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Heart failure is a leading cause of morbidity and mortality 1,2 . Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion 3-8 . Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect 9,10 . Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure., (© 2024. The Author(s).)

Various methods for indirect assessment of mean systemic filling pressure (MSFP) produce controversial results compared with MSFP at zero blood flow. We recently reported that the difference between MSFP at zero flow measured by right atrial balloon occlusion (MSFP RAO ) and MSFP estimated using inspiratory holds depends on the volume status. We now compare three indirect estimates of MSFP with MSFP RAO in euvolemia, bleeding, and hypervolemia in a model of anesthetized pigs ( n = 9) with intact circulation. MSFP was estimated using instantaneous beat-to-beat venous return during tidal ventilation (MSFP inst_VR ), right atrial pressure-flow data pairs at flow nadir during inspiratory holds (MSFP nadir_hold ), and a dynamic model analog adapted to pigs (MSFP a ). MSFP RAO was underestimated by MSFP nadir_hold and MSFP a in all volume states. Volume status modified the difference between MSFP RAO and all indirect methods (method × volume state interaction, P ≤ 0.020). All methods tracked changes in MSFP RAO concordantly, with the lowest bias seen for MSFP a [bias (confidence interval): -0.4 (-0.7 to -0.0) mmHg]. We conclude that indirect estimates of MSFP are unreliable in this experimental setup. NEW & NOTEWORTHY For indirect estimations of MSFP using inspiratory hold maneuvers, instantaneous beat-to-beat venous return, or a dynamic model analog, the accuracy was affected by the underlying volume state. All methods investigated tracked changes in MSFP RAO concordantly.

Objective: To investigate vascular adaptations to eight weeks of resistance exercise, with and without different pressures of blood flow restriction (BFR), in the upper and lower body., Approach: Forty individuals (men  =  20, women  =  20) completed eight weeks of resistance exercise at very low loads (15% of one-repetition maximum (1RM)), with two levels of BFR (40% arterial occlusion pressure (AOP), 80% AOP), without BFR, and 70% of 1RM. Vascular conductance and venous compliance were measured via plethysmography before and following training in the forearms and in the calves., Main Results: Values reported as means (95% confidence intervals). Pre to post changes in vascular conductance occurred only in the high-pressure conditions (upper body:  +8.29 (3.01-13.57) ml · mmHg -1 ; lower body:  +7.86 (3.37-12.35) ml · mmHg -1 ) and high-load conditions (upper body:  +8.60 (3.45-13.74) ml · mmHg -1 ); lower body:  +7.20 (2.71-11.69) ml · mmHg -1 ) only. In the upper body, the change was significantly greater in the high-pressure and high-load conditions compared to the change observed in the low-pressure condition (-0.41 (-5.56, 4.73) ml · mmHg -1 ). These changes were not greater than the change observed in the low-load condition without pressure (+1.81 (-3.47, 7.09) ml · mmHg -1 ). In the lower body, the change in the high-pressure and high-load conditions were significantly greater than the changes observed with low-load training with (-0.86 (-5.60, 3.87) ml · mmHg -1 ) and without (-1.22 (-5.71, 3.27) ml · mmHg -1 ) a low pressure. Venous compliance increased in all groups in the upper body (+0.003 (.000 08, 0.006) ml · 100 ml -1 · mmHg -1 ) only, with no changes in the lower body., Significance: High-pressure BFR causes adaptations in vascular function following eight weeks of training at mechanical loads not typically associated with such adaptations.

The Pathophysiology of Aortic Cross-clamping and Unclamping. By Gelman S. ANESTHESIOLOGY 1995; 82:1026-60. Reprinted with permission.Aortic cross-clamping (AoX) and unclamping are associated with severe hemodynamic disturbances in virtually all organs and systems. The main hemodynamic changes induced by AoX result from an increase in impedance to aortic flow, an increase in systemic vascular resistance and afterload, blood volume redistribution caused by collapse and constriction of venous vasculature distal to the aortic clamp, and a subsequent increase in preload. Preload may not increase if the aorta is clamped distal to the celiac artery; in that case, blood volume from distal venous vasculature may be redistributed to the splanchnic vasculature without associated increases in preload. Increases in afterload and preload demand an increase in contractility, which results in an autoregulatory increase in coronary blood flow. Without increases in coronary blood flow and myocardial contractility, decompensation may occur. Aortic cross-clamping is associated with the formation and release of many mediators which constitute a double-edged sword: they may mitigate or aggravate the harmful hemodynamic effects of AoX and unclamping. Injuries to the lungs, kidneys, spinal cord, or abdominal viscera are caused mainly by ischemia and reperfusion of organs distal to aortic cross-clamping. A clear understanding of the pathophysiologic mechanisms involved in these processes should help to promote rational, well-focused, and effective measures to prevent and treat homeostatic disturbances occurring during AoX and unclamping.

Distension of peripheral veins in humans elicits a pressor and sympathoexcitatory response that is mediated through group III/IV skeletal muscle afferents. There is some evidence that autonomic reflexes mediated by these sensory fibers are blunted with increasing age, yet to date the venous distension reflex has only been studied in young adults. Therefore, we tested the hypothesis that the venous distension reflex would be attenuated in middle-aged compared with young adults. Nineteen young (14 men/5 women, 25 ± 1 yr) and 13 middle-aged (9 men/4 women, 50 ± 2 yr) healthy normotensive participants underwent venous distension via saline infusion through a retrograde intravenous catheter in an antecubital vein during limb occlusion. Beat-by-beat blood pressure, muscle sympathetic nerve activity (MSNA), and model flow-derived cardiac output (Q), and total peripheral resistance (TPR) were recorded throughout the trial. Mean arterial pressure (MAP) increased during the venous distension in both young (baseline 83 ± 2, peak 94 ± 3 mmHg; P < 0.05) and middle-aged adults (baseline 88 ± 2, peak 103 ± 3 mmHg; P < 0.05). MSNA also increased in both groups [young: baseline 886 ± 143, peak 1,961 ± 242 arbitrary units (AU)/min; middle-aged: baseline 1,164 ± 225, peak 2,515 ± 404 AU/min; both P < 0.05]. TPR (P < 0.001), but not Q (P = 0.76), increased during the trial. However, the observed increases in blood pressure, MSNA, and TPR were similar between young and middle-aged adults. Additionally, no correlation was found between age and the response to venous distension (all P > 0.05). These findings suggest that peripheral venous distension elicits a pressor and sympathetic response in middle-aged adults similar to the response observed in young adults., (Copyright © 2016 the American Physiological Society.)

