Leg vasoconstriction during head-up tilt in patients with autonomic failure is not abolished

Maintaining blood pressure during orthostatic challenges is primarily achieved by baroreceptor-mediated activation of the sympathetic nervous system, which can be divided into preganglionic and postganglionic parts. Despite their preganglionic autonomic failure, spinal cord-injured individuals demonstrate a preserved peripheral vasoconstriction during orthostatic challenges. Whether this also applies to patients with postganglionic autonomic failure is unknown. Therefore, we assessed leg vasoconstriction during 60° head-up tilt in five patients with pure autonomic failure (PAF) and two patients with autonomic failure due to dopamine-β-hydroxylase (DBH) deficiency. Ten healthy subjects served as controls. Leg blood flow was measured using duplex ultrasound in the right superficial femoral artery. Leg vascular resistance was calculated as the arterial-venous pressure gradient divided by blood flow. DBH-deficient patients were tested off and on the norepinephrine pro-drug l-threo-dihydroxyphenylserine (l-DOPS). During 60° head-up tilt, leg vascular resistance increased significantly in PAF patients [0.40 ± 0.38 (+30%) mmHg·ml(-1)·min(-1)]. The increase in leg vascular resistance was not significantly different from controls [0.88 ± 1.04 (+72%) mmHg·ml(-1)·min(-1)]. In DBH-deficient patients, leg vascular resistance increased by 0.49 ± 0.01 (+153%) and 1.52 ± 1.47 (+234%) mmHg·ml(-1)·min(-1) off and on l-DOPS, respectively. Despite the increase in leg vascular resistance, orthostatic hypotension was present in PAF and DBH-deficient patients. Our results demonstrate that leg vasoconstriction during orthostatic challenges in patients with PAF or DBH deficiency is not abolished. This indicates that the sympathetic nervous system is not the sole or pivotal mechanism inducing leg vasoconstriction during orthostatic challenges. Additional vasoconstrictor mechanisms may compensate for the loss in sympathetic nervous system control.     

Effects of 18 days of bed rest on leg and arm venous properties.

Venous function may be altered by bed rest deconditioning. Yet the contribution of altered venous compliance to the orthostatic intolerance observed after bed rest is uncertain. The purpose of this study was to assess the effect of 18 days of bed rest on leg and arm (respectively large and small change in gravitational gradients and use patterns) venous properties. We hypothesized that the magnitude of these venous changes would be related to orthostatic intolerance. Eleven healthy subjects (10 men, 1 woman) participated in the study. Before (pre) and after (post) 18 days of 6 degrees head-down tilt bed rest, strain gauge venous occlusion plethysmography was used to assess limb venous vascular characteristics. Leg venous compliance was significantly decreased after bed rest (pre: 0.048 +/- 0.007 ml x 100 ml(-1) x mmHg(-1), post: 0.033 +/- 0.007 ml x 100 ml(-1) x mmHg(-1); P < 0.01), whereas arm compliance did not change. Leg venous flow resistance increased significantly after bed rest (pre: 1.73 +/- 1.08 mmHg x ml(-1) x 100 ml x min, post: 3.10 +/- 1.00 mmHg x ml(-1) x 100 ml x min; P < 0.05). Maximal lower body negative pressure tolerance, which was expressed as cumulative stress index (pressure x time), decreased in all subjects after bed rest (pre: 932 mmHg x min, post: 747 mmHg x min). The decrease in orthostatic tolerance was not related to changes in leg venous compliance. In conclusion, this study demonstrates that after bed rest, leg venous compliance is reduced and leg venous outflow resistance is enhanced. However, these changes are not related to measures of orthostatic tolerance; therefore, alterations in venous compliance do not to play a major role in orthostatic intolerance after 18 days of head-down tilt bed rest.     

