INTRODUCTION

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THE MECHANISM FOR REDUCTION of cerebral blood pressure resulting in syncope (fainting) in humans is not clear. Multiple interactive factors such as hypovolemia (11), altered baroreceptor function (17, 23), attenuated sympathetic vascular resistance (16), and the action of vasoactive hormones (7, 9, 11, 12, 17, 18, 21) are probably involved in this mechanism. Although the effect of various interactive catecholamine and cardiovascular responses on hypotension have been investigated intensively (24), relatively few investigators have studied the hypotensive association of the noncatecholamine vasoactive hormonal responses, e.g., the renin-angiotensin-aldosterone (RAA) axis in the kidney and the vasopressin system in the brain (7-9, 11, 12, 18, 21). ANG II is one of the most powerful vasoconstrictors in the body, and its attenuated action might inhibit vasoconstriction during extreme hypotensive stress, such as lower body negative pressure (LBNP), where the usual muscular pressure on the caudal veins is absent. Oparil et al. (19) reported that in the 5 of 20 normotensive men and women who exhibited vasovagal syncope after 80° head-up tilt, the increase in plasma renin activity (p_RA) was smaller in magnitude and duration than in the other subjects. On the other hand, Harrison et al. (9) found that 7 of 13 subjects who exhibited tilt intolerance had consistently lower systolic and pulse pressures (PP) and significantly higher p_RA.

However, these vasoactive hormones do not act independently but appear to have significant interaction. On the basis of serial blood samples taken during progressive hypotension at 55 mmHg LBNP, it has been reported that the vasoactive hormone response starts with the catecholamines, progresses to the RAA system, and ends with the vasopressin axis (21), a sequence that also occurred during 70° head-up tilting in both men and women (6).

Thus the purpose for this study was to determine whether the neuroendocrine activation would differ in higher and lower tolerance subjects and to test the hypothesis that the RAA system is the more important for differentiating men with lower hypotensive tolerances.

	METHODS

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Fifteen healthy, nonsmoking, male volunteers were selected as test subjects after passing a medical examination and giving informed consent. After LBNP testing was completed, they were allocated into two groups: those who tolerated 20 min of 50 mmHg LBNP [HiTol, n = 7, 25 ± 2 yr (SD), 184 ± 11 cm height, 78.2 ± 15.1 kg weight, and 2.01 ± 0.24 m² surface area] and those who did not (LoTol, n = 8, 26 ± 3 yr, 185 ± 6 cm height, 81.8 ± 8.7 kg weight, and 2.05 ± 0.12 m² surface area). This study was approved by the Regional Scientific Ethics Committee of Copenhagen and Frederiksberg (KF 01-299/96) and performed according to the Declaration of Helsinki.

All subjects consumed a controlled daily diet for 3 days before testing that consisted of normal food (bread, meat, fruit, vegetables, milk, etc.) containing 2,822 kcal/day (16% protein, 55% carbohydrate, 29% fat). Dietary NaCl content was 2 mmol · kg¹ · day¹, i.e., 156 ± 29 (SD) mmol Na⁺/day (HiTol) and 161 ± 15 mmol Na⁺/day (LoTol). Mean (±SE) respective urinary excretion rates in the HiTol and LoTol groups were 1.8 ± 0.4 and 1.7 ± 0.4 ml · min¹ · day¹ [not significant (NS)], and urinary Na⁺ excretions were 135 ± 24 and 135 ± 14 mmol/day (8.6 ± 1.2 and 8.0 ± 0.8 g Na⁺/day, NS).

The men slept in the laboratory the night before testing and consumed no food or fluid after 2100 from the previous day to experiment termination. They were awakened at 0745, urinated to close their 24-h sample, were weighed, and then entered the LBNP chamber supine onto a narrow padded saddle without foot support to start the experiment at 0800 when the central venous pressure (CVP) catheter was inserted and electrocardiogram electrodes applied. The protocol for the 165-min ambient control period was 60 min rest supine with the last 15 min for plasma volume (PV) measurement, then 60 min sitting (last 15 min for PV) and a final 45 min supine to determine that PV increases from sitting to supine (Fig. 1). Changing body position required ~2 min. This 165-min ambient period was followed by the LBNP period (supine): 10 min at ambient pressure, 10 min at 15 mmHg, 20 min at 50 mmHg or until onset of presyncopal signs or symptoms (point of intolerance), and finally 10 min of recovery at ambient pressure. Presyncopal signs and symptoms included stomach awareness, nausea, sweating, narrowing of vision, or dizziness or, if those did not occur, a rapid drop in mean arterial pressure and/or bradycardia. Time (min) on the figures indicated the start of the 3-min interval when blood sampling commenced. The final 50-mmHg blood sample was taken as close as possible to the onset of presyncopal signs or symptoms. Mean (±SE) ambient dry-bulb temperature was 25.6 ± 1.3°C, and relative humidity was 38 ± 4%.

