Peripheral Vascular Responses Research Articles

A Systematic Review of Dynamic Cerebral and Peripheral Endothelial Function in Lacunar Stroke Versus Controls

The etiology of cerebral small vessel disease is unknown. An association with endothelial dysfunction has been suggested. We systematically assessed all relevant studies of dynamic endothelial function in patients with lacunar stroke as a marker of small vessel disease. We searched for studies of cerebral or peripheral vascular reactivity in patients with lacunar or cortical (ie, large artery atheromatous) ischemic stroke or nonstroke control subjects. We calculated standardized mean difference (SMD) in vascular reactivity+/-95% CIs between small vessel disease and control groups. Sixteen publications (974 patients) were included. In lacunar stroke, cerebrovascular reactivity (n=534) was reduced compared with age-matched normal (SMD -0.94, 95% CI -1.17 to -0.70), but not age+risk factor-matched control subjects (SMD 0.08, 95% CI -0.36 to 0.53) or cortical strokes (SMD -0.29, 95% CI -0.69 to 0.11); forearm flow-mediated dilatation (n=401) was reduced compared with age-matched normal control subjects (SMD -1.04, 95% CI -1.33 to -0.75) and age+risk factor-matched control subjects (SMD -0.94, 95% CI -1.26 to -0.61), but not cortical strokes (SMD -0.23, 95% CI -0.55 to 0.08). Endothelial dysfunction is present in patients with lacunar stroke but may simply reflect exposure to vascular risk factors and having a stroke, because a similar degree of dysfunction is found in cortical (large artery atheromatous) stroke. Current data do not confirm that endothelial dysfunction is specific to small vessel stroke. Future studies should include control subjects with nonlacunar stroke.

Peripheral vascular responses to an orthostatic challenge and plasma volume in Parkinson's disease patients with orthostatic hypotension

Orthostatic hypotension (OH) is present in 50% of Parkinson's disease (PD) patients. A reduced peripheral vasoconstriction and an inadequate plasma volume may contribute to OH in these patients. Indeed, plasma volume expansion is considered as an effective therapy. The objective was to compare baseline plasma volume and peripheral vascular responses to an orthostatic challenge in PD patients with OH (PD+OH, n=15) with PD patients without OH (PD‐OH, n=17) and controls (C, n=15). We examined superficial femoral artery blood flow using duplex ultrasound during a 60° head‐up tilt (HUT). Leg vascular resistance (LVR) was calculated. In a subset (9 PD+OH, 9 PD‐OH and 8 C), we determined plasma volume by indicator dilution method with radio‐labeled albumin. We found a lower baseline LVR in PD+OH (0.6±0.3 mmHg/ml/min) compared with PD‐OH (1.2±0.6 mmHg/ml/min) and C (1.3±0.5 mmHg/ml/min). LVR increased during 60° HUT to a similar magnitude in all groups (PD+OH +0.3 to 0.9±0.1; PD‐OH +0.5 to 1.7±0.3; C +0.7 to 2.1±0.3 mmHg/ml/min). Plasma volume was larger in PD+OH (62±3 ml/kg) compared with PD‐OH (54±6 ml/kg) and C (54±8 ml/kg). In conclusion, PD+OH have a lower LVR in combination with a higher plasma volume compared with PD‐OH and C. Although PD+OH increase LVR during 60° HUT to a similar extend as the other groups, they are unable to maintain their blood pressure in an upright position, possibly due to the attenuated basal LVR.

Increased ANG II sensitivity following recovery from acute kidney injury: role of oxidant stress in skeletal muscle resistance arteries

Ischemia-reperfusion (I/R)-induced acute kidney injury (AKI) results in prolonged impairment of peripheral (i.e., nonrenal) vascular function since skeletal muscle resistance arteries derived from rats 5 wk post-I/R injury, show enhanced responses to ANG II stimulation but not other constrictors. Because vascular superoxide increases ANG II sensitivity, we hypothesized that peripheral responsiveness following recovery from AKI was attributable to vascular oxidant stress. Gracilis arteries (GA) isolated from post-I/R rats (approximately 5 wk recovery) showed significantly greater superoxide levels relative to sham-operated controls, as detected by dihydroeithidium, which was further augmented by acute ANG II stimulation in vitro. Hydrogen peroxide measured by dichlorofluorescein was not affected by ANG II. GA derived from postischemic animals manifested significantly greater constrictor responses in vitro to ANG II than GA from sham-operated controls. The addition of the superoxide scavenging reagent Tempol (10(-5) M) normalized the response to values similar to sham-operated controls. Apocynin (10(-6) M) and endothelial denudation nearly abrogated all ANG II-stimulated constrictor activity in GA from post-AKI rats, suggesting an important role for an endothelial-derived source of peripheral oxidative stress. Apocynin treatment in vivo abrogated GA oxidant stress and attenuated ANG II-induced pressor responses post-AKI. Interestingly, gene expression studies in GA vessels indicated a paradoxical reduction in NADPH oxidase subunit and AT(1)-receptor genes and no effect on several antioxidant genes. Taken together, this study demonstrates that AKI alters peripheral vascular responses by increasing oxidant stress, likely in the endothelium, via an undefined mechanism.

