Effects of high altitude and water deprivation on arginine vasopressin release in men
C. M. Maresh,1
W. J. Kraemer,1
D. A. Judelson,1
J. L. VanHeest,1
L. Trad,2
J. M. Kulikowich,1
K. L. Goetz,3
A. Cymerman,2 and
A. J. Hamilton2,4
1Human Performance Laboratory, Department of Kinesiology, University of Connecticut, Storrs, Connecticut 06269;2United States Army Research Institute of Environmental Medicine, Natick, Massachusetts 01760;3Division of Experimental Medicine, St. Luke's Hospital and Foundation for Medical Education and Research, Kansas City, Missouri 64134; and 4Department of Surgery, University of Arizona Health Sciences Center, Tucson, Arizona 85724
Submitted 18 July 2003
; accepted in final form 27 August 2003
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ABSTRACT
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High-altitude exposure changes the distribution of body water and electrolytes. Arginine vasopressin (AVP) may influence these alterations. The purpose of this study was to examine the effect of a 24-h water deprivation trial (WDT) on AVP release after differing altitude exposures. Seven healthy males (age 22 ± 1 yr, height 176 ± 2 cm, mass 75.3 ± 1.8 kg) completed three WDTs: at sea level (SL), after acute altitude exposure (2 days) to 4,300 m (AA), and after prolonged altitude exposure (20 days) to 4,300 m (PA). Body mass, standing and supine blood pressures, plasma osmolality (Posm), and plasma AVP (PAVP) were measured at 0, 12, 16, and 24 h of each WDT. Urine volume was measured at each void throughout testing. Baseline Posm increased from SL to altitude (SL 291.7 ± 0.8 mosmol/kgH2O, AA 299.6 ± 2.2 mosmol/kgH2O, PA 302.3 ± 1.5 mosmol/kgH2O, P < 0.05); however, baseline PAVP measurements were similar. Despite similar Posm values, the maximal PAVP response during the WDT (at 16 h) was greater at altitude than at SL (SL 1.7 ± 0.5 pg/ml, AA 6.4 ± 0.7 pg/ml, PA 8.7 ± 0.9 pg/ml, P < 0.05). In conclusion, hypoxia appeared to alter AVP regulation by raising the osmotic threshold and increasing AVP responsiveness above that threshold.
acute mountain sickness; antidiuretic hormone; dehydration; fluid regulation; osmotic threshold
EXPOSURE TO HIGH ALTITUDES may lead to acute mountain sickness (AMS), which is considered an indication of poor acclimatization. One distinct characteristic of AMS normally seen at altitude is the lack of a diuresis (10, 11, 26). Arginine vasopressin (AVP) has been implicated in AMS (4, 10) because of its role in reducing free water excretion at the kidney and because of altitude-induced increases in plasma osmolality (3-5), decreases in plasma volume (7, 22, 25), and increases in blood pressure (5, 21, 28), the three primary determinants of AVP release (23, 27, 29).
Previous research examining the AVP response to altitude, however, does not support a role for AVP in AMS, because different exposures (1,900-5,400 m) of varying durations (3-30 days) have shown no rise in plasma AVP (PAVP) (16, 18, 22). The lack of a PAVP response is paradoxical when we consider that altitude significantly alters plasma osmolality (Posm) (3-5). Only one study has shown an augmentation in PAVP (24), this in response to 7 days of exposure to 4,200 m. Ramirez and colleagues (17, 19), however, have shown that high-altitude natives (2,600 m) have greater resting PAVP than sea-level natives.
Osmotic challenges to evaluate the AVP response at altitude normally take the form of salt infusion. Typical results have shown similar increases in Posm with no change in PAVP between altitude and sea level infusions (17, 18, 20). Bestle et al. (3) showed that 8 days of exposure to 4,559 m enhanced baseline Posm and decreased baseline PAVP. Saline infusion caused similar increases in Posm at sea level and altitude and an increase in PAVP at altitude, although technical problems prevented comparison with PAVP at sea level. On the basis of these and other results, Bestle et al. (3) concluded that altitude exposure altered the relation between Posm and PAVP, displacing the Posm-to-PAVP curve to the right.
As an osmotic challenge and model to examine AVP during altitude exposure, water deprivation may be more physiologically relevant than salt infusion. Little research, however, details the AVP response to voluntary dehydration at altitude. Griffen and Raff (9) examined the effects of water deprivation and 1 day of hypoxic exposure (10% O2) in rats, with hypoxia alone stimulating a small, transient rise in PAVP, whereas hypoxia in combination with water deprivation enhanced the AVP increase but had no effect on its duration.
When the significant external (exercise and dehydration) and internal (diuresis, AMS) hydrodynamic pressures applied to the human body with altitude exposure are considered, knowledge of altitude fluid balance physiology is key. Additionally, acclimatization to altitude is a dynamic process, altering the human body response over the course of weeks (8, 30). Therefore, the purpose of this study was to compare the AVP response to 24 h of water deprivation after acute and prolonged altitude exposure with that seen at sea level.
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METHODS
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Seven healthy men [age 22 ± 1 (SE) yr, height 176 ± 2 cm, mass 75.3 ± 1.8 kg] participated in the study after giving informed written consent. The appropriate institutional review boards approved the research, and authors adhered to 45 CFR 46 of the US Army during the conduct of this study. Subjects were life-long residents at low altitude and had not ventured above 2,500 m in the 6 mo preceding the study. Before inclusion, each subject provided a medical history and was examined by a physician. Potential subjects with contraindications to altitude exposure or 24-h fluid restriction were excluded from participation. Smoking and medication use were exclusionary criteria for study participation.
