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The measurement of vascular function in isolated vessels has revealed important insights into the structural, functional, and biomechanical features of the normal and diseased cardiovascular system and has provided a molecular understanding of the cells that constitutes arteries and veins and their interaction. Further, this approach has allowed the discovery of vital pharmacological treatments for cardiovascular diseases. However, the expansion of the vascular physiology field has also brought new concerns over scientific rigor and reproducibility. Therefore, it is appropriate to set guidelines for the best practices of evaluating vascular function in isolated vessels. These guidelines are a comprehensive document detailing the best practices and pitfalls for the assessment of function in large and small arteries and veins. Herein, we bring together experts in the field of vascular physiology with the purpose of developing guidelines for evaluating ex vivo vascular function. By using this document, vascular physiologists will have consistency among methodological approaches, producing more reliable and reproducible results.

Mixed venous oxygen (O 2 ) saturation ([Formula: see text]) is an important measure for evaluating the sufficiency of cardiac output (CO) relative to whole body O 2 consumption (V̇o 2 ), while clinical use is limited to the required invasive catheterization. According to Fick's equation, V̇o 2 (mL/min) = CO (L/min) × Hb (g/dL) × 1.36 (mL/g) × ([Formula: see text] - [Formula: see text])/10 (Hb = hemoglobin concentration, [Formula: see text] = arterial blood O 2 saturation). Because V̇o 2 , CO, Hb, and [Formula: see text] can be measured noninvasively with expired gas analysis, echocardiography, a simple blood test, and percutaneous O 2 saturation, respectively, [Formula: see text] can be calculated noninvasively. We hypothesized that noninvasively calculated [Formula: see text] shows a significant correlation and agrees well with invasively measured [Formula: see text]. In 47 patients (29 men; mean age, 70 ± 12 yr) who underwent right heart catheterization, [Formula: see text] was directly measured by sampling pulmonary artery blood. Noninvasively calculated [Formula: see text] was also obtained by the method described above. The calculated [Formula: see text] was significantly correlated with the measured [Formula: see text] ( r  = 0.79, P < 0.001) and was significantly smaller than the measured [Formula: see text] (70 ± 5.1 vs. 72.1 ± 4.9%, P < 0.001). Bias at [Formula: see text] was -2.2% (95% confidence interval, -3.2 to -1.1%) with limits of agreement from -9.5 to 5.2%, demonstrating acceptable agreement. The optimal cutoff value of calculated [Formula: see text] was 69% for reduced measured [Formula: see text] < 70% with an area under the curve of 0.94. Reduced calculated [Formula: see text] < 69% indicated a sensitivity of 92.9% and a specificity of 90.9% for reduced measured [Formula: see text] < 70%. Noninvasive [Formula: see text] calculated from echocardiography, expired gas analysis, percutaneous arterial blood O 2 saturation, and hemoglobin level significantly correlated and agreed well with direct [Formula: see text] measured by catheterization. This novel method allows for practical evaluation of [Formula: see text] to assess the sufficiency of CO according to whole body metabolism. NEW & NOTEWORTHY Clinical use of mixed venous oxygen saturation ([Formula: see text]) is limited to the required invasive procedure. With Fick's equation, expired gas analysis, echocardiography, simple blood tests, and percutaneous oxygen saturation, [Formula: see text] can be calculated noninvasively. We hypothesized that noninvasively calculated [Formula: see text] shows a significant correlation and agrees well with invasively measured [Formula: see text]. The present study examined the relationship between measured [Formula: see text] and calculated [Formula: see text] in patients who underwent right heart catheterization and demonstrated acceptable agreement. This novel method can expand the indication of evaluating [Formula: see text].

Although expansive remodeling of the maternal uterine circulation during pregnancy is essential for maintaining uteroplacental perfusion and normal fetal growth, the underlying physiological mechanisms are not well understood. Using a rat model, surgical approaches were used to alter uterine hemodynamics and wall shear stress (WSS) to evaluate the effects of WSS and venoarterial communication (e.g., transfer of placentally derived growth signals from postplacental veins to preplacental arteries) on gestational uterine vascular remodeling. Changes in WSS secondary to ligation of the cervical but not the ovarian end of the main uterine artery and vein provoked significant expansive remodeling at the opposite end of both vessels, but only in pregnant animals. The ≈50% increase in lumen diameter (relative to the contralateral horn) was associated with an upregulation of total endothelial nitric oxide (NO) synthase expression and was abolished by in vivo NO synthase inhibition with N-nitro-l-arginine methyl ester. Complete removal of a venous segment adjacent to the uterine artery to eliminate local venous influences significantly attenuated the WSS-induced remodeling by about one-half ( P < 0.05). These findings indicate that, during pregnancy, 1) increased WSS stimulates uterine artery growth via NO signaling and 2) the presence of an adjacent vein is required for arterial remodeling to fully occur. NEW & NOTEWORTHY This study provides the first in vivo evidence for the importance of venous influences on arterial growth within the uteroplacental circulation.