View larger version (13K): [in this window] [in a new window]   Fig. 1.   Experimental protocol. PV, plasma volume; Hct, hematocrit; B, blood sample; D, diameter of left atrium; LBNP, lower body negative pressure.

The integrated heart rate was displayed on a Diascope monitor (model DS 521, Simonsen and Weel, Copenhagen, Denmark) and was counted manually from a three-lead electrocardiogram. Arm cuff blood pressures were displayed on a Protocol Systems monitor (model Propaq 102, Beaverton, OR), but PP and MAP {1/3 [systolic blood pressure (SBP)  diastolic blood pressure (DPB)] + DBP} pressures were calculated manually from a Finapres Monitor trace (model Ohmeda 2300, Englewood, CO) with the sensor positioned on the mid- and distal phalanx of the right middle or third finger. A CVP catheter assembly (16 gauge, 1.7 mm ID with a 14-gauge injection catheter, model Cavafix Certo, B. Braun, Melsungen, Germany) was inserted via a right antecubital vein. Another catheter (18 gauge, model Venflon 2, BOC Ohmeda AB, Helsingborg, Sweden) was inserted into a left forearm vein for injection of Evans blue dye (Pharmacie Hopital E. Herriot, Lyon, France). Heart rate, systemic (Propac) blood pressures, and CVP data were displayed and recorded continuously on a Gould (model V1000, Ballainvilliers, France) oscilloscope and model ES1000 strip-chart recorder, respectively. Heart images were displayed on an echocardiograph (model SSD-500, Aloka, Tokyo, Japan), recorded on a Sony (model SVO 9500 MPD) videocassette recorder, and printed for analysis later.

The CVP catheter was advanced to an intrathoracic vein near the superior vena cava, where its position was verified by the characteristic waveform and responses to respiratory maneuvers. The subject's arms were supported horizontally at heart level, and the electronically integrated pressure trace was calibrated frequently. Pressure calibration levels were determined manually with a water column.

Mean end-expiratory left atrial diameter (LAD) measurements, obtained at 3-min intervals during the LBNP period from 3 M-mode prints, were taken by echocardiography from the parasternal long-axis view. The LAD were measured blind (3).

The two PV determinations required 10 3-ml blood samples (30 ml) and four 2-ml samples (8 ml) for hematocrit (Hct) plus a maximum of 14 20-ml samples (280 ml) for p_RA and for plasma vasoactive hormone concentrations [epinephrine (p_Epi), norepinephrine (p_NE), ANG II (p_{ANG II}), and vasopressin (p_VP)] analyses (at 3-min intervals) and five 5-ml samples for plasma vasoactive hormone concentration of endothelin-1 (p_ET-1, 25 ml at 10-min intervals) during the LBNP period depending on the onset of presyncopal signs or symptoms (when the experiment was terminated; Fig. 1). Maximal blood volume withdrawn was 343 ml/experiment; of that, the discarded presample dead-space volume was 42 ml, whereas that from the Evans blue test was reinjected.

The blood was transferred to chilled polyethylene tubes containing appropriate anticoagulants and buffers. For p_Epi and p_NE, the tubes contained 20 µl/ml of blood with 0.195 M reduced glutathione and 0.250 M EGTA adjusted with NaOH to pH range 6-7. For p_VP, p_{ANG II}, and p_ET-1, the tubes contained 25 µl EDTA and 2,700 KIU of Trasylol R, i.e., aprotinin (Novo Nordisk, Bagsvaerd, Denmark). The tubes were oscillated gently, iced, centrifuged at 1,500 g for 10 min at 4°C, and stored at 18°C for batch analysis.

