When body temperature increases above thermoregulatory set points, heat dissipation depends on both autonomic and behavioral adjustments. The major autonomic adjustments include activation of sympathetic cholinergic fibers that leads to sweating and cutaneous va sodilation (8). The behavioral adjustments are prompted by thermal discomfort and include heat avoidance and external cooling. In humans, these simple behavioral responses can be more important than autonomic adjustments in maintaining normal body temperature during heat stress (9). We sought to test the effect of cocaine on thermoregulatory adjustments in humans. Because cocaine has a profound influence on both cardiovascular and cognitive function, we conducted a randomized, placebo-controlled study to assess the effects of a low, noneuphoric dose of intranasal cocaine on autonomic and behavioral thermoregulation in healthy cocaine-naive volunteers. Methods Participants We studied 7 healthy male and female volunteers who ranged in age from 23 to 37 years. The Institutional Review Board of the University of Texas Southwestern Medical Center at Dallas, Texas, approved the protocol, and all volunteers provided written informed consent. All participants were normotensive and had no history of cardiovascular disease, cocaine abuse, or other recreational drug use. No participant was taking prescription or nonprescription drugs with cardiovascular or autonomic effects. Participants refrained from smoking cigarettes or drinking alcohol- or caffeine-containing beverages for at least 12 hours before the experiment. Measurements Internal temperature was measured by using a thermistor placed in the esophagus at a depth equal to 25% of each participants standing height, and skin temperature was measured from the weighted electrical average of six thermocouples attached to the skin. Each participant wore a tube-lined suit that controlled skin temperature by changing the temperature of the water perfusing the suit. The suit covered the entire body surface with the exception of the head, arms, and feet. We assessed skin blood flow from each participants forearm during heat stress. The water-perfused suit did not cover the forearm where skin blood flow measurements were obtained; thus, any change in skin blood flow during heat stress was not directly related to mechanisms associated with local heating. Skin blood flow was measured by using multifiber laser Doppler flowmeter (Perimed, North Royalton, Ohio). Heart rate was obtained from the electrocardiogram by using a cardiotachometer (CWE, Inc., Ardmore, Pennsylvania), and blood pressure was obtained by using the oscillometric technique (Welch Allyn, Beaverton, Oregon). Mean arterial blood pressure was calculated as one third of the pulse pressure plus diastolic blood pressure. Cutaneous vascular conductance, which is the reciprocal of vascular resistance, was calculated from the ratio of the laser Doppler signal to mean arterial pressure. Forearm sweat rate was measured continuously with the ventilated capsule method, in which a capsule with a window of 2.8 cm2 is attached to the surface of the skin. Nitrogen gas is perfused through the capsule at a fixed rate, and as the person begins to sweat, the water on the skin evaporates through the window into the nitrogen gas. The humidity of the effluent nitrogen gas is quantified through a humidity detector downstream from the capsule. The sweat rate is then calculated from the humidity, temperature, and flow of the nitrogen gas. Throughout the heat stress, participants rated thermal sensation by using a standardized 9-point thermal comfort scale ranging from 4.0 (neutral) to 8.0 (unbearably hot) at increments of 0.5 (10). Experimental Protocol All experiments were conducted with the participants in a supine position. In a randomized, double-blind, crossover trial, each participant was exposed to whole-body heating after receiving intranasal cocaine hydrochloride (2 mg/kg of body weight, 10% solution) or lidocaine hydrochloride (2 mg/kg, 10% solution). Lidocaine was used as an internal control for the local anesthetic property of cocaine (11). The experiments were conducted on 2 separate days, at the same time of day, 3 to 6 days apart. The dose of cocaine administered is half the standard dose administered for rhinolaryngologic procedures (12). The heat stress test was performed by perfusing the tube-lined suit with water at 46 C. To assess maximal vasodilator responses, a heater surrounding the laser Doppler flow probe was used on completion of the heat stress to increase local skin