Leg intravenous pressure during head-up tilt

Leg vascular resistance is calculated as the arterial-venous pressure gradient divided by blood flow. During orthostatic challenges it is assumed that the hydrostatic pressure contributes equally to leg arterial, as well as to leg venous pressure. Because of venous valves, one may question whether, during orthostatic challenges, a continuous hydrostatic column is formed and if leg venous pressure is equal to the hydrostatic pressure. The purpose of this study was, therefore, to measure intravenous pressure in the great saphenous vein of 12 healthy individuals during 30 degrees and 70 degrees head-up tilt and compare this with the calculated hydrostatic pressure. The height difference between the heart and the right medial malleolus level represented the hydrostatic column. The results demonstrate that there were no differences between the measured intravenous pressure and the calculated hydrostatic pressure during 30 degrees (47.2 +/- 1.0 and 46.9 +/- 1.5 mmHg, respectively) and 70 degrees head-up tilt (83.9 +/- 0.9 and 85.1 +/- 1.2 mmHg, respectively). Steady-state levels of intravenous pressure were reached after 95 +/- 12 s during 30 degrees and 161 +/- 15 s during 70 degrees head-up tilt. In conclusion, the measured leg venous pressure is similar to the calculated hydrostatic pressure during orthostatic challenges. Therefore, the assumption that hydrostatic pressure contributes equally to leg arterial as well as to leg venous pressure during orthostatic challenges can be made.     

Lower limb-localized vascular phenomena explain initial orthostatic hypotension upon standing from squat

The cause(s) of initial orthostatic hypotension (transient fall in blood pressure within 15 s upon active rising) have not been established. We tested the hypothesis that this hypotension is due to local vascular phenomena in contracting leg muscles from the brief effort of standing up. Seventeen young healthy subjects (2 male and 15 female, 22.5 ± 1.0 years) performed an active rise from resting squat after a 10-s squat, a 1-min squat, or a 5-min squat. Beat-by-beat arterial blood pressure, cardiac output, heart rate, and stroke volume (Finometer finger photoplethysmography) and right common femoral artery blood flow (Doppler and Echo ultrasound) were recorded. Data are means ± SE. Quiet standing before squat represented baseline. Peak increases in lower limb and total vascular conductance (ml·min(-1)·mmHg(-1)) upon standing were not different within squat conditions (10-s squat, 50.0 ± 12.4 vs. 44.3 ± 5.0; 1-min squat, 54.7 ± 9.2 vs. 50.5 ± 4.5; 5-min squat, 67.4 ± 13.7 vs. 58.8 ± 3.9; all P > 0.574). Mean arterial blood pressure (in mmHg) fell to a nadir well below standing baseline in all conditions despite increases in cardiac output. The hypotension predicted by the increase in leg vascular conductance accounted for this hypotension [observed vs. predicted (in mmHg): 10-s squat, -17.1 ± 2.1 vs. -18.3 ± 5.5; 1-min squat, -22.0 ± 3.8 vs. -25.3 ± 4.9; 5-min squat, -28.3 ± 4.0 vs. -29.2 ± 6.7]. We conclude that rapid contraction induced dilation in leg muscles with the effort of standing, along with a minor potential contribution of elevated lower limb arterio-venous pressure gradient, outstrips compensatory cardiac output responses and is the cause of initial orthostatic hypotension upon standing from squat.     

Enhanced open-loop but not closed-loop cardiac baroreflex sensitivity during orthostatic stress in humans

The neural interaction between the cardiopulmonary and arterial baroreflex may be critical for the regulation of blood pressure during orthostatic stress. However, studies have reported conflicting results: some indicate increases and others decreases in cardiac baroreflex sensitivity (i.e., gain) with cardiopulmonary unloading. Thus the effect of orthostatic stress-induced central hypovolemia on regulation of heart rate via the arterial baroreflex remains unclear. We sought to comprehensively assess baroreflex function during orthostatic stress by identifying and comparing open- and closed-loop dynamic cardiac baroreflex gains at supine rest and during 60° head-up tilt (HUT) in 10 healthy men. Closed-loop dynamic "spontaneous" cardiac baroreflex sensitivities were calculated by the sequence technique and transfer function and compared with two open-loop carotid-cardiac baroreflex measures using the neck chamber system: 1) a binary white-noise method and 2) a rapid-pulse neck pressure-neck suction technique. The gain from the sequence technique was decreased from -1.19 ± 0.14 beats·min(-1)·mmHg(-1) at rest to -0.78 ± 0.10 beats·min(-1)·mmHg(-1) during HUT (P = 0.005). Similarly, closed-loop low-frequency baroreflex transfer function gain was reduced during HUT (P = 0.033). In contrast, open-loop low-frequency transfer function gain between estimated carotid sinus pressure and heart rate during white-noise stimulation was augmented during HUT (P = 0.01). This result was consistent with the maximal gain of the carotid-cardiac baroreflex stimulus-response curve (from 0.47 ± 0.15 beats·min(-1)·mmHg(-1) at rest to 0.60 ± 0.20 beats·min(-1)·mmHg(-1) at HUT, P = 0.037). These findings suggest that open-loop cardiac baroreflex gain was enhanced during HUT. Moreover, under closed-loop conditions, spontaneous baroreflex analyses without external stimulation may not represent open-loop cardiac baroreflex characteristics during orthostatic stress.     