Albumin space was determined after 45 min rest supine and sitting with intravenous injection of Evans blue dye via the forearm catheter in eight subjects (5 HiTol and 3 LoTol group). The central venous catheter allowed for a 3-ml preinjection blood sample taken at 1 min and postinjection samples at 5, 7, 10, and 15 min into tubes containing 12.5 IU heparin/ml. Plasma dye concentration was measured on each sample at 620 and 740 nm (Hitachi, model U-1000 spectrophotometer) before each injection of dye and also in the postinjection samples, so extraction was unnecessary. Quadruplicate microhematocrit tubes were centrifuged at 12,000 g for 5 min in a Struers Kebo model 3K10 centrifuge (Sigma Laborzentrifugen, Osterode am Harz, Germany) and corrected with a plasma centrifugation trapping factor of 0.96 and body-venous F-cell factor of 0.91. Plasma and blood volumes were measured and calculated (4).

p_VP was measured by radioimmunoassay (2) with plasma extracted by Sep-Pak C₁₈ columns (Waters, Milford, MA) preconditioned sequentially with 5 ml each of 4% acetic acid in 96% ethanol, 100% methanol, water, and 4% acetic acid. Two milliliters of plasma acidified with 6 ml of 4% acetic acid were run through the columns that were then washed with 5 ml of water. The peptide was eluted with 3 ml of 4% acetic acid in 60% ethanol into Minisorp R tubes (Nunc, Roskilde, Denmark) containing 10 µl (0.1%) of Triton X-100 (octyl phenoxy polyethoxyethanol, Sigma Aldrich Vallensbaek, Strand, Denmark). The air-dried eluate was adjusted to pH 7.4 with 750 µl of assay buffer, (0.1 M phosphate buffer with [0.01 M K₂ EDTA, 0.01 M NaN₃, and 1.0 mg/ml of serum albumin) (Behringwerke, Marburg, Germany). Then 300 µl each of test sample and standard were incubated for 24 h with 300 µl of antibody (AB3096). ¹²⁵I vasopressin (New England Nuclear, Life Sciences Products, Boston, MA), containing 2,200 Ci/mmol (100 µl, 8,000 disintegrations/min), was added, and incubation was continued for an additional 24 h. Bound was separated from free antigen with 1,050 µl of a charcoal-plasma suspension (10.8 g charcoal, and 60 µl of plasma in 300 µl of buffer). After centrifugation, the supernate radioactivity was measured. The detection limit of the assay was 0.1-0.2 pg/ml. Mean recovery was 73% and the intra-assay coefficiant of variation (CV) was ± 6.5% at 2.0 pg/ml and 9.0% at 2.4 pg/ml.

p_{ANG II} was measured by radioimmunoassay (13) with plasma extracted by Sep-Pak C₁₈ columns activated with 5 ml methanol followed by 5 ml water. Then, 2.2 ml of plasma containing a tracer amount of ANG II (for recovery determination) were added to the columns, which were washed with 5 ml water and 5 ml 20% methanol in water, and the ANG II was then eluated with 2 ml of methanol. The eluate, dried with N₂ at 37°C, was dissolved in 1.5 ml of buffer (0.1 M Tris · HCl with 0.2% BSA and 10 mM Na₂ EDTA). ¹²⁵I-labeled ANG II and diluted antiserum were added to aliquots of the extracted plasma and incubated at 4°C for 18 h. Separation of bound from free antibody-radioiodinated ANG II was by charcoal absorption. The detection limit of the assay (1.4 pg) was estimated as the quantity of ANG II that displaced 10% of the binding of the radioiodinated label alone. Mean recovery of ANG II was 69 ± 7%, and intra-assay CV was ± 8%. Results were not corrected for incomplete recovery.

p_ET-1 was measured by radioimmunoassay (1, 22) with plasma extracted by Sep-Pak C₁₈ columns (Waters Milford, MA) preconditioned sequentially with 5 ml each of 4% acetic acid in 96% ethanol, 100% methanol, water, and 4% acetic acid. Two milliliters of plasma, acidified with 6 ml of 4% acetic acid, were run through the columns that were then washed with 5 ml of water. The peptide was eluted with 3 ml of 4% acetic acid in 96% ethanol into minisorp R tubes (Nunc, Roskilde, Denmark) containing 10 µl (0.1%) of Triton X-100. The air-dried eluate was adjusted to pH 7.4 with 550 µl of assay buffer (0.01 M phosphate buffer with 0.01 M K₂EDTA and 0.001 M NaN₃ and 1.0 mg/ml of human serum albumin) (Behringwerke, Marburg, Germany). Then 200 µl each of test sample and standard were incubated for 24 h with 100 µl of antibody RAS6901 (Peninsula Laboratories Europe, St. Helens, UK). Then, 50 µl (6,000 disintegrations/min) of I¹²⁵-labeled ET-1 (New England Nuclear Life Sciences Products, Boston, MA) were added, and incubation was continued for an additional 24 h. Bound was separated from free antigen with 1,050 µl of a charcoal-plasma suspension (10.8 g charcoal and 60 µl of plasma in 300 µl of buffer). After centrifugation, the supernatant radioactivity was measured. The detection limit of the assay was <0.6 pg/tube, and the extraction recovery of unlabeled ET-1 was 100% from plasma. Interassay CV was 10% at an ET-1 concentration of 6 pg/ml.