Assessment of Vascular Endothelial Function With Peripheral Arterial Tonometry

Endothelial dysfunction is an important component in the pathogenesis of atherosclerosis. The ability to assess the endothelium in a meaningful manner has been the subject of intense investigation over decades. Since the function of endothelial cells is a gauge of vascular health, assessment of vascular function is emerging as a useful tool for predicting cardiovascular risk and as a surrogate outcome measure for cardiovascular reduction intervention studies. This review highlights techniques for assessing endothelial function, focusing on a novel method of determining peripheral vascular reactivity via arterial tonometry.

The effect of allopurinol on the cerebral vasculature of patients with subcortical stroke; a randomized trial

New preventative strategies for stroke are required. One promising strategy is uric acid reduction and xanthine oxidase inhibition with allopurinol. We sought to investigate whether allopurinol improves cerebrovascular reactivity (CVR) following subcortical stroke. We performed a randomized, double-blind, controlled study to investigate the effect of a 3-month course of 300 mg allopurinol once daily vs. placebo on CVR in individuals with recent (within 6 months) subcortical stroke. Participants were randomized on a 1:1 basis. CVR was defined as the percentage change in middle cerebral artery flow velocity following an intravenous injection of 15 mg kg(-1) of acetazolamide. Our primary end-point was the CVR difference between baseline and 3 months. Secondary end-points included measures of peripheral vascular reactivity and blood markers of inflammation and endothelial activation. We enrolled 50 participants; 45 completed the protocol. Baseline serum urate was 0.35 mmol l(-1) (SD 0.1) and 0.34 mmol l(-1) (SD 0.1) in the allopurinol and placebo groups, respectively. There were no serious adverse events related to treatment. CVR did not change following treatment with allopurinol [median CVR change 0.89% after allopurinol (n = 20) and -0.68% after placebo (n = 25); 95% confidence interval for estimated difference in medians -13.4, 25.5, P = 0.64]. Urate was significantly lowered by allopurinol but no change in other secondary end-points was seen. Xanthine oxidase inhibition with allopurinol has previously been shown to improve cerebrovascular function, but no benefit was seen in this study. It may therefore be that previous encouraging findings will not translate into important clinical benefits.

Continuous, non-invasive measurement of the haemodynamic response to submaximal exercise in patients with diabetes mellitus: evidence of impaired cardiac reserve and peripheral vascular response

Background:Reduced exercise capacity in diabetics has been attributed to limitations in cardiac function and microvascular dysfunction leading to impaired oxygen supply and nutritive perfusion to exercising muscles.Objective:To study changes in...

Microcirculatory disturbances – relationship with peripheral vascular reactivity and structure-functional properties of endothelium in systemic sclerosis

Microcirculatory disturbances – relationship with peripheral vascular reactivity and structure- functional properties of endothelium in systemic sclerosis. Objective. To assess basal capillary blood flow and examine degree of microcirculatory disturbances depending on plasma endothelin 1 content and structure-functional status of endothelium in pts with systemic sclerosis (SS). Material and methods. 31 pts with SS (31 female and 3 male) with mean age 48±2,1 years and disease duration 9,9±1,3 years and 15 healthy persons match on age and sex were included. Laser Doppler flowmetry, assessment of plasma endothelin-1 (ET1), peripheral blood circulating endothelial cells (CEC), endothelium-dependent (EDVD) and endothelium-independent vasodilatation (EIVD) was performed. Results. All pts with SS had decrease of capillary perfusion and disturbance of peripheral vessel reactivity in comparison with healthy persons. Microcirculatory disorders intensity in SS was shown to depend on plasma ET1 level. Basal values of ET1 concentration were significantly higher in comparison with control group. Peripheral microcirculation measures tightly correlated with plasma ET1 and CEC what point to systemic character of capillary blood flow disturbances in SS. Conclusion. Microcirculatory disorders intensity in SS depends on degree of structure-functional endothelium changes on peripheral and systemic vessel levels.