Leg crossing improves orthostatic tolerance in healthy subjects: a placebo-controlled crossover study

Vasovagal syncope is the most common cause of transient loss of consciousness, and recurrent vasovagal fainting has a profound impact on quality of life. Physical countermaneuvers are applied as a means of tertiary prevention but have so far only proven useful at the onset of a faint. This placebo-controlled crossover study tested the hypothesis that leg crossing increases orthostatic tolerance. Nine na?ve healthy subjects [6 females, median age 25 yr (range 20-41 yr), mean body mass index 23 (SD 2)] were subjected to passive head-up tilt combined with a graded lower body negative pressure challenge (20, 40, and 60 mmHg) determining orthostatic tolerance thrice, in randomized order: 1) control, 2) with leg crossing, and 3) with oral placebo. Blood pressure (Finometer), heart rate, and changes in thoracic blood volume (impedance), stroke volume, and cardiac output (Modelflow) were followed during orthostatic stress. Primary outcome was time to presyncope (systolic blood pressure /=140 beats/min). With leg crossing, orthostatic tolerance increased from 26 +/- 2 to 34 +/- 2 min (placebo 23 +/- 3 min, P < 0.001). During leg crossing, mean arterial pressure (81 vs. 81 mmHg) and cardiac output (95 vs. 94% supine) remained unchanged; heart rate increase was lower (13 vs. 18 beats/min, P < 0.05); stroke volume was higher (79 vs. 74% supine, P < 0.05); and there was a trend toward lower thoracic impedance. Leg crossing increases orthostatic tolerance in healthy human subjects. As a measure of prevention, it is a worthwhile addition to the management of vasovagal syncope.     

Pathophysiology of orthostatic hypotension after bed rest: paradoxical sympathetic withdrawal

Although orthostatic hypotension is a common clinical syndrome after spaceflight and its ground-based simulation model, 6 degrees head-down bed rest (HDBR), the pathophysiology remains unclear. The authors' hypothesis that a decrease in sympathetic nerve activity is the major pathophysiology underlying orthostatic hypotension after HDBR was tested in a study involving 14-day HDBR in 22 healthy subjects who showed no orthostatic hypotension during 15-min 60 degrees head-up tilt test (HUT) at baseline. After HDBR, 10 of 22 subjects demonstrated orthostatic hypotension during 60 degrees HUT. In subjects with orthostatic hypotension, total activity of muscle sympathetic nerve activity (MSNA) increased less during the first minute of 60 degrees HUT after HDBR (314% of resting supine activity) than before HDBR (523% of resting supine activity, P < 0.05) despite HDBR-induced reduction in plasma volume (13% of plasma volume before HDBR). The postural increase in total MSNA continued during several more minutes of 60 degrees HUT while arterial pressure was maintained. Thereafter, however, total MSNA was paradoxically suppressed by 104% of the resting supine level at the last minute of HUT (P < 0.05 vs. earlier 60 degrees HUT periods). The suppression of total MSNA was accompanied by a 22 +/- 4-mmHg decrease in mean blood pressure (systolic blood pressure <80 mmHg). In contrast, orthostatic activation of total MSNA was preserved throughout 60 degrees HUT in subjects who did not develop orthostatic hypotension. These data support the hypothesis that a decrease in sympathetic nerve activity is the major pathophysiological factor underlying orthostatic hypotension after HDBR. It appears that the diminished sympathetic activity, in combination with other factors associated with HDBR (e.g., hypovolemia), may predispose some individuals to postural hypotension.     