Purpose: We hypothesized that lower body microvessels are particularly challenged during exposure to gravity and hypergravity leading to failure of resistance vessels to withstand excessive transmural pressure during hypergravitation and gravitation-dependent microvascular blood pooling., Methods: Using a short-arm human centrifuge (SAHC), 12 subjects were exposed to +1Gz, +2Gz and +1Gz, all at foot level, for 4 min each. Laser Doppler imaging and near-infrared spectroscopy were used to measure skin perfusion and tissue haemoglobin concentrations, respectively., Results: Pretibial skin perfusion decreased by 19% during +1Gz and remained at this level during +2Gz. In the dilated area, skin perfusion increased by 24 and 35% during +1Gz and +2Gz, respectively. In the upper arm, oxygenated haemoglobin (Hb) decreased, while deoxy Hb increased with little change in total Hb. In the calf muscle, O2Hb and deoxy Hb increased, resulting in total Hb increase by 7.5 ± 1.4 and 26.6 ± 2.6 µmol/L at +1Gz and +2Gz, respectively. The dynamics of Hb increase suggests a fast and a slow component., Conclusion: Despite transmural pressures well beyond the upper myogenic control limit, intact lower body resistance vessels withstand these pressures up to +2Gz, suggesting that myogenic control may contribute only little to increased vascular resistance. The fast component of increasing total Hb indicates microvascular blood pooling contributing to soft tissue capacitance. Future research will have to address possible alterations of these acute adaptations to gravity after deconditioning by exposure to micro-g.

Vein maladaptation, leading to poor long-term patency, is a serious clinical problem in patients receiving coronary artery bypass grafts (CABGs) or undergoing related clinical procedures that subject veins to elevated blood flow and pressure. We propose a computational model of venous adaptation to altered pressure based on a constrained mixture theory of growth and remodeling (G&R). We identify constitutive parameters that optimally match biaxial data from a mouse vena cava, then numerically subject the vein to altered pressure conditions and quantify the extent of adaptation for a biologically reasonable set of bounds for G&R parameters. We identify conditions under which a vein graft can adapt optimally and explore physiological constraints that lead to maladaptation. Finally, we test the hypothesis that a gradual, rather than a step, change in pressure will reduce maladaptation. Optimization is used to accelerate parameter identification and numerically evaluate hypotheses of vein remodeling.

Purpose: Calf venous compliance (C calf) is commonly evaluated with venous occlusion plethysmography (VOP) during a standard cuff deflation protocol. However, the technique relies on two not previously validated assumptions concerning thigh cuff pressure (P cuff) transmission and the impact of net fluid filtration (F filt) on C calf. The aim was to validate VOP in the lower limb and to develop a model to correct for F filt during VOP., Methods: Strain-gauge technique was used to study calf volume changes in 15 women and 10 age-matched men. A thigh cuff was inflated to 60 mmHg for 4 and 8 min with a subsequent decrease of 1 mmHg s(-1). Intravenous pressure (P iv) was measured simultaneously. C calf was determined with the commonly used equation [Compliance = β 1 + 2β 2 × P cuff] describing the pressure-compliance relationship. A model was developed to identify and correct for F filt., Results: Transmission of P cuff to P iv was 100 %. The decrease in P cuff correlated well with P iv reduction (r = 0.99, P < 0.001). Overall, our model showed that C calf was underestimated when F filt was not accounted for (all P < 0.01). F filt was higher in women (P < 0.01) and showed a more pronounced effect on C calf compared to men (P < 0.05). The impact of F filt was similar during 4- and 8-min VOP., Conclusions: P cuff is an adequate substitute for P iv in the lower limb. F filt is associated with an underestimation of C calf and differences in the effect of F filt during VOP can be accounted for with the correction model. Thus, our model seems to be a valuable tool in future studies of venous wall function.

Hemodialysis patients require a vascular access that is, preferably, surgically created by connecting an artery and vein in the arm, i.e. an arteriovenous fistula (AVF). The site for AVF creation is chosen by the surgeon based on preoperative diagnostics, but AVFs are still compromised by flow-associated complications. Previously, it was shown that a computational 1D-model is able to describe pressure and flow after AVF surgery. However, predicted flows differed from measurements in 4/10 patients. Differences can be attributed to inaccuracies in Doppler measurements and input data, to neglecting physiological mechanisms or to an incomplete physical description of the pulse wave propagation after AVF surgery. The physical description can be checked by validating against an experimental setup consisting of silicone tubes mimicking the aorta and arm vasculature both before and after AVF surgery, which is the aim of the current study. In such an analysis, the output uncertainty resulting from measurement uncertainty in model input should be quantified. The computational model was fed by geometrical and mechanical properties collected from the setup. Pressure and flow waveforms were simulated and compared with experimental waveforms. The precision of the simulations was determined by performing a Monte Carlo study. It was concluded that the computational model was able to simulate mean pressures and flows accurately, whereas simulated waveforms were less attenuated than experimental ones, likely resulting from neglecting viscoelasticity. Furthermore, it was found that in the analysis output uncertainties, resulting from input uncertainties, cannot be neglected and should thus be considered., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Investigated the relationship between pulmonary artery pressure (P(LA)) and the oxygen saturation of mixed venous blood (S(V)) in 12 group's of surveyed individuals (1750 men and 1026 women). We have identified a function (P(LA)) between P(LA) = f(S(V)), and a function (S(V)) S(V) = f(P(LA)) was estimated for each group based on direct measurements of P(LA) and S(V). We found, that factors were subordinated to the dependences for a P(LA) = f(S(V)), P(LA) = a x (S(V))(-b), where b = = -0.2284a + 0.6564 men - and b = -0.285a + 1.2947 in women and the other for -S(V) = f(P(LA)), S(V) = c x (P(LA))(-d) where d = -0.251311n(c) + 1.0212; (R2 = 0.8993) men and d = -1.96451n(c) + 2.852; (R2 = 0.9674) women. Each group occupies a position on the curves represented by equations. The subjects with a diagnosis of functional murmur in the heart and patients with congenital stenos is of the aortic valve form a group, provisionally designated as "group norms", which is characterized by its dependence P(LA) = f(S(V)), and -S(V) = f(P(LA)). The men in "group norms" additionally include patients with coronary heart disease. The equation - CO = Cons.O2/(KEK(S(A) - (c x (P(LA))(-d). It relates the P(LA), caused by different reasons, with the corresponding saturation of mixed venous blood, and when the saturation of mixed venous blood is also caused by various factors, set the corresponding P(LA). Interdependent changes in physiological parameters of blood circulation and gas exchange in humans is established equilibrium between systemic and pulmonary circulation.