Based on observations that as cardiac output (as determined by an artificial pump) was experimentally increased the right atrial pressure decreased, Arthur Guyton and coworkers proposed an interpretation that right atrial pressure represents a back pressure restricting venous return (equal to cardiac output in steady state). The idea that right atrial pressure is a back pressure limiting cardiac output and the associated idea that "venous recoil" does work to produce flow have confused physiologists and clinicians for decades because Guyton's interpretation interchanges independent and dependent variables. Here Guyton's model and data are reanalyzed to clarify the role of arterial and right atrial pressures and cardiac output and to clearly delineate that cardiac output is the independent (causal) variable in the experiments. Guyton's original mathematical model is used with his data to show that a simultaneous increase in arterial pressure and decrease in right atrial pressure with increasing cardiac output is due to a blood volume shift into the systemic arterial circulation from the systemic venous circulation. This is because Guyton's model assumes a constant blood volume in the systemic circulation. The increase in right atrial pressure observed when cardiac output decreases in a closed circulation with constant resistance and capacitance is due to the redistribution of blood volume and not because right atrial pressure limits venous return. Because Guyton's venous return curves have generated much confusion and little clarity, we suggest that the concept and previous interpretations of venous return be removed from educational materials.

Experimental studies have suggested a role for the local renin-angiotensin-aldosterone system in the response to vascular injury. Clinical data support that aldosterone, via activation of the mineralocorticoid receptor (MR), is an important mediator of vascular damage in humans with cardiovascular disease. In mineralocorticoid-sensitive target tissue, aldosterone specificity for MR is conferred enzymatically by the cortisol-inactivating enzyme 11β-hydroxysteroid-dehydrogenase-2 (11βHSD2). However, the role of MR/aldosterone signaling in the venous system has not been explored. We hypothesized that MR expression and signaling in venous smooth muscle cells contributes to the arterialization of venous conduits and the injury response in vein bypass grafts. MR immunostaining was observed in all samples of excised human peripheral vein graft lesions and in explanted experimental rabbit carotid interposition vein grafts, with minimal staining in control greater saphenous vein. We also found upregulated transcriptional expression of both MR and 11βHSD2 in human vein graft and rabbit vein graft, whereas control greater saphenous vein expressed minimal MR and no detectable 11βHSD2. The expression of MR and 11βHSD2 was confirmed in cultured human saphenous venous smooth muscle cells (hSVSMCs). Using an adenovirus containing a MR response element-driven reporter gene, we demonstrate that MR in hSVSMCs is capable of mediating aldosterone-induced gene activation. The functional significance for MR signaling in hSVSMCs is supported by the aldosterone-induced increase of angiotensin II type-1 receptor gene expression that was inhibited by the MR antagonist spironolactone. The upregulation of MR and 11βHSD2 suggests that aldosterone-mediated tissue injury plays a role in vein graft arterialization.

We investigated whether hypoxemia without acidemia affects ductus venosus (DV) blood velocity waveform pattern in sheep fetuses with intact placenta and whether worsening acidemia and impending fetal death are related to changes in DV velocimetry in fetuses with increased placental vascular resistance. A total of 34 fetuses were instrumented at 115-136/145 days of gestation. Placental embolization was performed in 22 fetuses on the fourth postoperative day, 24 h before the experiment. The control group was comprised of 12 fetuses with intact placenta. The experimental protocol consisted of fetal hypoxemia that was induced by replacing maternal inhaled oxygen with medical air. To further deteriorate fetal oxygenation and blood-gas status, uterine artery volume blood flow was reduced by maternal hypotension. Fetuses that underwent placental embolization were divided into two groups according to fetal outcome. Group 1 consisted of 12 fetuses that completed the experiment, and group 2 comprised 10 fetuses that died during the experiment. DV pulsatility index for veins (PIV) and fetal cardiac outputs (COs) were calculated. Placental volume blood flow, fetal blood pressures, and acid base and lactate values were monitored invasively. On the experimental day, the mean gestational age did not differ significantly between the groups. In groups 1 and 2, the baseline mean DV PIV and fetal COs were not statistically significantly different from the control group. In the control group, the DV PIV values increased significantly with hypoxemia. In groups 1 and 2, the DV PIV values did not change significantly, even with worsening acidemia and imminent fetal death in group 2. During the experiment, the fetal COs remained unchanged. We conclude that fetal hypoxemia increases the pulsatility of DV blood velocity waveform pattern. In fetuses with elevated placental vascular resistance, DV pulsatility does not increase further in the presence of severe and worsening fetal acidemia and impending fetal death.