Reflex vascular defects in the orthostatic tachycardia syndrome of adolescents.

Dependent pooling occurs in postural orthostatic tachycardia syndrome (POTS) related to defective vasoconstriction. Increased venous pressure (Pv) >20 mmHg occurs in some patients (high Pv) but not others (normal Pv). We compared 22 patients, aged 12-18 yr, with 13 normal controls. Continuous blood pressure and strain-gauge plethysmography were used to measure supine forearm and calf blood flow, resistance, venous compliance, and microvascular filtration, and blood flow and swelling during 70 degrees head-up tilt. Supine, high Pv had normal resistance in arms (26 +/- 2 mmHg x ml(-1) x 100 ml x min) and legs (34 +/- 3 mmHg x ml(-1) x 100 ml x min) but low leg blood flow (1.5 +/- 0.4 ml x 100 ml(-1) x min(-1)). Supine leg Pv (30 +/- 2 vs. 13 +/- 1 mmHg in control) exceeded the threshold for edema (isovolumetric pressure = 19 +/- 3 mmHg). Supine, normal Pv had high blood flow in arms (4.1 +/- 0.2 vs. 3.5 +/- 0.2 ml x 100 ml(-1) x min(-1) in control) and legs (3.8 +/- 0.4 vs. 2.7 +/- 0.3 ml x 100 ml(-1) x min(-1) in control) with low resistance. With tilt, calf blood flow increased steadily in POTS with high Pv and transiently increased in normal Pv. Calf volume increased in all POTS patients. Arm blood flow increased in normal Pv only with forearm maintained at heart level. These data suggest that there are (at least) two subgroups of POTS characterized by high Pv and low flow or normal Pv and high flow. These may correspond to abnormalities in local or baroreceptor-mediated vasoconstriction, respectively.     

Cardiovascular response to functional electrical stimulation and dynamic tilt table therapy to improve orthostatic tolerance

Orthostatic hypotension is a common condition for individuals with stroke or spinal cord injury. The inability to regulate the central nervous system will result in pooling of blood in the lower extremities leading to orthostatic intolerance. This study compared the use of functional electrical stimulation (FES) and passive leg movements to improve orthostatic tolerance during head-up tilt. Four trial conditions were assessed during head-up tilt: (1) rest, (2) isometric FES of the hamstring, gastrocnemius and quadriceps muscle group, (3) passive mobilization using the Erigo dynamic tilt table; and (4) dynamic FES (combined 2 and 3). Ten healthy male subjects experienced 70 degrees head-up tilt for 15 min under each trial condition. Heart rate, blood pressure and abdominal echograms of the inferior vena cava were recorded for each trial. Passive mobilization and dynamic FES resulted in an increase in intravascular blood volume, while isometric FES only resulted in elevating heart rate. No significant differences in blood pressure were observed under each condition. We conclude that FES combined with passive stepping movements may be an effective modality to increase circulating blood volume and thereby tolerance to postural hypotension in healthy subjects.     

Role of splanchnic constriction in governing the hemodynamic responses to gravitational stress in conscious dogs

Octreotide is a somatostatin analog that constricts the splanchnic circulation, thereby improving orthostatic tolerance. We tested the hypotheses that octreotide improves orthostatic tolerance by 1)increasing cardiac filling (right atrial) pressure via reductions in vascular capacity; 2) by causing an upward (i.e., cranial) shift of the hydrostatic indifferent point; and 3) by increasing arterial pressure via a reduction in total vascular conductance. Studies were carried out in acepromazine-sedated, hexamethonium-treated atrioventricular-blocked conscious dogs lightly restrained in lateral recumbency. Beat-by-beat cardiac output was held constant via computer-controlled ventricular pacing at rest and during 30 s of 30° head-up tilt. Octreotide (1.5 μg/kg iv) raised right atrial pressure by 0.5 mmHg and raised mean arterial pressure by 11 mmHg by reducing total vascular conductance (all P < 0.05). Right atrial pressure fell by a similar amount in response to tilting before and after octreotide, thus there was no difference in location of the hydrostatic indifferent point. These data indicate that octreotide improves orthostatic tolerance by decreasing total vascular conductance and by increasing cardiac filling pressure via a reduction in unstressed vascular volume and not by eliciting a cranial shift of the location of the hydrostatic indifferent point.     