In acute experiments on cats, in applying of original methodical approach--control of systemic circulation by the aid of computerized negative feedback loop changing the volume of circulating blood (method of biological feedback)--first were experimentally measured and analyzed the dynamic characteristics of relationship between central venous pressure and venous return of blood to the right heart. The following positions are offered and validated in the work. (1) It is shown that the passive component (mechanical compliance) is more important than active one (active myogenic component) in the small circle of circulation being compared to large one. (2) Venous return plays the leading role in forming the shifts of central venous pressure directly during developing of the transition processes of systemic circulation caused by the norepinephrine injection and the linear type of this link is proved directly during the development of the cardiovascular shift. (3) The dynamic characteristics of relationship between venous return and central venous pressure during the geodynamical reaction caused by the shifts of intravascular blood volume are experimentally measured and mathematically analyzed. It is revealed that dynamic summands of this link may overbalance the static ones known before in influence on the total shifts in developing of the systemic reaction of circulation and this influence increases when the velocity of changes in studied parameters of circulation becomes more.

The paper generalizes unclear problems of venous return to the heart under different conditions. Data are presented on the venous return/cardiac output ratio, general peripheral resistance, arterial pressure and vascular bed capacity. A concept of double wave nature of formation of the circulation pressor systemic responses is advanced.

Purpose of Review: The focus of intraoperative monitoring is moving away from invasive monitoring. This has been attributed to procedure time, cost, and the known risks, which include carotid artery puncture, arrhythmia, pneumothorax, and infection. Until recently, the venous system's contribution to the circulatory system has been incorrectly identified as being insignificant. This article summarizes the unique characteristics of the peripheral venous system., Recent Findings: Numerous studies done in the last few years have paid attention to peripheral venous pressure and more specifically its pressure waveform. The popularity of, and further focus on, the field of photoplethysmography has described a strong venous component. Analysis of venous waveforms has indicated that, like arterial waveforms, they too exhibit respiratory variations and change in response to physiologic challenges., Summary: The veins play a critical role in cardiovascular homeostasis; they do more than conduct blood to the heart. Considering the ease of measurement from a peripheral intravenous catheter, further study should be conducted to investigate the usefulness and limitations of such a minimally invasive and inexpensive monitoring device.

Animal studies have shown that the increased intravenous pressure stimulates the group III and IV muscle afferent fibres, and in turn induce cardiovascular responses. However, this pathway of autonomic regulation has not been examined in humans. The aim of this study was to examine the hypothesis that infusion of saline into the venous circulation of an arterially occluded vascular bed evokes sympathetic activation in healthy individuals. Blood pressure, heart rate, and muscle sympathetic nerve activity (MSNA) responses were assessed in 19 young healthy subjects during local infusion of 40 ml saline into a forearm vein in the circulatory arrested condition. From baseline (11.8 +/- 1.2 bursts min(-1)), MSNA increased significantly during the saline infusion (22.5 +/- 2.6 bursts min(-1), P < 0.001). Blood pressure also increased significantly during the saline infusion. Three control trials were performed during separate visits. The results from the control trial show that the observed MSNA and blood pressure responses were not due to muscle ischaemia. The present data show that saline infusion into the venous circulation of an arterially occluded vascular bed induces sympathetic activation and an increase in blood pressure. We speculate that the infusion under such conditions stimulates the afferent endings near the vessels, and evokes the sympathetic activation.

Background: It is widely accepted that venous valves play an important role in reducing the pressure applied to the veins under dynamic load conditions, such as the act of standing up. This understanding is, however, qualitative and not quantitative. The purpose of this paper is to quantify the pressure shielding effect and its variation with a number of system parameters., Methods: A one-dimensional mathematical model of a collapsible tube, with the facility to introduce valves at any position, was used. The model has been exercised to compute transient pressure and flow distributions along the vein under the action of an imposed gravity field (standing up)., Results: A quantitative evaluation of the effect of a valve, or valves, on the shielding of the vein from peak transient pressure effects was undertaken. The model used reported that a valve decreased the dynamic pressures applied to a vein when gravity is applied by a considerable amount., Conclusion: The model has the potential to increase understanding of dynamic physical effects in venous physiology, and ultimately might be used as part of an interventional planning tool.

The causes of the regional differences in venous grafts patency rates are partially understood. Differences in vein dynamics during physiological situations could determine differences in veins' capability to face arterial conditions and could contribute to the dissimilar performance of veins as arterial grafts. In vitro pressure and diameter were measured in four different veins during physiological and arterial (graft) pressure conditions. A diameter-pressure transfer function was designed. Compliance, viscous and inertial properties; circumferential stresses and deformation; and buffering function were calculated. Regional differences in veins' dynamics, but not in buffering function were found during physiological and arterial conditions. The back vein (femoral) showed the least changes when submitted to arterial conditions. Arterial conditions represent different changes in vein dynamics depending on the segment considered. The regional differences in vein dynamics, both at physiological and graft conditions, could contribute to explain the dissimilar results of venous grafts.