p_E and p_NE were measured with a radioenzymatic assay (14). Plasma was precipitated with an equal volume of perchloric acid, and 100 µl of the supernatant were incubated with the enzyme carboxy-O-methyl-transferase. After incubation, unlabeled metanephrine and normetanephrine were added to the supernatant, and samples were extracted with an isoamylalcohol-toluene mixture. These extracted samples were acidified with HCl, and 120 µl were injected into an HPLC (Waters model 600) where a 120 × 3 mm Nucleosil C₁₈ reverse-phase column separated the metanephrine and normetanephrine. The mobile phase consisted of dilute phosphoric acid (30 mM, pH 1.8) with 2% methanol added before use. The cold metanephrines were measured at 276 nm (ultraviolet) to ensure that the labeled samples were collected at appropriate elution times (for example, at 2.6 min for normetanephrine and 4.0 min for metanephrine). The eluate was collected in 1.0-min fractions centered on those intervals. There was no crossover between the two peaks. Then, ³H-labeled metanephrine and normetanephrine were oxidized to vanillin and counted with liquid scintillation spectrometry. Intra-assay CV for normal, basal levels of epinephrine and norepinephrine were 8% and 6%, respectively; corresponding interassay CV were 11% and 7%, respectively. Intra-assay sensitivity (3 × standard deviation of the blank) was 0.3 pg/assay for epinephrine and 0.5 pg/assay for norepinephrine; corresponding inter-assay sensitivity was 0.5 pg/assay for both variables.

Statistical analyses. Anthropometric, environmental, dietary control, and LBNP tolerance data were analyzed with the t-statistic for independent groups (HP-65, Stat-Pac 1 no. 1-30A, Hewlett-Packard, Cupertino, CA). The difference between PV in the supine and sitting positions was determined with the paired t-test (HP-65, no. 1-29A). Remaining data from the two groups over time were analyzed first with one-way ANOVA (SPSS 7.5 for Windows, SPSS, 1996, Chicago, IL). Because of the inconsistent experiment termination times in the LoTol group, subsequent differences between groups were also determined with the Kruskal-Wallis H-test (15), a nonparametric analog of one-way ANOVA. All presyncopal data through 12 min were included in the analysis; data for the one subject at 15 min were omitted. Significant data indicated in the figures were significant by both ANOVA and the Kruskal-Wallis tests. An intercorrelation matrix (Pearson-product moment, SPSS 7.5 for Windows) was calculated with cardiovascular and hormonal variables. The null hypothesis was rejected when P < 0.05, and nonsignificant differences were denoted NS.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

LBNP tolerance. All HiTol subjects completed 20 min of 50-mmHg pressure with no adverse signs, symptoms, or discontinuities in their cardiovascular or hormonal data (Figs. 2 and 3). The LoTol group's intolerance ranged from 6 to 15 min (mean = 11 ± 1 min, t = 9.01, P < 0.001). Numbers of subjects at each intolerance time at 50 mmHg were as follows: 6 min for all 8 subjects, 9 min for 7 subjects, 12 min for 6 subjects, and 15 min for 1 subject. The mean values at 18 min in the figures are their final intolerance levels irrespective of time.

View larger version (29K): [in this window] [in a new window]   Fig. 2.   Mean (±SE) central venous pressure (A), left atrial diameter (B), mean arterial pressure (C), pulse pressure (D), and heart rate (E) in the supine control and LBNP and recovery periods for the higher and lower tolerance groups. Numbers of subjects at each intolerance time at 50 mmHg were 6 min for all 8 subjects, 9 min for 7 subjects, 12 min for 6 subjects, and 15 min for 1 subject. Mean values at 18 min are final intolerance levels irrespective of time (dashed lines between 12 and 18 min). * P < 0.05 from the mean of the control values;  P < 0.05 between groups.