Effect of lower-body positive pressure on postural fluid shifts in men

To quantify the effect of 60 mm Hg lower-body positive pressure (LBPP) on orthostatic blood-volume shifts, the mass densities (+/- 0.1 g.1-1) of antecubital venous blood and plasma were measured in five men (27-42 years) during combined tilt table/antigravity suit inflation and deflation experiments. The densities of erythrocytes, whole-body blood, and of the shifted fluid were computed and the magnitude of fluid and protein shifts were calculated during head-up tilt (60 degrees) with and without application of LBPP. During 30-min head-up tilt with LBPP, blood density (BD) and plasma density (PD) increased by 1.6 +/- 0.3 g.1-1, and by 0.8 +/- 0.2 g.1-1 (+/- SD) (N = 9), respectively. In the subsequent period of tilt without LBPP, BD and PD increased further to + 3.6 +/- 0.9 g.1-1, and to + 2.0 +/- 0.7 g.1-1 (N = 7), compared to supine control. The density increases in both periods were significant (p less than 0.05). Erythrocyte density remained unaltered with changes in body position and pressure suit inflation/deflation. Calculated shifted-fluid densities (FD) during tilt with LBPP (1006.0 +/- 1.1 g.1-1, N = 9), and for subsequent tilt after deflation (1002.8 +/- 4.1 g.1-1, N = 7) were different from each other (p less than 0.03). The plasma volume decreased by 6.0 +/- 1.2% in the tilt-LBPP period, and by an additional 6.4 +/- 2.7% of the supine control level in the subsequent postdeflation tilt period. The corresponding blood volume changes were 3.7 +/- 0.7% (p less than 0.01), and 3.5 +/- 2.1% (p less than 0.05), respectively. Thus, about half of the postural hemo-concentration occurring during passive head-up tilt was prevented by application of 60 mm Hg LBPP.     

Impact of chronic exercise training on the blood pressure response to orthostatic stimulation

Exercise training elicits morphological adaptations in the left ventricle (LV) and large-conduit arteries that are specific to the type of training performed (i.e., endurance vs. resistance exercise). We investigated whether the mode of chronic exercise training, and the associated cardiovascular adaptations, influence the blood pressure responses to orthostatic stimulation in 30 young healthy men (10 sedentary, 10 endurance trained, and 10 resistance trained). The endurance-trained group had a significantly larger LV end-diastolic volume normalized by body surface area (vs. sedentary and resistance-trained groups), whereas the resistance-trained group had a significantly higher LV wall thickness and aortic pulse wave velocity (PWV) compared with the endurance-trained group. In response to 60° head-up tilt (HUT), mean arterial pressure (MAP) rose in the resistance-trained group (+6.5 ± 1.6 mmHg, P < 0.05) but did not change significantly in sedentary and the endurance-trained groups. Systolic blood pressure (SBP) decreased in endurance-trained group (-8.3 ± 2.4 mmHg, P < 0.05) but did not significantly change in sedentary and resistance-trained groups. A forward stepwise multiple regression analysis revealed that LV wall thickness and aortic PWV were significantly and independently associated with the MAP response to HUT, explaining ～41% of its variability (R(2) =0.414, P < 0.001). Likewise, aortic PWV and the corresponding HUT-mediated change in stroke volume were significantly and independently associated with the SBP response to HUT, explaining ～52% of its variability (R(2) = 0.519, P < 0.0001). Furthermore, the change in stroke volume significantly correlated with LV wall thickness (r = 0.39, P < 0.01). These results indicate that chronic resistance and endurance exercise training differentially affect the BP response to HUT, and that this appears to be associated with training-induced morphological adaptations of the LV and large-conduit arteries.     

Vascular perturbations in the chronic orthostatic intolerance of the postural orthostatic tachycardia syndrome.