In order to evaluate hemodynamics in the complex vascular system of phocid seals, intravascular pressure profiles were measured during periods of rest-associated apnea in young elephant seals (Mirounga angustirostris). There were no significant differences between apneic and eupneic mean arterial pressures. During apnea, venous pressure profiles (pulmonary artery, thoracic portion of the vena cava (thoracic vena cava), extradural vein, and hepatic sinus) demonstrated only minor, transient fluctuations. During eupnea, all venous pressure profiles were dominated by respiratory fluctuations. During inspiration, pressures in the thoracic vena cava and extradural vein decreased -9 to -21 mm Hg, and -9 to -17 mm Hg, respectively. In contrast, hepatic sinus pressure increased 2-6 mm Hg during inspiration. Nearly constant hepatic sinus and intrathoracic vascular pressure profiles during the breath-hold period are consistent with incomplete constriction of the caval sphincter during these rest-associated apneas. During eupnea, negative inspiratory intravascular pressures in the chest ("the respiratory pump") should augment venous return via both the venae cavae and the extradural vein. It is hypothesized that, in addition to the venae cavae, the prominent para-caval venous system of phocid seals (i.e., the extradural vein) is necessary to allow adequate venous return for maintenance of high cardiac outputs and blood pressure during eupnea.

The role of the alpha-adrenergic system in the control of cardiac preload (central venous blood pressure; P(ven)) and venous capacitance during exercise was investigated in rainbow trout (Oncorhynchus mykiss). In addition, the antihypotensive effect of the renin-angiotesin system (RAS) was investigated during exercise after alpha-adrenoceptor blockade. Fish were subjected to a 20-min exercise challenge at 0.66 body lengths s(-1) (BL s(-1)) while P(ven), dorsal aortic blood pressure (P(da)) and relative cardiac output (Q) was recorded continuously. Heart rate (f(H)), cardiac stroke volume (SV) and total systemic resistance (R(sys)) were derived from these variables. The mean circulatory filling pressure (MCFP) was measured at rest and at the end of the exercise challenge, to investigate potential exercise-mediated changes in venous capacitance. The protocol was repeated after alpha-adrenoceptor blockade with prazosin (1 mg kg(-1)M(b)) and again after additional blockade of angiotensin converting enzyme (ACE) with enalapril (1 mg kg(-1)M(b)). In untreated fish, exercise was associated with a rapid (within approx. 1-2 min) and sustained increase in Q and P(ven) associated with a significant increase in MCFP (0.17+/-0.02 kPa at rest to 0.27+/-0.02 kPa at the end of exercise). Prazosin treatment did not block the exercise-mediated increase in MCFP (0.25+/-0.04 kPa to 0.33+/-0.04 kPa at the end of exercise), but delayed the other cardiovascular responses to swimming such that Q and P(ven) did not increase significantly until around 10-13 min of exercise, suggesting that an endogenous humoral control mechanism had been activated. Subsequent enalapril treatment revealed that these delayed responses were in fact due to activation of the RAS, because resting P(da) and R(sys) were decreased further and essentially all cardiovascular changes during exercise were abolished. This study shows that the alpha-adrenergic system normally plays an important role in the control of venous function during exercise in rainbow trout. It is also the first study to suggest that the RAS may be an important modulator of venous pressure and capacitance in fish.

We investigated the effect of intermedin/adrenomedullin-2 (3 and 10 nmol/kg, i.v.), a member of the calcitonin gene-related peptide family, relative to the vehicle (0.9% NaCl) on mean circulatory filling pressure (index of venous tone) in conscious rats: intact (unblocked) or ganglionic blocked through treatment with mecamylamine (10 mg/kg, i.v.) and noradrenaline (4 microg/kg/min, i.v.). In intact rats, both doses of intermedin/adrenomedullin-2 reduced mean arterial pressure (-14+/-3, -30+/-3 mmHg), but did not alter mean circulatory filling pressure; the high dose also increased heart rate. In ganglionic-blocked rats, both doses decreased mean arterial pressure (-22+/-3, -46+/-5 mmHg) and the high dose also decreased mean circulatory filling pressure (-2.81+/-0.82 mmHg), but neither dose affected heart rate. The vehicle did not have any effects in any of the groups. In addition, intermedin/adrenomedullin-2 did not have any effect on blood volume in both intact and ganglion-blocked rats. The results show that intermedin/adrenomedullin-2 is a dilator of arterial resistance and capacitance vessels.

Substance P is an undecapeptide that belongs to the mammalian tachykinin family. We investigated the effects of substance P on venous tone in conscious rats through measurement of mean circulatory filling pressure. The effects of substance P (10 and 30 nmol/kg, IV) and the vehicle (0.9% NaCl) on mean arterial pressure, heart rate, and mean circulatory filling pressure were examined in 2 groups each of conscious rats: rats without or with ganglionic blockade through pretreatment with mecamylamine (10 mg/kg, IV) and norepinephrine (4 microg/kg/min, IV). In the unblocked rats, both doses of substance P reduced mean arterial pressure (-19 +/- 1 and -35 +/- 2 mm Hg) and increased heart rate (+113 +/- 14 and +115 +/- 23 beats/min). The high dose of substance P also decreased mean circulatory filling pressure (-1.7 +/- 0.3 mm Hg). In the ganglionic-blocked rats, both doses of substance P decreased mean arterial pressure (-48 +/- 6 and -73 +/- 6 mm Hg) and mean circulatory filling pressure (-2.9 +/- 0.4 and -4.2 +/- 0.8 mm Hg) but did not affect HR. In conclusion, substance P is a vasodilator peptide that has a prominent venodilator action.