Transfer function characteristics of the neural and peripheral arterial baroreflex arcs at rest and during postexercise muscle ischemia in humans

Previous studies have demonstrated an increase in the arterial baroreflex (ABR) control of muscle sympathetic nerve activity (MSNA) during isolated activation of the muscle metaboreflex with postexercise muscle ischemia (PEMI). However, the increased ABR-MSNA control does not appear to manifest in an enhancement in the ABR control of arterial blood pressure (BP), suggesting alterations in the transduction of MSNA into a peripheral vascular response and a subsequent ABR-mediated change in BP. Thus we examined the operating gains of the neural and peripheral arcs of the ABR and their interactive relationship at rest and during muscle metaboreflex activation. In nine healthy subjects, graded isolation of the muscle metaboreflex was achieved by PEMI following isometric handgrip performed at 15% and 30% maximal voluntary contraction (MVC). To obtain the sensitivities of the ABR neural and peripheral arcs, the transfer function gain from BP to MSNA and MSNA to femoral vascular conductance, respectively, was analyzed. No changes from rest were observed in the ABR neural or peripheral arcs during PEMI after 15% MVC handgrip. However, PEMI following 30% MVC handgrip increased the low frequency (LF) transfer function gain between BP and MSNA (ABR neural arc; +58 +/- 28%, P = 0.036), whereas the LF gain between MSNA and femoral vascular conductance (ABR peripheral arc) was decreased from rest (-36 +/- 8%, P = 0.017). These findings suggest that during high-intensity muscle metaboreflex activation an increased ABR gain of the neural arc appears to offset an attenuation of the peripheral arc gain to help maintain the overall ABR control of systemic BP.

The late gestation fetal cardiovascular response to hypoglycaemia is modified by prior peri‐implantation undernutrition in sheep

Undernourished late gestation fetuses display asymmetric growth restriction, suggestive of a redistribution of nutritional resources. The modification of fetal organ blood supply in response to acute hypoxia is well characterized, but it is not known whether similar responses occur in response to acute reductions in nutrition, or if such late gestation responses can be influenced by early gestation nutrition. In pregnant sheep, total nutrient requirements were restricted during the peri-implantation period (PI40, 40%; PI50, 50% of total, days 1-31) or in late gestation (L, 50% total, days 104-postmortem). Control animals were fed 100% nutrient requirements. Fetal organ blood flows were measured at baseline, and during acute fetal hypoglycaemia induced by maternal insulin infusion at 125 dGA. Baseline heart rate was increased in PI40 fetuses. During hypoglycaemia, an initial rise in fetal heart rate was followed by a slower fall. Fetal femoral artery blood flow decreased, and adrenal blood flow and femoral vascular resistance increased in all fetuses during hypoglycaemia. These changes were accompanied by increased fetal plasma adrenaline and cortisol, and reduced plasma insulin levels. The maximum femoral artery blood flow response to hypoglycaemia occurred earlier in PI50 and PI40 compared with control fetuses. The late gestation fetal cardiovascular response to acute hypoglycaemia was consistent with a redistribution of combined ventricular output away from the periphery and towards central organs. One element of the peripheral vascular response was modified by peri-implantation nutrient restriction, indicating that nutritional challenges early in gestation can have an enduring impact on cardiovascular control.

Blood lead (Pb) levels: Further evidence for an environmental mechanism explaining the association between socioeconomic status and psychophysiological dysregulation in children.

The authors recently reported that blood lead (Pb) was a significant mediator for the positive association between socioeconomic status (SES) and peripheral vascular responses to acute stress in children (B. B. Gump et al., 2007). The present study considers the possibility that Pb may also mediate an association between SES and cortisol responses to acute stress. Early childhood Pb exposure was tested as a mediator for cross-sectional associations between SES and cortisol responses. The primary outcome was cortisol responses to acute stress in 9.5-year-old children (N = 108). Lower family income was associated with significantly greater cortisol levels following an acute stress task. A mediational analysis confirmed that Pb was a significant mediator for this association. These results reaffirm the importance of considering the chemical environment as well as social and psychological environment when evaluating psychophysiological effects of low SES.