Chronic orthostatic intolerance is often related to the postural orthostatic tachycardia syndrome (POTS). POTS is characterized by upright tachycardia. Understanding of its pathophysiology remains incomplete, but edema and acrocyanosis of the lower extremities occur frequently. To determine how arterial and venous vascular properties account for these findings, we compared 13 patients aged 13-18 yr with 10 normal controls. Heart rate and blood pressure were continuously recorded, and strain-gauge plethysmography was used to measure forearm and calf blood flow, venous compliance, and microvascular filtration while the subject was supine and to measure calf blood flow and calf size change during head-up tilt. Resting venous pressure was higher in POTS compared with control (16 vs. 10 mmHg), which gave the appearance of decreased compliance in these patients. The threshold for edema formation decreased in POTS patients compared with controls (8.3 vs. 16.3 mmHg). With tilt, early calf blood flow increased in POTS patients (from 3.4 +/- 0.9 to 12.6 +/- 2.3 ml. 100 ml(-1). min(-1)) but did not increase in controls. Calf volume increased twice as much in POTS patients compared with controls over a shorter time of orthostasis. The data suggest that resting venous pressure is higher and the threshold for edema is lower in POTS patients compared with controls. Such findings make the POTS patients particularly vulnerable for edema fluid collection. This may signify a redistribution of blood to the lower extremities even while supine, accounting for tachycardia through vagal withdrawal.     

Myogenic origin of the hypotension induced by rapid changes in posture in awake dogs following autonomic blockade

The "push-pull" effect denotes the reduced tolerance to +G(z) (hypergravity) when +G(z) stress is preceded by exposure to hypogravity, i.e., fractional, zero, or negative G(z). The purpose of this study was to test the hypothesis that an exaggerated, myogenically mediated rise in leg vascular conductance contributes to the push-pull effect, using heart level arterial blood pressure as a measure of G tolerance. The approach was to impose control (30 s of 30 degrees head-up tilt) and push-pull (30 s of 30 degrees head-up tilt immediately preceded by 10 s of -15 degrees head-down tilt) gravitational stress after administration of hexamethonium (5 mg/kg) to inhibit autonomic ganglionic neurotransmission in seven dogs. Cardiac output or thigh level arterial pressure (myogenic stimulus) was maintained constant by computer-controlled ventricular pacing. The animals were sedated with acepromazine and lightly restrained in lateral recumbency on a tilt table. Following the onset of head-up tilt, the magnitude of the fall in heart level arterial pressure from baseline was -11.6 +/- 2.9 and -17.1 +/- 2.2 mmHg for the control and push-pull trials, respectively (P < 0.05), when cardiac output was maintained constant. Over 40% of the exaggerated fall in heart level arterial pressure was attributable to an exaggerated rise in hindlimb vascular conductance (P < 0.05). Maintaining thigh level arterial pressure constant abolished the exaggerated rise in hindlimb blood flow. Thus a push-pull effect largely attributable to a myogenically induced rise in leg vascular conductance occurs when autonomic function is inhibited.     

Skin surface cooling improves orthostatic tolerance following prolonged head-down bed rest

Prolonged exposure to microgravity, as well as its ground-based analog, head-down bed rest (HDBR), reduces orthostatic tolerance in humans. While skin surface cooling improves orthostatic tolerance, it remains unknown whether this could be an effective countermeasure to preserve orthostatic tolerance following HDBR. We therefore tested the hypothesis that skin surface cooling improves orthostatic tolerance after prolonged HDBR. Eight subjects (six men and two women) participated in the investigation. Orthostatic tolerance was determined using a progressive lower-body negative pressure (LBNP) tolerance test before HDBR during normothermic conditions and on day 16 or day 18 of 6° HDBR during normothermic and skin surface cooling conditions (randomized order post-HDBR). The thermal conditions were achieved by perfusing water (normothermia ～34°C and skin surface cooling ～12-15°C) through a tube-lined suit worn by each subject. Tolerance tests were performed after ～30 min of the respective thermal stimulus. A cumulative stress index (CSI; mmHg LBNP·min) was determined for each LBNP protocol by summing the product of the applied negative pressure and the duration of LBNP at each stage. HDBR reduced normothermic orthostatic tolerance as indexed by a reduction in the CSI from 1,037 ± 96 mmHg·min to 574 ± 63 mmHg·min (P < 0.05). After HDBR, skin surface cooling increased orthostatic tolerance (797 ± 77 mmHg·min) compared with normothermia (P < 0.05). While the reduction in orthostatic tolerance following prolonged HDBR was not completely reversed by acute skin surface cooling, the identified improvements may serve as an important and effective countermeasure for individuals exposed to microgravity, as well as immobilized and bed-stricken individuals.     