There are sex-related differences in venous compliance and capillary filtration in the lower limbs, which to some extent can explain the susceptibility to orthostatic intolerance in young women. With age, venous compliance and capacitance are reduced in men. This study was designed to evaluate age-related changes in venous compliance and capillary filtration in the lower limbs of healthy women. Included in this study were 22 young and 12 elderly women (23.1 +/- 0.4 and 66.4 +/- 1.4 yr). Lower body negative pressure (LBNP) of 11, 22, and 44 mmHg created defined transmural pressure gradients in the lower limbs. A plethysmographic technique was used on the calf to assess venous capacitance and net capillary filtration. Venous compliance was calculated with the aid of a quadratic regression equation. No age-related differences in venous compliance and capacitance were found. Net capillary filtration and capillary filtration coefficient (CFC) were lower in elderly women at a LBNP of 11 and 22 mmHg (0.0032 vs. 0.0044 and 0.0030 vs. 0.0041 ml.100 ml(-1).min(-1).mmHg(-1), P < 0.001). At higher transmural pressure (LBNP, 44 mmHg), CFC increased by approximately 1/3 (0.010 ml.100 ml(-1).min(-1).mmHg(-1)) in the elderly (P < 0.001) but remained unchanged in the young women. In conclusion, no age-related decrease in venous compliance and capacitance was seen in women. However, a decreased CFC was found with age, implying reduced capillary function. Increasing transmural pressure increased CFC in the elderly women, indicating an increased capillary susceptibility to transmural pressure load in dependent regions. These findings differ from earlier studies on age-related effects in men, indicating sex-specific vascular aging both in the venous section and microcirculation.

We have previously reported that the prolonged transient acidosis during early reperfusion mediates the cardioprotective effects in canine hearts. Recently, postconditioning has been shown to be one of the novel strategies to mediate cardioprotection. We tested the contribution of the prolonged transient acidosis to the cardioprotection of postconditioning. Open-chest anesthetized dogs subjected to 90-min occlusion of the left anterior descending coronary artery and 6-h reperfusion were divided into four groups: 1) control group; no intervention after reperfusion (n = 6); 2) postconditioning (Postcon) group; four cycles of 1-min reperfusion and 1-min reocclusion (n = 7); 3) Postcon + sodium bicarbonate (NaHCO(3)) group; four cycles of 1-min reperfusion and 1-min reocclusion with the administration of NaHCO(3) (n = 8); and 4) NaHCO(3) group; administration of NaHCO(3) without postconditioning (n = 6). Infarct size, the area at risk (AAR), collateral blood flow during ischemia, and pH in coronary venous blood were measured. The phosphorylation of Akt and extracellular signal-regulated kinase (ERK) in ischemic myocardium was assessed by Western blot analysis. Systemic hemodynamic parameters, AAR, and collateral blood flow were not different among the four groups. Postconditioning induced prolonged transient acidosis during the early reperfusion phase. Administration of NaHCO(3) completely abolished the infarct size-limiting effects of postconditioning. Furthermore, the phosphorylation of Akt and ERK in ischemic myocardium induced by postconditioning was also blunted by the cotreatment of NaHCO(3). In conclusion, postconditioning mediates its cardioprotective effects possibly via prolonged transient acidosis during the early reperfusion phase with the activation of Akt and ERK.

A dip in blood pressure (BP) in response to head-up tilt (HUT) or active standing might be due to rapid pooling in the veins below the heart (preload) or muscle activation-induced drop in systemic vascular resistance (afterload). We hypothesized that, in the cardiovascular response to passive HUT, where, in contrast to active standing, little BP dip is observed, features affecting the preload play a key role. We developed a baroreflex model combined with a lumped-parameter model of the circulation, including viscoelastic stress-relaxation of the systemic veins. Cardiac contraction is modeled using the varying-elastance concept. Gravity affects not only the systemic, but also the pulmonary, circulation. In accordance with the experimental results, model simulations do not show a BP dip on HUT; the tilt-back response is also realistic. If it is assumed that venous capacities are steady-state values, the introduction of stress-relaxation initially reduces venous pooling. The resulting time course of venous pooling is comparable to measured impedance changes. When venous pressure-volume dynamics are neglected, rapid (completed within 30 s) venous pooling leads to a drop in BP. The direct effect of gravity on the pulmonary circulation influences the BP response in the first approximately 5 s after HUT and tilt back. In conclusion, the initial BP response to HUT is mainly determined by the response of the venous system. The time course of lower body pooling is essential in understanding the response to passive HUT.

Compared with arterial hemodynamics, there has been relatively little study of venous hemodynamics. We propose that the venous system behaves just like the arterial system: waves propagate on a time-varying reservoir, the windkessel, which functions as the reverse of the arterial windkessel. During later diastole, pressure increases exponentially to approach an asymptotic value as inflow continues in the absence of outflow. Our study in eight open-chest dogs showed that windkessel-related arterial resistance was approximately 62% of total systemic vascular resistance, whereas windkessel-related venous resistance was only approximately 7%. Total venous compliance was found to be 21 times larger than arterial compliance (n = 3). Inferior vena caval compliance (0.32 +/- 0.015 ml x mmHg(-1) x kg(-1); mean +/- SE) was approximately 14 times the aortic compliance (0.023 +/- 0.002 ml x mmHg(-1) x kg(-1); n = 8). Despite greater venous compliance, the variation in venous windkessel volume (i.e., compliance x windkessel pulse pressure; 7.8 +/- 1.1 ml) was only approximately 32% of the variation in aortic windkessel volume (24.3 +/- 2.9 ml) because of the larger arterial pressure variation. In addition, and contrary to previous understanding, waves generated by the right heart propagated upstream as far as the femoral vein, but excellent proportionality between the excess pressure and venous outflow suggests that no reflected waves returned to the right atrium. Thus the venous windkessel model not only successfully accounts for variations in the venous pressure and flow waveforms but also, in combination with the arterial windkessel, provides a coherent view of the systemic circulation.