Short- and long-term modulation of microvascular responses in streptozotocin-induced diabetic rats by glycosylated products

Objective This study aimed to determine the role of early and late glycation products in modulating inflammation in early diabetes. Materials Sprague–Dawley rats (130–170 g) were injected with streptozotocin (75 mg/kg, ip) and treated with daily aminoguanidine (AG, 25 mg/kg, ip) or vehicle for 2 or 4 weeks. Methods The base of a vacuum-induced blister raised on the hind paw was perfused with substance P (SP, 1 μM) and sodium nitroprusside (SNP, 100 μM). Changes in blood flow and plasma extravasation (PE) were measured. Amadori (1 mg/ml), advanced glycation end products (AGEs, 10 mg/ml), and anti-RAGE IgG (antibody against AGE receptors, 100 μg/ml) were individually perfused prior to SP. Results In diabetic rats, responses to SNP and SP were reduced by 60% and 70%, respectively ( P<.05). Amadori increased responses to SNP by 50% and 90% and to SP by 70% and 80% in control and diabetic rats, respectively (both P<.05). SP responses were significantly increased after anti-RAGE IgG (70%) or AG treatments (175%) with PE responses normalized. Conclusion Amadori and anti-AGE agents enhance peripheral vascular responses in diabetes and may ameliorate microvascular damage.

Sphingosine-1-phosphate receptor signalling in the heart

The five known members of the sphingosine-1-phosphate (S1P) receptor family exhibit diverse tissue expression profiles and couple to distinct G-protein-mediated signalling pathways. S1P1, S1P2, and S1P3 receptors are all present in the heart, but the ratio of these subtypes differs for various cardiac cells. The goal of this review is to summarize data concerning which S1P receptor subtypes regulate cardiac physiology and pathophysiology, which G-proteins and signalling pathways they couple to, and in which cell types they are expressed. The available information is based on studies using a lamentably limited set of pharmacological agonists/antagonists, but is complemented by work with S1P receptor subtype-specific knockout mice and sphingosine kinase knockout mice. In cardiac myocytes, the S1P1 receptor subtype is the predominant subtype expressed, and the activation of this receptor inhibits cAMP formation and antagonizes adrenergic receptor-mediated contractility. The S1P3 receptor, while expressed at lower levels, mediates the bradycardic effect of S1P agonists. Studies using knockout mice indicate that S1P2 and S1P3 receptors play a major role in mediating cardioprotection from ischaemia/reperfusion injury in vivo. S1P receptors are also involved in remodelling, proliferation, and differentiation of cardiac fibroblasts, a cell type in which the S1P3 receptor predominates. Receptors for S1P are also present in endothelial and smooth muscle cells where they mediate peripheral vascular tone and endothelial responses, but the role of this regulatory system in the cardiac vasculature is unknown. Further understanding of the contributions of each cell and receptor subtype to cardiac function and pathophysiology should expedite consideration of the endogenous S1P signalling pathway as a therapeutic target for cardiovascular disease.

Role of the Multidomain Protein Spinophilin in Blood Pressure and Cardiac Function Regulation

Spinophilin controls intensity/duration of G protein-coupled receptor signaling and thereby influences synaptic activity. We hypothesize that spinophilin affects blood pressure through central mechanisms. We measured blood pressure and heart rate in SPL-deficient (SPL(-/-)), heterozygous SPL-deficient (SPL(+/-)), and wild-type (SPL(+/+)) mice by telemetry combined with fast Fourier transformation. We also assessed peripheral vascular reactivity and performed echocardiography. SPL(-/-) had higher mean arterial pressure than SPL(+/-) and SPL(+/+) (121+/-2, 112+/-1, and 113+/-1 mm Hg). Heart rate was inversely related to spinophilin expression (SPL(-/-) 565+/-0.4, SPL(+/-) 541+/-5, SPL(+/+) 525+/-8 bpm). The blood pressure response to prazosin, trimethapane, and the heart rate response to metoprolol were stronger in SPL(-/-) than SPL(+/+) mice, whereas heart rate response to atropine was attenuated in SPL(-/-). Mesenteric artery vasoreactivity after angiotensin II, phenylephrine, and the thromboxane mimetic (U46619) as well as change in heart rate, stroke volume, and cardiac output after dobutamine were similar in SPL(-/-) and SPL(+/+). Baroreflex sensitivity was attenuated in SPL(-/-) compared with SPL(+/-) and SPL(+/+), which was confirmed by pharmacological testing. Heart rate variability parameters were attenuated in SPL(-/-) mice. We suggest that an increase in central sympathetic outflow participates in blood pressure and heart rate increases in SPL(-/-) mice. The elevated blood pressure in SPL(-/-) mice was associated with attenuated baroreflex sensitivity and decreased parasympathetic activity. Our study is the first to show a role for the spinophilin gene in blood pressure regulation.

