INTRODUCTION

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DURING STANDING, ~750 ml of blood translocate from the upper body and thorax to the lower body (3), even while cerebral perfusion pressure decreases as a result of the hydrostatic effects of gravity. Without arterial vasoconstriction, bipeds cannot long remain upright (35). In response to orthostasis, active arterial vasoconstriction sustains blood pressure (BP) through increasing cardiac afterload and by redistributing venous blood, thereby enhancing venous return to the heart (4, 19, 43). Thus, for example, failure of arterial vasoconstriction in pure autonomic failure produces caudal blood pooling, resulting in falling BP and loss of consciousness (24). Arterial vasoconstriction limits venous filling during orthostasis by decreasing inflow (8). It is not clear in humans whether there is emptying of venous structures below the heart or only decreased venous filling resulting from arterial vasoconstriction (33). Even less clear is the role of active venoconstriction rather than passive elastic recoil. Although sympathetic venous innervation exists, such nerves may not be activated during orthostasis but may instead subserve other functions such as thermoregulation (35). Whereas evidence for active splanchnic venoconstriction exists (7), active limb venoconstriction has not been confirmed, especially in dependent limbs, which serve as a large venous reservoir during standing (15). This controversy has been particularly important to our work on postural tachycardia syndrome in adolescents, because malfunction of active peripheral venoconstriction has been proposed as an important mechanism for the syndrome (40).

Based on work (41) in which peripheral venoconstriction was induced by mental arithmetic or exercise (27) and work using lower body negative pressure as an orthostatic stimulus (43), we initially hypothesized that active venoconstriction does normally occur in the extremities during orthostasis in response to baroreflex activation. To test this hypothesis, we used incremental low-angle-tilt table testing to activate the baroreflexes. We measured capacitance vessel compliance (volume-pressure) relationships in each position in a series of normal volunteers. We studied healthy adolescents free from symptoms of orthostatic intolerance. Cardiovascular function and vascular regulation are essentially mature by puberty. Thereafter, cardiac and vascular remodeling depend primarily on disease and environmental forces such as athletic training rather than on genetics or age-dependent factors. Adolescents are similar to healthy young adults in providing a broad understanding of physiological principles that should apply across other populations.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Subjects. Eleven healthy volunteers, aged 13-19 yr [mean age = 16.1 ± 1.2 (SE) yr; 7 girls, 4 boys], were studied. Subjects were recruited from adolescents referred for innocent heart murmur. Subjects with a history of syncope or orthostatic intolerance were specifically excluded. Adequate tracings were obtained from all subjects. Only children found on cardiac examination to be free from structural or arrhythmic heart disease were eligible to participate. Routine cardiovascular physical examinations were performed and were supplemented by electrocardiographic and echocardiographic assessments to rule out heart disease. Subjects were also free of all obvious systemic illnesses and were not taking any medications. There were no trained competitive athletes. All protocols were approved by the Committee for the Protection of Human Subjects (Institutional Review Board) of New York Medical College.

Laboratory evaluation. Testing was performed in the laboratory during a single day. Some of our methods have been previously described (38, 39). After an overnight fast, tests began between 9 and 10 AM. The electrocardiogram was monitored continuously and recorded to assess cardiac rhythm. BP was continuously monitored with an arterial tonometer (Collin Instruments, San Antonio, TX) placed on the right radial artery and recalibrated every 5 min against an oscillometric sphygmomanometer pressure. The oscillometric BP unit is part of the Collin system, and the tonometer is automatically recalibrated against the cuff whenever oscillometric BP is taken. The tonometer has been tested against peripheral arterial blood invasive BP measurements in children and adolescents and is reliable (21). Leg BP was also obtained by oscillometry with a BP cuff placed around a calf.

Peripheral vascular evaluation. We used mercury-in-Silastic strain gauge plethysmography to measure nearly simultaneous forearm blood flow and calf blood flow and the forearm and calf compliance (volume-pressure) relation. Measurements were obtained in a steady-state condition at various angles of tilt during the study, as will be explained below. Plethysmographic methods were adapted from the work of Gamble et al. (12-14).