It is now established that S-nitroso-albumin (SNO-albumin) circulates at low nanomolar concentrations under physiological conditions, but concentrations may increase to micromolar levels during disease states (e.g., cirrhosis or endotoxemia). This study tested the hypothesis that high concentrations of SNO-albumin observed in some diseases modulate vascular function and that it acts as a stable reservoir of nitric oxide (NO), releasing this molecule when the concentrations of low-molecular-weight thiols are increased. SNO-albumin was infused into rats to increase the plasma concentration from <50 nmol/l to approximately 4 micromol/l. This caused a 29 +/- 6% drop in blood pressure, 20 +/- 4% decrease in aortic blood flow, and a 25 +/- 14% reduction of renal blood flow within 10 min. These observations were in striking contrast to those of an infused arterial vasodilator (hydralazine), which increased aortic blood flow, and suggested that SNO-albumin acts primarily as a venodilator in vivo. This was confirmed by the observations that glyceryl trinitrate (a venodilator) led to similar hemodynamic changes and that the hemodynamic effects of SNO-albumin are reversed by infusion of colloid. Infusion of N-acetylcysteine into animals with artificially elevated plasma SNO-albumin concentrations led to the rapid decomposition of SNO-albumin in vivo and reproduced the hemodynamic effects of SNO-albumin infusion. These data demonstrate that SNO-albumin acts primarily as a venodilator in vivo and represents a stable reservoir of NO that can release NO when the concentrations of low-molecular-weight thiols are elevated.

Physical inactivity or deconditioning is an independent risk factor for atherosclerosis and cardiovascular disease. In contrast to exercise, the vascular changes that occur as a result of deconditioning have not been characterized. We used 4 wk of unilateral lower limb suspension (ULLS) to study arterial and venous adaptations to deconditioning. In contrast to previous studies, this model is not confounded by denervation or microgravity. Seven healthy subjects participated in the study. Arterial and venous characteristics of the legs were assessed by echo Doppler ultrasound and venous occlusion plethysmography. The diameter of the common and superficial femoral artery decreased by 12% after 4 wk of ULLS. Baseline calf blood flow, as measured by plethysmography, decreased from 2.1 +/- 0.2 to 1.6 +/- 0.2 ml.min(-1).dl tissue(-1). Both arterial diameter and calf blood flow returned to baseline values after 4 wk of recovery. There was no indication of a decrease in flow-mediated dilation of the superficial femoral artery after ULLS deconditioning. This means that functional adaptations to inactivity are not simply the inverse of adaptations to exercise. The venous pressure-volume curve is shifted downward after ULLS, without any effect on compliance. In conclusion, deconditioning by 4 wk of ULLS causes significant changes in both the arterial and the venous system.

The Valsalva maneuver is frequently used to test autonomic function. Previous work demonstrated that the blood pressure decrease during the Valsalva maneuver relates to thoracic hypovolemia, which may preclude pressure recovery during phase II, even with normal resting peripheral vasoconstriction. We hypothesized that increased regional blood volume, specifically splanchnic hypervolemia, accounts for the degree of thoracic hypovolemia during the Valsalva maneuver. We studied 17 healthy volunteers aged 15-22 yr. All had normal blood volumes by dye dilution. Subjects also had normal vascular resistance while supine as well as normal vasoconstrictor responses during 35 degrees upright tilt. We assessed changes in estimated splanchnic, pelvic-thigh, and lower leg blood volume, along with thoracic blood volume shifts, by impedance plethysmography before and during the Valsalva maneuver performed in the supine position. Early increases in splanchnic blood volume dominated the regional vascular changes during the Valsalva maneuver. The increase in splanchnic blood volume correlated well (r2 = 0.65, P < 0.00001) with the decrease in thoracic blood volume, there was less correlation of the increase in pelvic blood volume (r2 = 0.21, P < 0.03), and there was no correlation of the increase in leg blood volume (r2 = 0.001, P = 0.9). There was no relation of thoracic hypovolemia with blood volume or peripheral resistance in supine or upright positions. Thoracic hypovolemia during the Valsalva maneuver is closely related to splanchnic hyperemia and weakly related to regional changes in blood volume elsewhere. Changes in baseline splanchnic vascular properties may account for variability in thoracic blood volume changes during the Valsalva maneuver.