Aging and chronic exercise training influence leg venous compliance. Venous compliance affects responses to an orthostatic stress; its effect on tolerance to maximal lower body negative pressure (LBNP) in the elderly is unknown. The purpose of this study was to determine the influence of age and fitness, a surrogate measure of exercise training, on calf venous compliance and tolerance to maximal LBNP in men and women. Forty participants, 10 young fit (YF; age = 22.6 +/- 0.5 yr, peak oxygen uptake = 57.1 +/- 2.0 ml.kg(-1).min(-1)), 10 young unfit (YU; 23.1 +/- 1.0 yr, 41.1 +/- 2.0 ml.kg(-1).min(-1)), 10 older fit (OF; 73.9 +/- 2.0 yr, 39.0 +/- 2.0 ml.kg(-1).min(-1)), and 10 older unfit (OU; 70.9 +/- 1.6 yr, 27.1 +/- 2.0 ml.kg(-1).min(-1)), underwent graded LBNP to presyncope or 4 min at -100 mmHg. By utilizing venous occlusion plethysmography, calf venous compliance was determined by using the first derivative of the pressure-volume relation during cuff pressure reduction. We found that the more fit groups had greater venous compliance than their unfit peers (P < 0.05) as did the young groups compared with their older peers (P < 0.05) such that OU < YU = OF < YF. LBNP tolerance did not differ between groups. In conclusion, these data suggest that aging reduces, and chronic exercise increases, venous compliance. However, these data do not support a significant influence of venous compliance on LBNP tolerance.

As a consequence of chronic orthostatic load of the organism several long-term antigravitation defense mechanism are activated in the lower extremity veins and microvessels. The following adaptive mechanisms are brought into focus: acute pressure-induced myogenic tone and its augmentation which promote the venous capacity autoregulation, potassium channels counterregulating the depolarization of the venous smooth muscle membrane, functional and structural remodeling of sympathetic innervation in the vascular wall, changes in venous network properties, decreased capillary supply in oxidative muscles of the extremities, and probably transendothelial homeostatic water transport in the wall of veins.

Increases in the concentration of interstitial potassium concentration during exercise may play a role in the modulation of the cardiovascular response to exercise. However, it is not known if changes in potassium correlate with indexes of muscle reflex engagement. Eight healthy subjects performed dynamic [rhythmic handgrip (RHG)] and static handgrip (SHG) exercise at 40% of maximal voluntary contraction. Forearm circulatory arrest was performed to assess the metaboreceptor component of the exercise pressor reflex. Mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA) were measured during each exercise paradigm. Venous plasma potassium concentrations ([K(+)](V)) were measured and used as a surrogate marker for interstitial potassium. [K(+)](V) were measured at baseline and at 1-min intervals during dynamic handgrip. During SHG, [K(+)](V) were measured at baseline, 30 and 90 s of exercise, and twice during forearm circulatory arrest. Mean [K(+)](V) was 3.6 mmol/l at rest before both paradigms. During RHG, [K(+)](V) rose by approximately 1.0 mmol/l by min 2 and remained constant throughout the rest of handgrip. During SHG, [K(+)](V) rose significantly at 30 s and rose an additional approximately 1.0 mmol/l by peak exercise. MAP and MSNA rose during both exercise paradigms. During posthandgrip circulatory arrest (PHG-CA), MSNA and blood pressure remained above baseline. [K(+)](V) and MSNA did not correlate during either exercise paradigm. Moreover, during PHG-CA, there was clear dissociation of MSNA from [K(+)](V). These data suggest that potassium does not play a direct role in the maintenance of the exercise pressor reflex.

Background: Although the sympathomimetic actions and cardiovascular complications of cocaine are ascribed to inhibition of norepinephrine (NE) reuptake, this hypothesis has not been tested in humans. We asked (a) whether cocaine can inhibit NE reuptake in the human peripheral circulation and (b) whether the NE-mediated peripheral vasoconstriction is the main mechanism mediating blood pressure-raising effect of cocaine., Methods and Results: In 15 healthy cocaine-naive subjects, we measured blood pressure, forearm blood flow, and forearm venous NE concentration during administration of (a) intrabrachial cocaine (0.15 and 15 mg), which produced no systemic neurohormonal effects, and (b) intranasal cocaine (2 mg/kg). Intrabrachial cocaine (0.15 mg) increased venous forearm NE concentration by 82% and vascular resistance by 71% (P<0.01). Increasing the intrabrachial cocaine dose by 100-fold to match the venous cocaine level of massive cocaine overdose caused a small additional increase in venous forearm NE concentration without causing significant additional vasoconstriction. Although intranasal cocaine (2 mg/kg) matched the venous cocaine concentrations caused by 0.15 mg of intrabrachial cocaine, venous NE concentration was unchanged as sympathetic nerve activity (SNA) decreased reflexively as the result of an increase in blood pressure. When SNA was restored to baseline by blunting the cocaine-induced rise in blood pressure (baroreflex activation) with nitroprusside, venous NE concentration increased to the same level caused by intrabrachial cocaine., Conclusions: In healthy cocaine-naive individuals, cocaine can inhibit NE reuptake in the human peripheral circulation. However, this mechanism does not contribute importantly to the blood pressure-raising effect of cocaine because activation of baroreceptor reflexes decreases SNA, the neural stimulus for NE release.

We determined lung microvascular pressure transients induced by 5-hydroxytryptamine (5HT), by the micropuncture technique. We mechanically ventilated anaesthetized (halothane 0.8%), open-chested rabbits, in which we recorded pulmonary artery (PA), left atrial (LA) and carotid artery pressures and cardiac output. For 4-min periods of stopped ventilation, we constantly inflated the lung with airway pressure of 7 cmH2O, then micropunctured the lung to determine pressures in arterioles and venules of 20-25 microm diameter. An intravenous bolus infusion of 5HT (100 microg), increased total pulmonary vascular resistance by 59%. Prior to 5HT infusion, the arterial, microvascular and venous segments comprised 30, 50 and 19% of the total pulmonary vascular pressure drop, respectively. However 14 s after 5HT infusion, the PA-arteriole pressure difference (arterial pressure drop) increased 46%, while the venule-LA pressure difference (venous pressure drop) increased >100%. The arteriole-venule pressure difference (microvascular pressure drop) was abolished. The increase in the arterial pressure drop was maintained for 4.8 min, whereas the increased venous pressure drop reverted to baseline in <1 min. We conclude that in the rabbit lung in situ, a 5HT bolus causes sustained arterial constriction and a strong but transient venous constriction.