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Incremental tilt table testing. An electrically driven tilt table (Cardiosystems 600, Dallas, TX) with a footboard for weight bearing was used. We have found that a quasi-steady state is required to collect data for the capacitance volume-pressure relation. Thus accurate data cannot be obtained during large tilts of 60-80° where rapid and dramatic changes in flow occur. We verified in pilot studies that accurate volume-pressure data could be obtained during quasi-steady states at tilt angles up to 30-45°. At these angles, no healthy volunteers had orthostatic intolerance or fainting. Thus, after supine vascular measurements were complete, the subjects underwent incremental tilt at 0, 10, +20, and +35°. The 10° angle was used to unload the baroreflexes. The +20 and +35° angles were used to load the baroreflexes. During these tilts, arm occlusion cuffs were rapidly inflated to 50 mmHg to measure blood flow, but leg occlusion cuffs were inflated to a pressure just below diastolic pressure, which was verified by oscillometric measured BP on the contralateral calf. This was necessary because upright tilt increases calf BP because of hydrostatic forces.

Data analysis of the compliance relation. To construct an overall compliance relation including all subjects, we normalized each subject curve by that subject's maximum change in volume in the supine position. Thus, for example, if the overall change in volume from emptied limb to maximum volume (from the largest percent volume change during occlusion cuff inflation) was 6 ml/100 ml, we divided all volume measurements made on that subject by 6. For purposes of analysis, we assumed a null hypothesis that compliance does not change with angle. First, we generated a complete volume-pressure curve for a given subject with the subject supine. During tilt, the arm was lifted from horizontal until no further emptying was obtained. The decrease in arm volume was used as the zero of venous volume. This enabled placement of Pv measured at the particular angle of tilt for a given subject at a volume measured from zero. Thereafter, normalized percent increases in volume in that subject at that angle during occlusion were added to this initial point at Pv_. This procedure was repeated for each angle and for every subject. Any consistent increase or decrease in distensibility with upright tilt would be detected as an increase or decrease in the ordinate of the curve with respect to the normalized supine position.

Statistics. Data were compared by one-way analysis of variance for repeated measures. Paired data were used whenever possible. When significant interactions were demonstrated and when deemed appropriate, the ratio of F values was converted to a t distribution using Scheffé's test, and probabilities were thereafter determined. A Bonferroni correction was also used to correct for small samples. Except for compliance curves, results are reported as means ± SE. Statistically significant differences are reported for P < 0.05. Compliance data (i.e., volume-pressure curves) are presented in their entirety (every data point).

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Results are depicted in Figs. 1-4. They indicate progressive peripheral sympathetic activation at +20 and +35°, with tachycardia at +35°, but no change in the venous volume-pressure relations in arms and legs during the orthostatic challenges.

View larger version (15K): [in this window] [in a new window]   Fig. 1.   Representative leg plethysmographic tracing during an experiment is shown. Blood flow was measured by rapidly inflating the occlusion cuff for a 10-s interval. After measurement of venous pressure, compliance was computed by using 10-mmHg pressure increments beginning at 20 mmHg. After supine measurements were complete, flow measurements were repeated, and the subject was tilted to 10°. The procedure of flow measurements, venous pressure measurement, and compliance measurements was repeated at tilt angles of +20 and +35°. See text for further details.

View larger version (16K): [in this window] [in a new window]   Fig. 2.   Arm (A) and leg (B) compliance (volume-pressure) relations from a single representative subject. The descending limb of the supine curve was obtained by lifting the limb. Ascending compliance relation at all angles of tilt is shown.

View larger version (19K): [in this window] [in a new window]   Fig. 3.   Mean arterial pressure (MAP; A), limb flow (B), and limb arterial resistance (C) are shown. Top: results during arm measurements; bottom: results during leg measurements. MAP increased in the leg during upright tilt because of the effects of gravity. Flow decreased in the arm and leg, whereas resistance increased during orthostasis. Values are means ± SE. * P < 0.05 compared with supine.

View larger version (21K): [in this window] [in a new window]   Fig. 4.   All volume-pressure data points from all subjects (n = 11) at all angles of tilt are shown. A: arm. B: leg. The lines represent a fit based on supine data alone. There is no difference among compliance relations derived at any angle. Points on x-axes show pressure (in mmHg), and points on y-axes show % volume (in ml/100 ml tissue).

A complete representative experimental sequence is shown in Fig. 1. The leg tracing is shown. Measurements of flow were made supine, and the volume-pressure relation was determined. The patient was tilted to 10, +20, and +35°, and measurements were repeated.