Numerous studies have shown that the female sex hormones estrogen and progesterone have multiple effects on the vasculature. Thus our goal was to investigate the effects of estrogen and progesterone on calf venous compliance by looking for cyclic changes during the early follicular, ovulatory, and midluteal phases of the menstrual cycle and during high and low hormone phases of oral contraceptive use. Additionally, we wanted to compare the venous compliance of normally menstruating women, oral contraceptive users, and men. We studied eight normally menstruating women (23 +/- 1 yr of age) during the early follicular, ovulatory, and midluteal phases of the menstrual cycle. Nine triphasic oral contraceptive users (21 +/- 1 yr of age) were studied during weeks of high and low hormone concentrations. Eight men (23 +/- 1 yr of age) were studied twice within 2-4 wk. With the use of venous occlusion plethysmography with mercury in-Silastic strain gauges, lower limb venous compliance was measured by inflating a venous collection cuff that was placed on the thigh to 60 mmHg for 8 min and then reducing the pressure to 0 mmHg at a rate of 1 mmHg/s. Venous compliance was calculated as the derivative of the pressure-volume curves. There were no differences between early follicular, ovulatory, and midluteal phases of the menstrual cycle or between high and low hormone phases of oral contraceptive use (P > 0.05). Male venous compliance was significantly greater than in normally menstruating women (P < 0.001) and oral contraceptive users (P < 0.002). These data support a sex difference but also suggest that venous compliance does not change with menstrual cycle phase or during the course of oral contraceptive use.

A novel framework of circulatory equilibrium was developed by extending Guyton's original concept. In this framework, venous return (CO(V)) for a given stressed volume (V) was characterized by a flat surface as a function of right atrial pressure (P(RA)) and left atrial pressure (P(LA)) as follows: CO(V) = V/W - G(S)P(RA) - G(P)P(LA), where W, G(S), and G(P) denote linear parameters. In seven dogs under total heart bypass, CO(V), P(RA), P(LA), and V were varied to determine the three parameters in each animal with use of multivariate analysis. The coefficient of determination (r(2) = 0.92-0.99) indicated the flatness of the venous return surface. The averaged surface was CO(V) = V/0.129 - 19.61P(RA) - 3.49P(LA). To examine the invariability of the surface parameters among animals, we predicted the circulatory equilibrium in response to changes in stressed volume in another 12 dogs under normal and heart failure conditions. This was achieved by equating the standard surface with the individually measured cardiac output (CO) curve. In this way, we could predict CO [y = 0.90x + 5.6, r(2) = 0.95, standard error of the estimate (SEE) = 8.7 ml.min(-1).kg(-1)], P(RA) (y = 0.96x, r(2) = 0.98, SEE = 0.2 mmHg), and P(LA) (y = 0.89x + 0.5, r(2) = 0.98, SEE = 0.8 mmHg) reasonably well. We conclude that the venous return surface accurately represents the venous return properties of the systemic and pulmonary circulations. The characteristics of the venous return surface are invariable enough among animals, making it possible to predict circulatory equilibrium, even if those characteristics are unknown in individual animals.

Standing translocates thoracic blood volume into the dependent body. The skeletal muscle pump participates in preventing orthostatic intolerance by enhancing venous return. We investigated the hypothesis that skeletal muscle pump function is impaired in postural tachycardia (POTS) associated with low calf blood flow (low-flow POTS) and depends in general on muscle blood flow. We compared 12 subjects that have low-flow POTS with 10 controls and 7 patients that have POTS and normal calf blood flow using strain-gauge plethysmography to measure peripheral blood flow, venous capacitance, and calf muscle pump function. Blood volume was estimated by dye dilution. We found that calf circumference was reduced in low-flow POTS (32 +/- 1 vs. 39 +/- 3 and 43 +/- 3 cm) and, compared with controls and POTS patients with normal blood flow, is related to the reduced fraction of calf venous capacity emptied during voluntary muscle contraction (ejection fraction, 0.52 +/- 0.07 vs. 0.76 +/- 0.07 and 0.80 +/- 0.06). We found that blood flow was linearly correlated (r(p) = 0.69) with calf circumference (used as a surrogate for muscle mass). Blood volume measurements were 2.2 +/- 0.3 in low-flow POTS vs. 2.6 +/- 0.5 in controls (P = 0.17) and 2.4 +/- 0.7 in normal-flow POTS patients. Decreased calf blood flow may reduce calf size in POTS and thereby impair the upright ejective ability of the skeletal muscle pump and further contribute to overall reduced blood flow and orthostatic intolerance in these patients.

Leg venous compliance is a determinant of peripheral venous pooling during orthostatic stress such that high venous compliance could contribute to reduced orthostatic tolerance. We tested the hypotheses that 1) calf venous compliance is reduced during baroreceptor unloading, and 2) calf venous compliance is greater in women than men. Twelve men (27 +/- 2 yr) and 12 women (25 +/- 2 yr) were studied in the supine posture. Calf venous compliance was determined by inflating a thigh venous collecting cuff to 60 mmHg for 8 min and then decreasing cuff pressure at a rate of 1 mmHg/s to 0 mmHg. The slope of the pressure-compliance relation (compliance = beta(1) + 2.beta(2).cuff pressure), which is the first derivative of the quadratic pressure-volume relation [(Deltalimb volume) = beta(0) + beta(1).(cuff pressure) + beta(2).(cuff pressure)(2)] during the reduction in collecting cuff pressure, was used to assess venous compliance at baseline and during one-legged lower body negative pressure (LBNP; -50 mmHg). At baseline, calf venous compliance was 48% lower (P < 0.001) in women than men and decreased in men (Delta-25 +/- 8%; P < 0.05) but not women (Delta1 +/- 11%) during LBNP. Rhythmic ischemic handgrip (Delta6 +/- 9%) and cold pressor testing (Delta-9 +/- 7%) did not alter calf venous compliance in a subgroup of men (n = 6). These data indicate gender-dependent effects on calf venous compliance under conditions associated with low sympathetic outflow (i.e., rest) and high sympathetic outflow (i.e., LBNP). However, they cannot explain gender-associated differences in orthostatic tolerance.