It is well documented that exposure to high gravitational (G)-load in the head-to-foot direction may induce arm pain. Such G-induced arm pain is of vascular origin and caused by markedly increased pressure in the arm vessels. It has been hypothesized that the arm pain is due to pressure-induced overdistension of local blood vessels. Indeed, elevation of local intravascular pressure to levels that induce considerable arm pain results in distension of both veins and arteries. There appears to be a paucity of data regarding the effects of repeatedly increasing intravascular pressure in the arms. Accordingly, the purpose of the present study was to investigate the effect of iterative exposures to moderate pressure elevations in the arm vessels (here termed "pressure training") on the pressure distension relationships of the vessels and on pressure-induced arm pain. To experimentally induce increased transmural pressure over the vessel walls of the arms we used a modified version of a method described elsewhere; this method has also proven a useful tool for simulating G-induced arm pain.

Background: The aim of this study was to determine the transmural pressure gradient of epidural veins located within the spinal column and to investigate the effects of increased intra-abdominal and intrathoracic pressure on this gradient., Methods: Fourteen pigs were sedated with ketamine and anesthetized with halothane. Ventilation was controlled after tracheotomy. Needles were inserted into the epidural and subarachnoid space, and a catheter was threaded into an epidural vein. Pressures in these structures were measured during controlled and spontaneous ventilation, increased abdominal pressure, and thoracic compression. Measurements were made in both the thoracic and lumbar regions., Results: The pressure gradient between the epidural vein and the surrounding epidural space was low-11 or 2 mmHg--in both the lumbar and thoracic areas. This gradient was not affected by the mode of ventilation or increased abdominal or thoracic pressure (or both), even though the absolute intramural pressure increased., Conclusion: The pressure gradient between the epidural vein and the surrounding space is low and does not change when abdominal or thoracic pressures are increased.

In dogs anesthetized with pentobarbital sodium, hilar venous pressure (Phv) and secretion were measured from the submandibular gland receiving spontaneous blood flow or vascular perfusion at the normal resting flow rate. Parasympathetic nerve stimulation and ACh-induced secretion increased Phv and its pulse pressure; Phv also showed an obvious arterial (or perfusion pressure)-like waveform. Vasoactive intestinal polypeptide (VIP) exerted similar effects on Phv but produced negligible secretion. Sympathetic nerve stimulation, phenylephrine, and clonidine did not induce secretion and had no significant action on Phv, whereas isoproterenol provoked secretion and changed Phv as with parasympathetic stimulation. Background or superimposed sympathetic nerve stimulation reduced the parasympathetic nerve-induced responses; the sympathetic inhibition was abolished by phentolamine and yohimbine but not by prazosin and propranolol. The results suggest a direct relationship between Phv and secretion during parasympathetic salivation: the elevation in Phv was primarily independent of the concurrent blood flow response, mediated via muscarinic and peptidergic mechanisms, and related to an opening of arteriovenous anastomoses. Sympathetic inhibition of parasympathetic salivation may be related to prevention of an increased Phv exerted primarily via the alpha2-adrenergic mechanism.

Cardiovascular deconditioning observed in humans during spaceflight has been suggested to be related in part to changes in venous compliance, mechanisms including skeletal muscle deconditioning. However, increased venous compliance was observed during very short term simulations (24 to 48 hours), and during an over 28-day simulation the hyperdistensibility tended to decrease whereas the muscular changes were still present (2). In the first case, muscular changes can not explain the venous alterations because of the short delay. In the second case, the relationship between muscular and venous alterations disappeared. Finally, it is suggested that factors other than muscular ones could explain the changes in venous compliance observed during spaceflights. The fact that orthostatic hypotension has never been observed after hindlimb suspension in the rat raises issue with the use of tail-suspended rats as a valid model for the study of the mechanisms involved in cardiovascular deconditioning induced by spaceflight in humans. However, in vitro altered responsiveness of the vena cava to norepinephrine were observed in rat after spaceflight and tail suspension. The purpose of the experiments was to verify if any change occurs in venous tone measured in vivo in rats after three-week tail suspension.

1. We studied human lower limbs to test the hypothesis that the application of small cumulative venous congestion pressure steps is associated with a reduction in precapillary resistance. 2. Strain gauge plethysmography was performed on twenty-one young subjects (22.7 +/- 0.6 years). At each of the small cumulative pressure steps, limb blood flow was estimated from the initial slope of the volume response to transient (10 s duration) elevations of venous congestion pressure to 90 mmHg, after which the congestion pressure was returned to the previous value. The blood flow at each pressure was also expressed as a percentage of the initial control value. Peak tibial arterial blood flux was assessed, in four of the subjects, using colour duplex ultrasonography and the same congestion pressure protocol. 3. We used Darcy's Law to predict the limb arterial blood flow and blood flux at each venous congestion pressure, assuming that both mean arterial blood pressure and precapillary resistance remained constant. 4. The mean +/- S.E.M. control arterial blood flow at the lowest venous congestion pressure, 4.8 +/- 0.1 mmHg, was 2.77 +/- 0.18 ml min-1 (100 ml)-1. At the highest venous congestion pressure, 59.2 +/- 0.2 mmHg, arterial blood flow was 2.45 +/- 0.35 ml min-1 (100 ml)-1 (121.6 +/- 16.9% of the initial value). This did not differ significantly from the initial control value, but was significantly greater than the predicted value of 0.77 +/- 0.13 ml min-1 (100 ml)-1 (28.6 +/- 2.1% of the initial value) calculated assuming constant resistance and sustained mean arterial pressure. The tibial arterial peak blood flux at 58.3 mmHg venous congestion pressure was 102.2 +/- 2.3% of the control value, which was significantly greater than the predicted 17.2 +/- 1.3% of control, calculated for this pressure, assuming constant resistance and sustained mean arterial pressure. 5. Our data show that lower limb arterial blood flow is sustained when venous congestion pressure is raised using small cumulative steps, even at congestion pressures approaching mean arterial blood pressure. These data support the notion that precapillary resistance is influenced by signals generated at the microvascular and post microvascular levels and transmitted via the endothelium.