Figure 2 depicts representative arm and leg compliance (volume-pressure) relations from a single representative subject. The descending limb of the supine curve was obtained by lifting the limb. Ascending compliance relation at all angles of tilt are shown. These are superimposed on the supine graph using the methods presented above. Figure 2 is quite representative of our tracings.

Pressure, flow, arterial resistance, and heart rate. MAP, flow, and arterial resistance are shown in Fig. 3. Arm MAP values did not change with tilt. Leg MAP values increased by an amount approximately equal to leg MAP = arm MAP + 0.776 × h × sin (angle of tilt), where h is the distance from the estimated location of the right atrium and the leg BP cuff. Thus the hydrostatic column of blood accounted for an increased leg arterial pressure when upright.

Capacitance vessel compliance. Figure 4 shows the volume-pressure relation for the arm and leg. Compliance data (i.e., volume-pressure curves) are presented in their entirety (every data point). The regularity of the abscissa for points on the arm compliance relation reflects the use of regular pressure steps starting at 20 mmHg. This regularity was disturbed in the leg compliance relation because the hydrostatic pressure caused by the column of venous blood between the occlusion cuff and the strain gauge was added to the imposed pressure to approximate the Pv at the level of the strain gauge.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Venous return to the heart is reduced during orthostasis (3). Major venous pooling within the limbs, pelvic, and gluteal regions is partly compensated by homeostatic neurovascular mechanisms that minimize the extent of pooling (3, 20, 25, 29). Based on prior literature (26-28, 41), we initially hypothesized that active venoconstriction occurs in the extremities during orthostasis in response to baroreflex loading and participates in the compensatory neurovascular response. Our results were contrary to expectations, instead demonstrating that the capacitance volume-pressure relationship does not change with orthostatic stress. Thus, although there is evidence for arterial vasoconstriction in response to low angles of upright tilt, capacitance vessel constriction fails to occur. Because capacitance resides primarily in the venous system, we infer that active venoconstriction of the extremities does not occur in response to orthostasis (at least for the angles used during upright tilt). Whereas it appears logical that veins should respond actively to orthostatic changes, it is equally reasonable to assume a passive role for the veins, as seems true from our work, with blood expelled as a result of arterial vasoconstriction. In the passive venous model, arterial vasoconstriction reduces Pv and allows for passive elastic recoil. We conclude that active venoconstriction in the limbs is not important to the orthostatic response for upright tilt at 20 and 35°.

When does venoconstriction usually occur? The results do not address whether venoconstriction occurs in general, although its role may be more regional than systemic, and the active response remains controversial. We are only stating that limb venoconstriction is not important during orthostasis. There is certainly support for the innervation of peripheral veins by adrenergic sympathetic nerves (1) and for venoconstriction in response to other stimuli, such as physical and mental stress (27, 32), exercise (41), and exogenous and endogenous biochemicals including adrenergic agents (6, 9, 10, 23). However, the response of veins to neurologically mediated adrenergic stimulation is regional and organ related. Thus, whereas there is excellent evidence dating to Donegan's work (8) on splanchnic and cutaneous venous innervation and venoconstriction in humans in response to sympathetic output (i.e., baroreflexes) or catecholamines, there is little convincing evidence for the response of other venous beds. Also, cutaneous nerves mainly subserve thermal reflexes (37), and not the arterial baroreflex, whereas even the splanchnic response depends more on passive redistribution than on active reflex changes (34).

Limitations. Relatively low angles of tilt were used. Inferences concerning absent venoconstriction should be tempered by the potential for venoconstriction at a higher angle of upright tilt. However, arterial vasoconstriction was activated at the angles of tilt employed, indicating at least a much lower threshold for arterial vasoconstriction compared with venoconstriction.

Importance. Orthostatic tolerance depends on a rapid response system that restricts blood entering dependent venous pools and potentially remobilizes pooled blood. Our results suggest that the arterial system serves this function in healthy adolescents. On the one hand, it would seem that venoconstriction, in addition to arterial vasoconstriction, would be an advantageous way to prevent venous pooling. On the other hand, venous resistance would likely increase along with venoconstriction, which might actually lower venous return to the heart (36), a definite disadvantage. Under those conditions, active venoconstriction would be a mixed blessing at best.