Trait anxiety and peripheral vascular response to mental stress — Sex differences

Trait anxiety and peripheral vascular response to mental stress — Sex differences

Interrelationships among noninvasive measures of postischemic macro- and microvascular reactivity

The clinical importance of vascular reactivity as an early marker of atherosclerosis has been well established, and a number of established and emerging techniques have been employed to provide measurements of peripheral vascular reactivity. However, relations between these methodologies are unclear as each technique evaluates different physiological aspects related to micro- and macrovascular reactive hyperemia. To address this question, a total of 40 apparently healthy normotensive adults, 19-68 yr old, underwent 5 min of forearm suprasystolic cuff-induced ischemia followed by postischemic measurements. Measurements of vascular reactivity included 1) flow-mediated dilatation (FMD), 2) changes in pulse wave velocity between the brachial and radial artery (DeltaPWV), 3) hyperemic shear stress, 4) reactive hyperemic flow, 5) reactive hyperemia index (RHI) assessed by fingertip arterial tonometry, 6) fingertip temperature rebound (TR), and 7) skin reactive hyperemia. FMD was significantly and positively associated with RHI (r=0.47) and TR (r=0.45) (both P<0.01) but not with reactive hyperemic flow or hyperemic shear stress. There was no correlation between two measures of macrovascular reactivity (FMD and DeltaPWV). Skin reactive hyperemia was significantly associated with RHI (r=0.55) and reactive hyperemic flow (r=0.35) (both P<0.05). There was a significant association between reactive hyperemia and RHI (r=0.30; P<0.05). In more than 75% of cases, vascular reactivity measures were not significantly associated. We concluded that associations among different measures of peripheral micro- and macrovascular reactivity were modest at best. These results suggest that different physiological mechanisms may be involved in changing different measures of vascular reactivity.

Conduit Artery Constriction Mediated by Low Flow: A Novel Noninvasive Method for the Assessment of Vascular Function

We describe and validate a novel noninvasive method that complements the data from "traditional" flow-mediated dilation (FMD) studies.The study of peripheral vascular reactivity provides important diagnostic and prognostic information in patients with (or at risk for) cardiovascular disease.High-resolution ultrasound and automatic computerized analysis were used to measure the diameter of the radial artery at rest and in conditions of locally decreased and increased shear stress (respectively, low-flow-mediated constriction [L-FMC] and flow-mediated dilation [FMD]). A composite end point (L-FMC + FMD) was also calculated. A total of 196 studies were performed.When the repeatability of the method was tested, the range of variation across measurements was 1.1% for L-FMC and 1.7% for FMD; the intraclass correlation coefficient was 0.80 and 0.68, respectively. Low-flow-mediated constriction, FMD, and their composite end point were significantly blunted after acute smoking, in coronary artery disease patients, and in hypertensive patients as compared with that seen in healthy age-matched volunteers (p < 0.01, analysis of variance). Low-flow-mediated constriction, but not FMD, was blunted (p < 0.05) after administration of fluconazole (an inhibitor of a cytochrome P450-derived endothelium-derived hyperpolarization factor) and aspirin (an inhibitor of cyclooxygenase). Flow-mediated dilation, but not L-FMC, was blunted (p < 0.05) by nitric oxide synthase inhibition.Low-flow-mediated constriction is a simple, rapid, and accurate measure of resting arterial tone that does not require further procedures as compared with "traditional" FMD measurements. While FMD measures endothelial responses to sudden increases in shear stress, L-FMC is a measure of the response to resting shear stress levels, and, therefore, it provides additional information that is complementary to FMD.