The initial stages of hypertension in the spontaneously hypertensive rat (SHR) are characterized by an increase in cardiac output. Venous capacitance plays an important role in the control of cardiac output. This study tested the hypothesis that venous tone is elevated in the developmental stages of spontaneous hypertension. Male SHR or normotensive Wistar-Kyoto (WKY) rats were instrumented for the measurement of arterial pressure (FAP) and intrathoracic vena caval pressure (FVP). A latex-tipped catheter was advanced into the right atrium via the jugular vein. Mean circulatory filling pressure (MCFP), an index of integrated venomotor tone, was calculated as MCFP=FVP+(FAP-FVP)/VAR. FAP and FVP were recorded after 5 seconds of right atrial balloon inflation. The venous to arterial compliance ratio (VAR) was estimated as 76 for WKY and 106 for SHR. Mean arterial pressure (MAP), heart rate, and MCFP were recorded in conscious rats of 4 to 6 and 8 to 10 weeks of age. In 4- to 6-week-old rats, both MAP and MCFP were significantly elevated in the SHR (MAP, 129+/-6 mm Hg; MCFP, 6.6+/-0.4 mm Hg) compared with the age-matched WKY (MAP, 91+/-6 mm Hg; MCFP, 5.4+/-0.4 mm Hg), whereas heart rate was not significantly different. The elevations in MAP (SHR, 144+/-4 mm Hg; WKY, 102+/-3 mm Hg) and MCFP (SHR, 7.7+/-0.3 mm Hg; WKY, 6.0+/-0.2 mm Hg) in SHR were exaggerated at 8 to 10 weeks of age. After ganglionic blockade (chlorisondamine; 10 mg/kg), the differences in MCFP were no longer statistically significant between SHR and WKY at both 4 to 6 weeks of age (3.9+/-0.2 versus 4.0+/-0.3 mm Hg) and 8 to 10 weeks of age (5.0+/-0.3 versus 4.3+/-0.3 mm Hg, respectively). The differences in MAP at 4 to 6 weeks of age (79+/-7 versus 67+/-5 mm Hg, respectively) also were not statistically significant after ganglionic blockade. However, a significant difference in MAP between strains remained after ganglionic blockade in 8- to 10-week-old rats (90+/-5 versus 63+/-3 mm Hg, respectively). These findings indicate that venous tone is increased via autonomic effector systems during the developmental stages of spontaneous hypertension. These data also suggest that autonomic mechanisms predominate at very early stages, whereas nonautonomic mechanisms assume more importance in maintaining the elevated MAP as hypertension progresses.

In this study, we compared the level of myogenic tone and its negative-feedback control through specific K+ channels in two types of human veins (saphenous [SV] and cephalic [CV] veins), which experience different ranges of pressure in vivo. We also investigated whether an experimental model of increased venous pressure in rats exposed to head-up tilt for 2 weeks produced changes similar to those observed in the human veins. Cylindrical vein segments were cannulated, their diameters were measured, and the intraluminal pressure was set at different levels (2 to 30 mm Hg) in vitro. Acetylcholine test showed that during the regular harvesting process 76% of the human SVs exposed for coronary bypass grafts had no functional endothelium. We found significant myogenic tone in the human SV, where the in vivo pressure is high, but it was not present in the human CV, where the in vivo pressure is low. The nonspecific K+ channel antagonist, tetraethylammonium (TEA), decreased the diameter of the human SV but not the CV. Iberiotoxin and 4-aminopyridine, blockers of the Ca(2+)-sensitive (KCa) and voltage-gated K+ (KV) channels, also decreased the diameter of the human SV by 10.2 +/- 4.8% and 19.5 +/- 4.7%, respectively. In the rat SV, significant myogenic tone was found, but TEA had no effect, even after 2 weeks of in vivo pressure increase in the hindlimb by head-up tilt. We conclude that (1) an increased venous myogenic tone correlates with higher chronic intraluminal pressure loads, (2) KCa and KV channels counterregulate the myogenic tone in human, but not in rat, saphenous vein, (3) the counterregulatory effect is more effective at high than at low intraluminal in vitro pressure levels, and (4) its development is probably a long-term process.

The aim of this study is to define the effect of sublingually administered nitroglycerin (NTG) on the diameters of the forearm arteries and veins as well as to define the relationship between these vascular changes and the forearm circumference in healthy volunteers. For this purpose, we employed a noninvasive method permitting the simultaneous quantitative recording of vascular diameters, forearm circumference and blood pressure using a miniature load cell, linear differential transformers and mercury-in-rubber strain gauge. Sublingually administered NTG (0.3 mg) increased the radial arterial diameter and the forearm circumference, whereas the cephalic vein capacitance was decreased; consequently, the cephalic vein acts to moderate the increase in forearm circumference. The results clearly indicate that nitroglycerin dilates forearm arteries but not forearm veins in the normal state.

The role of pressure pulsatility in the arterial pressure control by the carotid baroreflex was investigated by means of a mathematical model. The model describes the main hemodynamic properties of the cardiovascular system in pulsating conditions, the static and dynamic components of the carotid baroreflex, and their effect on systemic arterial resistance, heart frequency and systemic venous capacity. Experimental findings on the role of pressure pulsatility in the carotid baroreflex were reproduced in terms of a non-linear interaction between the static and dynamic components. Simulations of physiological experiments (mild haemorrhage, carotid occlusion manoeuvres, genesis of self-sustained arterial pressure waves) reveal that the role of pressure pulsatility is meaningful in response to those perturbations (such as carotid occlusion manoeuvres) characterized by different alterations in the mean and pulsating components.