The main purpose of the present study was to examine the relationships between measures of fitness [estimated peak oxygen consumption (V(O2) peak) and handgrip strength] and forearm vascular function in 55 young (22.6 +/- 3.5 yr) adults. In addition, the present study considered methodological and technical aspects regarding the examination of the venous system using mercury in-Silastic strain-gauge plethysmography (MSGP). Forearm venous capacitance and outflow were examined using five different [7, 14, 21, 28, and 35 mmHg < diastolic blood pressure (DBP)] venous occlusion pressures and after a 5- and 10-min period of venous occlusion. A pressure of 7 mmHg < DBP and a period of 10 min venous occlusion produced the greatest (P < 0.05) venous capacitance and outflow, without altering arterial indexes. Reproducibility of forearm arterial and venous indexes were evaluated at rest and after 5 min of upper arm arterial occlusion at 240 mmHg on three different occasions within 10 days with the interclass correlation coefficient ranging from 0.70 and 0.94. Estimated V(O2) peak correlated with postocclusion arterial inflow (r = 0.54, P = 0.012) and resting venous outflow (r = 0.56, P = 0.016). Finally, handgrip strength was associated with venous capacitance (r = 0.57, P = 0.007) and outflow (r = 0.67, P = 0.001). These results indicate that the examination of forearm vascular function using MSGP is reproducible. Moreover, the data show the importance of careful consideration of the selection of venous occlusion pressure and period when implementing these measures in longitudinal trials. Finally, the associations between fitness and venous measures suggest a link between venous function and exercise performance.

Postural tachycardia syndrome (POTS) is defined by orthostatic intolerance associated with abnormal upright tachycardia. Some patients have defective peripheral vasoconstriction and increased calf blood flow. Others have increased peripheral arterial resistance and decreased blood flow. In 14 POTS patients (13-19 yr) evenly subdivided among low-flow POTS (LFP) and high-flow POTS (HFP) we tested the hypothesis that myogenic, venoarteriolar, and reactive hyperemic responses are abnormal. We used venous occlusion plethysmography to measure calf venous pressure and blood flow in the supine position and when the calf was lowered by 40 cm to evoke myogenic and venoarteriolar responses and during venous hypertension by 40-mmHg occlusion to evoke the venoarteriolar response. We measured calf reactive hyperemia with plethysmography and cutaneous laser-Doppler flowmetry. Baseline blood flow in LFP was reduced compared with HFP and control subjects (0.8 +/- 0.2 vs. 4.4 +/- 0.5 and 2.7 +/- 0.4 ml.min-1.100 ml-1) but increased during leg lowering (1.2 +/- 0.5 ml.min-1. 100 ml-1) while decreasing in the others. Baseline peripheral arterial resistance was increased in LFP and decreased in HFP compared with control subjects (39 +/- 13 vs. 15 +/- 3 and 22 +/- 5 mmHg.ml-1. 100 ml. min) but decreased to 29 +/- 13 mmHg.ml-1.100 ml. min in LFP during venous hypertension. Resistance increased in the other groups. Maximum calf hyperemic flow and cutaneous flow were similar in all subjects. The duration of hyperemic blood flow was curtailed in LFP compared with either control or HFP subjects (plethysmographic time constant = 20 +/- 2 vs. 29 +/- 4 and 28 +/- 4 s; cutaneous time constant = 60 +/- 25 vs. 149 +/- 53 s in controls). Local blood flow regulation in low-flow POTS is impaired.