Enhanced vascular responses to hypocapnia in neurally mediated syncope

The susceptibility to suffer neurally mediated syncope and loss of consciousness varies markedly. In addition to vasodilatation and bradycardia, hyperventilation precedes loss of consciousness. The resultant hypocapnia causes cerebral vasoconstriction and peripheral vasodilatation. We postulate that more pronounced cerebral and peripheral vascular responses to reductions in arterial CO(2) levels underlie greater susceptibility to neurally mediated syncope. We compared vascular responses to CO(2) among 31 patients with histories of recurrent neurally mediated syncope and low orthostatic tolerance and 14 age- and sex-matched control subjects with no history of syncope and normal orthostatic tolerance. Vascular responses to CO(2) were calculated after all subjects had fully recovered and their blood pressures and heart rates were stable. We measured blood flow velocity in the middle cerebral artery (transcranial Doppler) and in the left brachial artery (brachial Doppler), and end-tidal CO(2) during voluntary hyperventilation and hypoventilation (end-tidal CO(2) from 21-45mm Hg), and determined the slopes of the relations. Hypocapnia produced a significantly greater reduction in cerebral blood flow velocity and in forearm vascular resistance in patients with neurally mediated syncope than in control subjects. Opposite changes occurred in response to hypercapnia. In all subjects, the changes in cerebral blood flow velocity and forearm vasodilatation were inversely related with orthostatic tolerance. Susceptibility to neurally mediated syncope can be explained, at least in part, by enhanced cerebral vasoconstriction and peripheral vasodilatation in response to hypocapnia. This may have therapeutic implications.

Inter‐relationships between Noninvasive Measures of Peripheral Vascular Reactivity

The clinical importance of peripheral vascular reactivity as an early marker of atherosclerosis has been well established. The relation between different methods employed to provide measurements of peripheral vascular reactivity are unclear as each technique evaluates different physiological aspects related to micro‐ and macro‐vascular reactive hyperemia. To address this, a total of 40 apparently healthy normotensive adults (age 19–68 yrs, 28 males) underwent 5‐minutes of suprasystolic forearm cuff‐induced ischemia followed by post‐ischemic measurements. Macrovascular reactivity measures included flow‐mediated dilatation (FMD) of brachial artery, and brachial to radial pulse wave velocity (ΔPWV; via Doppler flowmeters). Microvascular reactivity measures included reactive hyperemia index (RHI) assessed by fingertip arterial tonometry (RHI; via EndoPAT, Itamar) and fingertip temperature rebound (TR; via VENDYS, Endothelix). FMD was significantly and positively associated with RHI (r=0.54) and TR (r=0.44). There was a modest positive association between TR and RHI (r=0.29). ΔPWV was not significantly associated to any other measures. We concluded that different measures of peripheral micro‐ and macro‐vascular reactivity were not well correlated. These results suggest that a multi‐faceted approach may be necessary for the comprehensive assessment of peripheral vascular function.

Rebuttal from Drs. Richard, Zoll, Mettauer, Piquard, and Geny

Rebuttal from Drs. Richard, Zoll, Mettauer, Piquard, and Geny

Venous but not skeletal muscle interstitial nitric oxide is increased during hypobaric hypoxia

Systemic hypoxia leads to peripheral vasodilation that serves to counteract the decrease in peripheral oxygen (O(2)) delivery. Skeletal muscle vasodilation associated with hypoxia is due to release of vasodilator substances such as adenosine and/or nitric oxide (NO). We hypothesized that skeletal muscle may act as a source of NO during exposure to hypoxia. Therefore, we measured NO in forearm venous plasma and in skeletal muscle interstitial dialysate in seven healthy young men during exposure to simulated altitude of 2,438 and 4,877 m (20 min at each level) in a hypobaric chamber. O(2) saturation (mean +/- SEM) fell from 98.0 +/- 0.2% at ambient conditions to 91.0 +/- 0.4% at 2,438 m and to 73.2 +/- 4.4% at 4,877 m (P < 0.05). While blood pressure remained unchanged, heart rate increased in a graded fashion (P < 0.05). Plasma NO (chemiluminescence method) rose from 11.6 +/- 1.3 to 16.9 +/- 2.9 microM at 2,438 m (P < 0.05) but remained similar at 16.4 +/- 2.3 microM at 4,877 m (NS). In contrast, skeletal muscle microdialysate NO levels were lower than plasma NO (P < 0.01) and did not change during simulated altitude. Thus, hypoxia produced by simulated high altitude exposure leads to an increase in plasma but not skeletal muscle interstitial NO. These data support an important role of NO in the peripheral vascular responses to hypoxia. The differential responses of plasma vs. interstitial NO during hypoxia suggest an endothelial or intravascular source of NO.