temperature to 42 C for 30 minutes. Heating the skin at this temperature and duration elicits maximal cutaneous vasodilation (13). Skin blood flow during the final minutes of this 30-minute procedure was averaged, and maximal cutaneous vascular conductance was then calculated from the ratio of that value and mean arterial blood pressure. Values for cutaneous vascular conductance were then normalized to percentages of maximum for that site (13). Data Collection Temperatures, skin blood flow, and sweat rate data were sampled at 50 Hz (Biopac, Santa Barbara, California). The electrocardiogram was sampled by a cardiotachometer at 1000 Hz, using a multichannel digital data recorder (CWE, Inc.). These values were reduced to 20-second averages before statistical analysis. When cutaneous vascular conductance and sweat rate are plotted relative to esophageal temperature, two important variables can be identified to assess thermoregulatory function (14): the esophageal temperature threshold at which cutaneous vasodilation and sweating begin, and the slope of the line relating progressive elevations in cutaneous vascular conductance and sweating to increasing esophageal temperature. Esophageal temperature thresholds at which cutaneous vascular conductance and sweat rate began to increase were identified from individual plots of esophageal temperature versus cutaneous vascular conductance and esophageal temperature versus sweat rate. These points were selected as the internal temperatures at which pronounced and sustained increases in cutaneous vascular conductance and sweating were evident during the heating procedure. The investigator identifying these thresholds was blinded to the participants and to their experimental conditions (lidocaine or cocaine). Statistical Analysis Statistical comparisons of temperature thresholds and slopes during cocaine and lidocaine administration were performed by using the paired t-test. Differences in responses (internal temperature, skin temperature, cutaneous vascular conductance, and sweat rate) during cocaine and lidocaine administration throughout the heat stress were statistically analyzed by using two-way repeated-measures analysis of variance (SigmaStat 2.0, SPSS Science, Chicago, Illinois). Treatment order was also assessed in the models, and no effect of treatment order on any outcome variables was found. The effects of cocaine on thermal sensation were statistically analyzed by comparing the internal temperature at each perceived heating score between 5.0 and 7.5 using paired t-tests. All values are reported as the mean (SE), and the level for all statistical analyses was set at 0.05. Role of the Funding Sources The funding sources had no role in the design, a

Augmented sympathetic vasoconstriction in exercising forearms of postmenopausal women is reversed by oestrogen therapy

Sympathetic vasoconstriction is normally attenuated in exercising muscles of young men and women. Recent evidence indicates that such modulation, termed functional sympatholysis, may be impaired in older men. Whether a similar impairment occurs in older women, and what role oestrogen deficiency might play in this impairment, are not known. Based on the strong positive correlation between circulating oestrogen levels and functional sympatholysis previously reported in female rats, we hypothesized that sympatholysis would be impaired in oestrogen‐deficient postmenopausal women, and that this impairment would be reversed by oestrogen replacement. To test these hypotheses, we measured vasoconstrictor responses in the forearms of pre‐ and postmenopausal women using near infrared spectroscopy to detect decreases in muscle oxygenation in response to reflex activation of sympathetic nerves evoked by lower body negative pressure (LBNP). In eight premenopausal women, LBNP decreased muscle oxygenation by 20 ± 1% in resting forearm, but only by 3 ± 2% in exercising forearm (P < 0.05). In contrast, in eight postmenopausal women, LBNP decreased muscle oxygenation by 15 ± 3% in resting forearm, and by 12 ± 4% in exercising forearm (P > 0.05). After 1 month of transdermal oestradiol replacement in these women, the normal effect of exercise to blunt sympathetic vasoconstriction was restored (rest, −19 ± 3%; exercise, −2 ± 3%; P < 0.05). These data indicate that functional sympatholysis is impaired in oestrogen‐deficient postmenopausal women. The effect of short‐term unopposed oestrogen replacement to correct this impairment implicates a role for oestrogen in the sympathetic neural control of muscle haemodynamics during exercise.