Plasma volume restoration with salt tablets and water after bed rest prevents orthostatic hypotension and changes in supine hemodynamic and endocrine variables

Head-down bed rest changes the values of many cardiovascular and endocrine variables and also elicits significant hypovolemia. Because previous studies had not controlled for hypovolemia, it is unknown whether the reported changes were primary effects of bed rest or secondary effects of bed rest-induced hypovolemia. We hypothesized that restoring plasma volume with salt tablets and water after 12 days of head-down bed rest would result in an absence of hemodynamic and endocrine changes and a reduced incidence of orthostatic hypotension. In 10 men, we measured changes from pre-bed-rest to post-bed-rest in venous and arterial pressures; heart rate; stroke volume; cardiac output; vascular resistance; plasma norepinephrine, epinephrine, vasopressin, renin activity (PRA), and aldosterone responses to different tilt levels (0 degrees, -10 degrees, 20 degrees, 30 degrees, and 70 degrees); and plasma volume and platelet alpha2- and lymphocyte beta2-adrenoreceptor densities and affinities (0 degrees tilt only). Fluid loading at the end of bed rest restored plasma volume and resulted in the absence of post-bed-rest orthostatic hypotension and changes in supine hemodynamic and endocrine variables. Fluid loading did not prevent post-bed-rest increases in beta2-adrenoreceptor density or decreases in the aldosterone-to-PRA ratio (P = 0.05 for each). Heart rate, epinephrine, and PRA responses to upright tilt after bed rest were increased (P < 0.05), despite the fluid load. These results suggest that incidents of orthostatic hypotension and many of the changes in supine hemodynamic and endocrine variables in volume-depleted bed-rested subjects occur secondarily to the hypovolemia. Despite normovolemia after bed rest, beta2-adrenoreceptors were upregulated, and heart rate, epinephrine, and PRA responses to tilt were augmented, indicating that these changes are independent of volume depletion.     

Hemodynamics of orthostatic intolerance: implications for gender differences

Women have a greater incidence of orthostatic intolerance than men. We hypothesized that this difference is related to hemodynamic effects on regulation of cardiac filling rather than to reduced responsiveness of vascular resistance during orthostatic stress. We constructed Frank-Starling curves from pulmonary capillary wedge pressure (PCWP), stroke volume (SV), and stroke index (SI) during lower body negative pressure (LBNP) and saline infusion in 10 healthy young women and 13 men. Orthostatic tolerance was determined by progressive LBNP to presyncope. LBNP tolerance was significantly lower in women than in men (626.8 +/- 55.0 vs. 927.7 +/- 53.0 mmHg x min, P < 0.01). Women had steeper maximal slopes of Starling curves than men whether expressed as SV (12.5 +/- 2.0 vs. 7.1 +/- 1.5 ml/mmHg, P < 0.05) or normalized as SI (6.31 +/- 0.8 vs. 4.29 +/- 0.6 ml.m-2.mmHg-1, P < 0.05). During progressive LBNP, PCWP dropped quickly at low levels, and reached a plateau at high levels of LBNP near presyncope in all subjects. SV was 35% and SI was 29% lower in women at presyncope (both P < 0.05). Coincident with the smaller SV, women had higher heart rates but similar mean arterial pressures compared with men at presyncope. Vascular resistance and plasma norepinephrine concentration were similar between genders. We conclude that lower orthostatic tolerance in women is associated with decreased cardiac filling rather than reduced responsiveness of vascular resistance during orthostatic challenges. Thus cardiac mechanics and Frank-Starling relationship may be important mechanisms underlying the gender difference in orthostatic tolerance.     