This double-blind, placebo-controlled crossover study was designed to differentiate the pharmacodynamic effects of the angiotensin II receptor antagonist losartan from the angiotensin converting enzyme inhibitor enalapril. Effects of placebo, enalapril (10 mg), and losartan (20 and 100 mg) on local venous and systemic pressor responses to angiotensin I and II were compared in eight healthy male subjects. Treatments were administered orally approximately 4 hours before agonist infusions into a dorsal hand vein. Local changes in hand vein diameter and systemic blood pressure were monitored during the infusions. The 100 mg dose of losartan attenuated local venoconstrictor and systemic pressor responses to angiotensin I and II. In contrast, enalapril blocked only responses to angiotensin I. Both losartan and enalapril increased plasma renin concentration compared with placebo. These results are consistent with direct antagonism of angiotensin II receptors by losartan and with indirect effects of enalapril through inhibition of angiotensin converting enzyme.

1. The effects of the potassium channel opener, pinacidil, on mean arterial pressure (MAP), mean circulatory filling pressure (MCFP), total peripheral resistance (TPR), cardiac output (CO) and resistance to venous return (Rv) were studied in rats. 2. In pentobarbitone-anaesthetized rats given mecamylamine (ganglionic blocker, 3.7 micrograms kg-1) and noradrenaline (1.5 micrograms kg-1 min-1) to suppress autonomic reflexes, pinacidil (60 and 180 micrograms kg-1 min-1), relative to the vehicle, reduced MAP and TPR in a dose-dependent manner but did not significantly alter CO, MCFP or RV. 3. Pinacidil (10-300 micrograms kg-1 min-1) caused similar increases in MCFP, an inverse index of venous compliance, and similar dose-dependent reductions in mean arterial pressure (MAP) in conscious, intact rats and rats infused with the ganglionic blocker, hexamethonium (150 micrograms kg-1 min-1). In rats with vasomotor tone elevated by the infusion of noradrenaline (1.5 micrograms kg-1 min-1), pinacidil caused markedly greater depressor responses but did not significantly alter MCFP. 4. Our results show that pinacidil is an efficacious vasodilator of arterial resistance blood vessels but has little venodilator activity.

The relationship between strength of short-term whole body autoregulation and peripheral resistance in the reference state (initial resistance) was investigated in 9 anesthetized closed-chest dogs and 18 anesthetized open-chest cats. Baroreflex regulation was abolished in one of three ways: barodenervation, ganglionic blockade, or setting pressure constant in the isolated carotid sinuses after vagotomy. Ascending aortic pressure and flow and venous pressure were measured in the reference state and 1-3 min after partial occlusions of the inferior vena cava. Cardiac output and peripheral resistance (ratio between arteriovenous pressure difference and cardiac output) were normalized for body weight. Strength of autoregulation was quantified by a resistance gain (Gra), defined as the ratio between change in normalized peripheral resistance and corresponding change in normalized cardiac output. A broad range of values for peripheral resistance in the reference state (Ro) was obtained as a result of the different interventions used to abolish baroreflex regulation. Arteriovenous pressure difference and normalized cardiac output during multiple vena cava occlusions in the 9 dogs and in 8 of the cats were fitted with a parabola convex to the flow axis. From the best fit, Gra was estimated. In the remaining 10 cats Gra was estimated from a single occlusion of vena cava. When data of all dogs and cats were taken together, we found a linear relationship between Gra and Ro: Gra = K1.Ro + K2. The constants K1 and K2 were 17.9 x 10(-3) min.kg.ml-1 and -14.5 x 10(-3) mmHg.min2.kg2.ml-2, respectively. The correlation coefficient was 0.9.

1. Venous resistance contributes very little to total peripheral resistance; more than half of the total blood volume, however, is contained in the extrathoracic veins. Owing to marked differences between venous and arterial anatomy and physiology, studies on veins and arteries usually require different methodological approaches. Whereas for arteries the most relevant parameters are resistance, pressure and flow, for veins volume and compliance are most important. For studies of general aspects of the peripheral circulatory system, venous occlusion plethysmography is probably the most useful method. The determination of both the rate of rise in limb volume and the total volume rise after inflating a proximally applied occlusion cuff to a subdiastolic pressure permits the concomitant estimation of both arterial flow and venous compliance. 2. Studies of direct pharmacological or physiological effects on veins, interactions of various pharmacological or physiological stimuli, or pathophysiological changes in venous responsiveness have been facilitated by the development of investigational techniques relying on direct measurements of the compliance of single human veins in vivo. One of these, relying on the use of a linear variable differential transformer (LVDT) for determining changes in the compliance of superficial veins at a standardized congestion pressure, has been found very suitable for the practical application in both patients and healthy subjects. 3. Physiological studies were carried out on the effect of age, exercise, temperature, and the menstrual cycle on venous compliance and venous responsiveness to various stimuli. In addition, interindividual variability in venous responsiveness in monozygotic and dizygotic twins and in unrelated subjects was investigated, and studies on the function of the endothelium were carried out in man in vivo. 4. Pathophysiological studies using this technique were reported from patients with hypertension, orthostatic hypotension, myocardial infarction, varicosis, cystic fibrosis, asthma, diabetes, systemic sclerosis, and cluster headache. 5. Clinical pharmacological studies represent a most important field for the use of this method. Studies were carried out on the effects of a large number of constrictor and dilator agents, and also on drug interactions on human veins in vivo. Venoconstriction was observed after local administration of alpha-adrenoceptor and 5-HT-receptor agonists, ergot derivatives, angiotensinogen, angiotensin I and II, and several prostaglandins. 6. Owing to the low venous tone present under effects can usually be quantified only on veins e.g. noradrenaline or 5-hydroxytryptamine. Under these conditions dilatation was observed after the administration of beta-adrenoceptor agonists, cholinergic (muscarinic) agonists, nitrates, calcium antagonists, bradykinin, substance P and several prostaglandins.