View larger version (23K): [in this window] [in a new window]   Fig. 3.   Mean (±SE) plasma renin activity (A) and ANG II (B), vasopressin (C), and norepinephrine (D) concentrations in the supine control, LBNP, and recovery periods for the higher and lower tolerance groups. Numbers of subjects at each intolerance time at 50 mmHg were 6 min for all 8 subjects, 9 min for 7 subjects, 12 min for 6 subjects, and 15 min for 1 subject. Mean values at 18 min are final intolerance levels irrespective of time (dashed lines between 12 and 18 min). * P < 0.05 from the mean of the control values;  P < 0.05 between groups.

Plasma and blood volumes. PV data from the two groups (n = 8) were not significantly different, so they were combined for analysis. Mean (±SE) PV in the sitting position (3,557 ± 126 ml, 42 ml/kg) was increased in the supine position to 3,911 ± 153 ml (10.0%, t = 5.01, P < 0.001); corresponding calculated blood volumes increased from 5,975 ± 229 ml (71 ml/kg) sitting to 6,403 ± 259 ml (7.2%, t = 4.18, P < 0.002) supine.

Cardiovascular responses. After 60 min supine, there were no significant differences in heart rate (range 52 ± 3 to 60 ± 4 beats/min) or in SBP (range 116 ± 3 to 127 ± 3 mmHg), DBP (range 72 ± 2 to 77 ± 2 mmHg), or PP (range 40 ± 3 to 50 ± 2 mmHg) over time or between groups during the supine 10-min control period and the ensuing 10 min of 15 mmHg LBNP (Table 1, Fig. 2). Onset of 50 mmHg by minute 3 resulted in increases (P < 0.05) in heart rate in both groups of 76 ± 5 to 97 ± 6 beats/min, no significant changes in SBP (121 to 116 mmHg) or DBP (76 to 79 mmHg), but PP decreased (P < 0.05) in both groups. From 9 to 12 min at 50 mmHg, there were no significant changes in heart rate or in SBP, DBP, or PP in either group. Essentially all SBP at 50 mmHg were decreased from their respective mean control levels, whereas DBPs were not (Table 1).

Plasma enzyme-hormonal responses. There were no statistically significant differences in plasma endothelin-1, a potent vasoconstrictor, between groups or over time during control through recovery: mean (±SE) values ranged from 3.2 ± 0.4 to 4.1 ± 0.3 pg/ml.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Our protocol was designed to prolong the presyncopal period to better delineate vasoactive enzyme-hormonal activation by using an initial negative pressure of only 15 mmHg for 10 min and progressing to 50 mmHg for 20 min or until onset of presyncopal responses. This protocol was sufficient to allocate otherwise unresponsive men with "normal" tolerance into approximately equal higher and lower tolerance groups where there appears to be a wide range of normal LBNP tolerance from 16 min to more than 30 min. None of the subjects was aware of any abnormal syncopal responses in their daily lives.

It is clear that significant hormonal activation occurred in both groups at 15 mmHg when heart rate, PP, and MAP were unresponsive. Our data indicated the onset sequence was p_VPp_Epip_NE(p_RAp_{ANG II}) in the LoTol group and essentially the same in the HiTol group [p_VPp_NEp_Epi ( p_RAp_{ANG II})], with the RAA system at the terminal end in both. The activation patterns of p_RA and p_{ANG II} were also similar in both tolerance groups at 50 mmHg (with due regard for the large difference in their y-axis scales in Fig. 3), i.e., they increased progressively during both lower and especially the higher levels of LBNP.

This RAA system response was probably not due to large variations in plasma cations, because the subjects were consuming the same sodium intake per kilogram of body weight coupled with similar urinary Na⁺ excretions before the experiment. Also, plasma cation and osmotic concentrations remain within normal control limits during the hypotensive hypovolemia that occurs during 70° head-up tilt (6). Controlled sodium intake is important because it controls the extracellular fluid volume and renal sodium excretion (including distal tubular delivery) and because of its close interaction with control of blood pressure; e.g., exaggerated symptoms of hypotension are attenuated in orthostatically intolerant patients on a high-sodium diet (20).