We hypothesized that blockade of alpha(1)-adrenergic receptors would prevent the rise in peripheral vascular resistance that normally occurs during acclimatization. Sixteen eumenorrheic women were studied at sea level (SL) and at 4,300 m (days 3 and 10). Volunteers were randomly assigned to take the selective alpha(1)-blocker prazosin or placebo. Venous compliance, forearm vascular resistance, and blood flow were measured using plethysmography. Venous compliance fell by day 3 in all subjects (1.39 +/- 0.30 vs. 1.62 +/- 0.43 ml. Delta 30 mmHg(-1) x 100 ml tissue(-1) x min(-1) at SL, means +/- SD). Altitude interacted with prazosin treatment (P < 0.0001) such that compliance returned to SL values by day 10 in the prazosin-treated group (1.68 +/- 0.19) but not in the placebo-treated group (1.20 +/- 0.10, P < 0.05). By day 3 at 4,300 m, all women had significant falls in resistance (35.2 +/- 13.2 vs. 54.5 +/- 16.1 mmHg x ml(-1) x min(-1) at SL) and rises in blood flow (2.5 +/- 1.0 vs. 1.6 +/- 0.5 ml. 100 ml tissue(-1) x min(-1) at SL). By day 10, resistance and flow returned toward SL, but this return was less in the prazosin-treated group (resistance: 39.8 +/- 4.6 mmHg x ml(-1) x min(-1) with prazosin vs. 58.5 +/- 9.8 mmHg x ml(-1) x min(-1) with placebo; flow: 1.9 +/- 0.7 ml. 100 ml tissue(-1) x min(-1) with prazosin vs. 2.3 +/- 0.3 ml x 100 ml tissue(-1) x min(-1) with placebo, P < 0.05). Lower resistance related to higher circulating epinephrine in both groups (r = -0.50, P < 0.0001). Higher circulating norepinephrine related to lower venous compliance in the placebo-treated group (r = -0.42, P < 0.05). We conclude that alpha(1)-adrenergic stimulation modulates peripheral vascular changes during acclimatization.

Microgravity is associated with an impaired stroke volume and, therefore, cardiac output response to orthostatic stress. We hypothesized that a decreased venous filling pressure due to increased venous compliance may be an important contributing factor in this response. We used a constant flow, constant right atrial pressure cardiopulmonary bypass procedure to measure total systemic vascular compliance (C(T)), arterial compliance (C(A)), and venous compliance (C(V)) in seven control and seven 21-day hindlimb unweighted (HLU) rats. These compliance values were calculated under baseline conditions and during an infusion of 0.2 microg*kg(-1)*min(-1) norepinephrine (NE). The change in reservoir volume, which reflects changes in unstressed vascular volume (DeltaV(0)) that occurred upon infusion of NE, was also measured. C(T) and C(V) were larger in HLU rats both at baseline and during the NE infusion (P < 0.05). Infusion of NE decreased C(T) and C(V) by ~20% in both HLU and control rats (P < 0.01). C(A) was also significantly decreased in both groups of rats by NE (P < 0.01), but values of C(A) were similar between HLU and control rats both at baseline and during the NE infusion. Additionally, the NE-induced DeltaV(0) was attenuated by 53% in HLU rats compared with control rats (P < 0.05). The larger C(V) and attenuated DeltaV(0) in HLU rats could contribute to a decreased filling pressure during orthostasis and thus may partially underlie the mechanism leading to the exaggerated fall in stroke volume and cardiac output seen in astronauts during an orthostatic stress after exposure to microgravity.

We determined the independent and interactive influences of aging and habitual endurance exercise on calf venous compliance in humans. We tested the hypotheses that calf venous compliance is 1) reduced with age in sedentary and endurance-trained men, and 2) elevated in young and older endurance-trained compared with age-matched sedentary men. We studied 8 young (28 +/- 1 yr) and 8 older (65 +/- 1) sedentary, and 8 young (27 +/- 1) and 8 older (63 +/- 2) endurance-trained men. Calf venous compliance was measured in supine subjects by inflating a venous collecting cuff, placed above the knee, to 60 mmHg for 8 min and then decreasing cuff pressure at 1 mmHg/s to 0 mmHg. Calf venous compliance was determined using the first derivative of the pressure-volume relation during cuff pressure reduction (compliance = beta(1) + 2. beta(2). cuff pressure). Calf venous compliance was reduced with age in sedentary (approximately 40%) and endurance-trained men (approximately 20%) (both P < 0.01). Furthermore, calf venous compliance was approximately 70-120% greater in endurance-trained compared with age-matched sedentary men and approximately 30% greater in older endurance-trained compared with young sedentary men (both P < 0.01). These data indicate that calf venous compliance is reduced with age in sedentary and endurance-trained men, but compliance is better preserved in endurance-trained men.

Axial migration of red blood cells in small glass tubes can cause blood viscosity to be effectively independent of shear rate. However, this phase separation may not occur to the same degree in the venous network due to infusion of cells and aggregates at branch points. To investigate this hypothesis, we followed trajectories of fluorescently labeled red blood cells in the venular network of the rat spinotrapezius muscle at normal and reduced flow with and without red blood cell aggregation. Cells traveling near the wall of an unbranched venular segment migrated approximately 1% of the longitudinal path length without aggregation and migrated slightly more with aggregation. Venular segment length between branch points averaged three to five times the diameter. Cells in the main vessel were shifted centrally by up to 20% of diameter at branch points, reducing the migration rate of cells near the opposite wall to <1% even in the presence of aggregation. We conclude that formation of a cell-free marginal layer in the venular network is attenuated due to the time dependence of axial migration and the frequent branching of the network.