Microvascular response to metabolic and pressure challenge in the human coronary circulation

In vivo observations of microcirculatory behavior during autoregulation and adaptation to varying myocardial oxygen demand are scarce in the human coronary system. This study assessed microvascular reactions to controlled metabolic and pressure provocation [bicycle exercise and external counterpulsation (ECP)]. In 20 healthy subjects, quantitative myocardial contrast echocardiography and arterial applanation tonometry were performed during increasing ECP levels, as well as before and during bicycle exercise. Myocardial blood flow (MBF; ml·min(-1)·g(-1)), the relative blood volume (rBV; ml/ml), the coronary vascular resistance index (CVRI; dyn·s·cm(-5)/g), the pressure-work index (PWI), and the pressure-rate product (mmHg/min) were assessed. MBF remained unchanged during ECP (1.08 ± 0.44 at baseline to 0.92 ± 0.38 at high-level ECP). Bicycle exercise led to an increase in MBF from 1.03 ± 0.39 to 3.42 ± 1.11 (P < 0.001). The rBV remained unchanged during ECP, whereas it increased under exercise from 0.13 ± 0.033 to 0.22 ± 0.07 (P < 0.001). The CVRI showed a marked increase under ECP from 7.40 ± 3.38 to 11.05 ± 5.43 and significantly dropped under exercise from 7.40 ± 2.78 to 2.21 ± 0.87 (both P < 0.001). There was a significant correlation between PWI and MBF in the pooled exercise data (slope: +0.162). During ECP, the relationship remained similar (slope: +0.153). Whereas physical exercise decreases coronary vascular resistance and induces considerable functional capillary recruitment, diastolic pressure transients up to 140 mmHg trigger arteriolar vasoconstriction, keeping MBF and functional capillary density constant. Demand-supply matching was maintained over the entire ECP pressure range.     

Possible benefit of selective beta 2-blockade in orthostatic hypotension a 'model' study in the cat

In anesthetized cats head-up tilt was associated with a marked beta 2-adrenergic dilator interaction with the evoked constrictor response in the resistance vessels. The beta-adrenergic inhibition of vascular tone was revealed by measurements of total peripheral resistance and of regional resistance in skeletal muscle and in the intestine. Tentatively, the results may suggest that 'selective' blockade of vascular beta 2-adrenoceptors can be beneficial in states of orthostatic hypotension.     

Bionic epidural stimulation restores arterial pressure regulation during orthostasis.

A bionic baroreflex system (BBS) is a computer-assisted intelligent feedback system to control arterial pressure (AP) for the treatment of baroreflex failure. To apply this system clinically, an appropriate efferent neural (sympathetic vasomotor) interface has to be explored. We examined whether the spinal cord is a candidate site for such interface. In six anesthetized and baroreflex-deafferentiated cats, a multielectrode catheter was inserted into the epidural space to deliver epidural spinal cord stimulation (ESCS). Stepwise changes in ESCS rate revealed a linear correlation between ESCS rate and AP for ESCS rates of 2 pulses/s and above (r2, 0.876-0.979; slope, 14.3 +/- 5.8 mmHg.pulses(-1).s; pressure axis intercept, 35.7 +/- 25.9 mmHg). Random changes in ESCS rate with a white noise sequence revealed dynamic transfer function of peripheral effectors. The transfer function resembled a second-order, low-pass filter with a lag time (gain, 16.7 +/- 8.3 mmHg.pulses(-1).s; natural frequency, 0.022 +/- 0.007 Hz; damping coefficient, 2.40 +/- 1.07; lag time, 1.06 +/- 0.41 s). On the basis of the transfer function, we designed an artificial vasomotor center to attenuate hypotension. We evaluated the performance of the BBS against hypotension induced by 60 degrees head-up tilt. In the cats with baroreflex failure, head-up tilt dropped AP by 37 +/- 5 mmHg in 5 s and 59 +/- 11 mmHg in 30 s. BBS with optimized feedback parameters attenuated hypotension to 21 +/- 2 mmHg in 5 s (P < 0.05) and 8 +/- 4 mmHg in 30 s (P < 0.05). These results indicate that ESCS-mediated BBS prevents orthostatic hypotension. Because epidural stimulation is a clinically feasible procedure, this BBS can be applied clinically to combat hypotension associated with various pathophysiologies.