p_RA in the LoTol group was significantly lower than that in the HiTol group in the control period and throughout LBNP. Jacob et al. (11) suggested that reduced p_RA, possibly from defective sympathetic activation of the kidney, could have facilitated fainting in chronically orthostatically intolerant patients via hypovolemia. They found a significant correlation (r = +0.84) between p_RA and blood volume. It is well known that total body dehydration and hypovolemia reduce tilt tolerance (8) and accentuate p_VP, p_RA, and plasma aldosterone responses during tilt (7). But resting control PVs from five high- and three low-tolerance men in the present study were not significantly different, and their plasma and blood volumes increased similarly when they moved from sitting to the supine position. However, the differences in LAD between the two groups suggest a change in volume in the central venous system. The similar decrease in CVP in both groups and different LADs imply low compliance in the low-pressure system. Even though the LoTol group had the usual increased catecholamine activity and p_VP release during 50 mmHg, the discrepancy between increases in p_{ANG II} and p_VP in the two groups during LBNP is clear: when compared with HiTol group responses, the increase in p_{ANG II} in the LoTol group was attenuated, whereas the increases in p_NE and p_VP were accentuated, suggesting no defect in the sympathetic nervous response. As a result, the LoTol group was unable to maintain MAP, leading to impending syncope.

The significant activation of norepinephrine in both groups during 15 mmHg LBNP was probably a result of the decreased CVP. This activation also reflects an increase in renal sympathetic nervous activity (RSNA), which released renin significantly in both groups at the end of 15 mmHg LBNP, but increased ANG II significantly only in the HiTol group at that point. Thus from the similar decrease in CVP, greater intolerance may be associated with the ability to increase RSNA and hence renin angiotensin in the kidney. Hence, differential intolerance may be determined by ability to increase RSNA.

Although p_VP was activated somewhat during 15 mmHg LBNP, its massive release, which occured only during impending syncope at the end of the presyncopal cascade, is well documented (5, 9, 10). The vasopressin system has tremendous reserve capacity in that p_VP concentrations in excess of 500 pg/ml (normal 1.5 pg/ml) have been measured at syncope (J. E. Greenleaf, personal observation). So it seems more likely that the large vasopressin release is a consequence and not a causal factor of impending syncope and nausea. Jardine et al. (12) also observed significant increases in p_VP and the plasma hormone concentration of ACTH after 5 min of 60° head-up tilt in patients with a history suggestive of vasovagal reactions. It is unclear whether this large p_VP response was induced by a sinoaortic baroreceptor response or vice versa. The similar significant rise in p_NE in both groups might be an early stimulus that signals the possible impending vasopressor reaction. Thus increased sympathetic activity rather than the attenuated response to secrete more ANG II may have been a major initiating stimulus that resulted in the hypotensive intolerance. If the LoTol group was more predisposed to the vasopressor syncope by the increased sympathetic activity that resulted in a strong vagal stimulus, this stimulus could have inhibited RAA system activity. This explanation implies that the mechanism of the intolerance was a graded response in subjects of varying intolerance thresholds and should function similarly in all subjects at their varying presyncopal points. The question arises if the depressed p_RA and/or p_{ANG II} in the LoTol group was increased to equal that in the HiTol group, would the LoTol group's tolerance be increased significantly? If so, it would confirm the pivotal role of the RAA system in this hypotensive mechanism.

Our results confirm those of Mark et al. (17) who first reported that 40 mmHg LBNP decreased CVP and arterial PP which attenuated, respectively, both low- and high-pressure baroreceptor inhibition, i.e., reactivated baroreceptor function. But their p_RA increased significantly (to 7.4 ± 1.4 ng · ml¹ · h¹) only when both low- and high-pressure inhibition occurred and not with low pressure (10- to 20 mmHg LBNP) inhibition alone. This pressure was comparable with the 15 mmHg LBNP used in the present study, in which p_RA was also unchanged in both groups, whereas p_{ANG II} was increased significantly in the HiTol group but was unchanged (inhibited?) in the LoTol group due to presumably reactivated low-pressure baroreceptors from the LBNP.

Norsk et al. (18) indicated that p_VP during LBNP responds more to narrowing of the PP than to reduction of CVP. Results from the present study support this conclusion from the significant correlation between PP and p_VP (r = 0.52, P < 0.01) in the HiTol group, but not in the LoTol group (r = 0.12, NS). We found similar results in the RAA system only in our HiTol group between PP vs. p_RA and PP vs. p_{ANG II}: the r were 0.55 and 0.56 (both P < 0.01), respectively. However, the respective r in our LoTol group were 0.36 and 0.24 (both NS). These findings strengthen the high-pressure hypothesis regarding the hormonal release action on PP, but it may not apply to lower-tolerance subjects.

It is concluded that the response of the renin-angiotensin system appears to be linked inversely to the occurrence of presyncopal symptoms, and measurements of resting p_RA may have predictive value for those with lower hypotensive tolerance.

Perspectives