Myocardial edema occurs in many pathological conditions. We hypothesized that protein washdown at the myocardial microvascular exchange barrier would change the distribution of interstitial proteins from large to small molecules and diminish the effect of washdown on the colloid osmotic pressure (COP) of interstitial fluid and lymph. Dogs were instrumented with coronary sinus balloon-tipped catheters and myocardial lymphatic cannulas to manipulate myocardial lymph flow and to collect lymph. Myocardial venous pressure was elevated by balloon inflation to increase transmicrovascular fluid flux and myocardial lymph flow. COP of lymph was measured directly and was also calculated from protein concentration. Decreases occurred in both protein concentration and COP of lymph. The proportion of lymph protein accounted for by albumin increased significantly, whereas that accounted for by beta-lipoprotein decreased significantly. The change in the calculated plasma-to-lymph COP gradient was significantly greater than the change in the measured COP gradient. We conclude that the change in the distribution of interstitial fluid protein species decreases the effect of protein washdown on interstitial fluid COP and limits its effectiveness as a defense mechanism against myocardial edema formation.

We tested the hypothesis that venous emptying serves as a stimulus for vasodilation in the human forearm. We compared the forearm blood flow (FBF; pulsed Doppler mean blood velocity and echo Doppler brachial artery diameter) response to temporary elevation of a resting forearm from below to above heart level when venous volume was allowed to drain versus when venous drainage was prevented by inflation of an upper arm cuff to approximately 30 mmHg. Arm elevation resulted in a rapid reduction in venous volume and pressure. Cuff inflation just before elevation effectively prevented these changes. FBF was briefly reduced by approximately 16% following arm elevation. A transient (86%) increase in blood flow began by approximately 5 s of arm elevation and peaked by 8 s, indicating a vasodilation. This response was completely abolished by preventing venous emptying. Arterial inflow below heart level was markedly elevated by 343% following brief (4 s) forearm elevation. This hyperemia was minor when venous emptying during forearm elevation had been prevented. We conclude that venous emptying serves as a stimulus for a transient (within 10 s) vasodilation in vivo. This vasodilation can substantially elevate arterial inflow.

In pentobarbital-anesthetized male Sprague-Dawley rats, a small cranial window was trephined, and the cortex was transilluminated with a fine glass fiber inserted into the brain parenchyma. The light intensity at the surface area of 2 x 2 mm was recorded during intracarotid injection of 25 microl of carbon black (CB) solution. The region of interest (ROI) was divided into a 50 x 50 matrix, and the mean transit time of CB transport was calculated in each matrix element. We found rapid transits of CB along the microvasculature, with considerable heterogeneity in the avascular area, and heterogeneous efficiency in autoregulatory capacity in the ROI during hypotension. The method was validated by comparison with laser-Doppler flowmetry. The average mean difference was 0.03 +/- 0. 05%. Five percent CO(2) inhalation increased the flow by 85%, but heterogeneously. We concluded that the technique is exclusively sensitive to indicator transits in a very small area on the brain surface with potential usefulness in detecting regional heterogeneity in blood flow.

The problem of diffusion of O(2) across the endothelial surface in precapillary vessels and its utilization in the vascular wall remains unresolved. To establish a relationship between precapillary release of O(2) and vascular wall consumption, we estimated the intravascular flux of O(2) on the basis of published in vivo measurements. To interpret the data, we utilized a diffusion model of the vascular wall and computed possible physiological ranges for O(2) consumption. We found that many flux values were not consistent with the diffusion model. We estimated the mitochondrial-based maximum O(2) consumption of the vascular wall (M(mt)) and a possible contribution to O(2) consumption of nitric oxide production by endothelial cells (M(NO)). Many values of O(2) consumption predicted from the diffusion model exceeded M(mt) + M(NO). In contrast, reported values of O(2) consumption for endothelial and smooth muscle cell suspensions and vascular strips in vitro do not exceed M(mt). We conjecture that most of the reported values of intravascular O(2) flux are overestimated, and the likely source is in the experimental estimates of convective O(2) transport at upstream and downstream points of unbranched vascular segments.

Isolated porcine pial veins in the presence of active muscle tone have been shown to exhibit rhythmic contractions (RC) that are inhibited by serotonin (5-HT) in a concentration-dependent manner. The 5-HT inhibition of RC is mediated by an as yet unidentified 5-HT receptor subtype located on the vascular smooth muscle. 5-carboxamidotryptamine, which is a potent but nonselective agonist at 5-HT(7) receptors, has been shown to be the most potent inhibitor of RC in porcine pial veins. Therefore, the present study was designed to determine if the 5-HT-mediated inhibition of RC in pial veins is mediated by 5-HT(7) receptors and if 5-HT(7) receptor mRNA is expressed in endothelium-denuded pial veins; the study was done with the use of an in vitro tissue bath and RT-PCR techniques. Our findings indicated that 5-HT inhibition of RC in porcine pial veins was prevented by 5-HT(7)-receptor antagonists (clozapine, pimozide, and LY-215840) in a concentration-dependent manner. Furthermore, a strong PCR signal for the 5-HT(7) receptor was consistently detected in endothelium-denuded pial veins. Sequence analysis of the amplified products confirmed their high degree of homology with the porcine and/or human 5-HT(7)-receptor gene. Taken together, these data suggest that the 5-HT-induced inhibition of RC in porcine pial veins is at least in part mediated by 5-HT(7) receptors located on the venous smooth muscle.