Each subject completed three water deprivation trials (WDTs): at sea level (SL), immediately after their second complete day at 4,300 m [acute altitude trial (AA)], and immediately after their 20th complete day at 4,300 m [prolonged altitude trial (PA)]. All SL testing occurred at the United States Army Research Institute of Environmental Medicine in Natick, MA. Subjects were then exposed to altitude at the United States Army Pikes Peak Laboratory Facility located at the summit of Pikes Peak, CO. Before each WDT, subjects were awakened at 0600 and voided. Fluid restriction then began, lasting 24 h (i.e., completed at 0600 the following day). Subjects ate standard, military-issue solid food and avoided exercise and thermal stress throughout the WDT. Direct supervision ensured strict adherence to all protocol guidelines. To avoid excessive, potentially harmful dehydration in subjects at the relatively isolated Pikes Peak location, Posm was measured at regular intervals throughout each WDT, as we will describe. If a subject's Posm reached 310 mosmol/kgH2O, the WDT was immediately stopped, both for subject safety and because we thought that this degree of hypertonicity provided an adequate stimulus for AVP secretion.
At 0, 12, 16, and 24 h into each WDT, physiological and biochemical measurements were made. Standing and supine blood pressures (BP) were used to calculate mean arterial pressure (MAP) via the formula 1/3[systolic BP + 2(diastolic BP)]. Nude body weights were measured to an accuracy of ±45 g on the same scale for all subjects in each treatment; the scale was calibrated before each weighing. Peripheral venous blood was drawn into prechilled, heparinized containers and centrifuged for 5 min at 3,000 rpm at 0°C. Posm determinations were performed in duplicate, with fresh plasma maintained at 0°C by a properly calibrated Fiske Osmometer (model S; Fiske, Needham, MA). PAVP was determined on samples frozen and maintained at -190°C in liquid nitrogen until measurement. Radioimmunoassays for PAVP were carried out in triplicate by methods reported previously (27). The source of standard was USP Posterior Pituitary Reference Standard. The lowest detectable amount of AVP ranged between 0.5 and 0.75 pg per assay tube. The interassay coefficient of variability (CV) ranged from 3.7 to 8.5% at the extremes of the standard curve. The intra-assay CV was 4.0% at both extremes of the standard curve. Urine volume and osmolality were measured at each void, including immediately before completion of the WDT.
A two-way repeated-measures ANOVA was calculated to determine the effects of time and treatment on the measured variables. Post hoc significant differences were identified using Tukey's test. Curve estimations using both linear and nonlinear models were calculated to describe the relation between Posm and PAVP for each treatment. All data are presented as means ± SE. Significance was set at P < 0.05.
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RESULTS
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All subjects tolerated the WDT trials well. No episodes of severe nausea or vomiting were noted at SL or altitude, and only one subject was unable to complete the AA and PA trials because of excessive hypertonicity (withdrawn at 16 h for both trials).
Body mass data are shown in Table 1. Although baseline measurements (0 h) were similar among all trials, body mass significantly decreased during each WDT. No significant differences among trials existed in percent body mass lost (0-24 h) during the WDT (SL, -1.57%; AA, -1.82%; PA, -1.95%).
Twenty-four-hour urine volumes were similar among trials, averaging 988 ± 213, 1,129 ± 131, and 1,375 ± 125 ml during the SL, AA, and PA WDTs, respectively.
BP data are shown in Table 2. Baseline standing MAP was significantly higher at altitude than at SL, as were standing and supine MAP at the conclusion of the WDTs (range 20.35-28.60%). Although small, significant differences were occasionally noted in MAP (supine SL measurements at 24 h, standing AA measurements at 12 h, and supine PA measurements at 16 h), the majority of MAP measurements remained relatively stable throughout each trial.
Posm data are shown in Fig. 1. Subjects were significantly more hypertonic at baseline (0 h) during AA (299.62 ± 2.24 mosmol/kgH2O) and PA (302.29 ± 1.50 mosmol/kgH2O) than at SL (291.71 ± 0.75 mosmol/kgH2O). Posm peaked 16 h into SL and rose continually through PA. No statistically significant fluctuations in Posm were noted during AA. At the conclusion of the WDT, Posm was significantly greater at PA (309.23 ± 1.28 mosmol/kgH2O) than at SL (301.86 ± 1.07 mosmol/kgH2O) and AA (303.78 ± 2.14 mosmol/kgH2O).

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Fig. 1. Plasma osmolality (Posm; group means ± SE) during 3 water deprivation trials (WDTs): at sea level (SL), during acute altitude exposure (AA), and during prolonged altitude exposure (PA). *Significant difference from corresponding (SL) value; **significant difference from corresponding SL and AA values; significant within-group difference compared with preceding time point.
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PAVP data are shown in Fig. 2. Baseline PAVP levels were similar among the three treatments (SL 0.90 ± 0.21 pg/ml, AA 1.72 ± 1.24 pg/ml, PA 2.19 ± 0.77 pg/ml). PAVP increased significantly with water deprivation during AA and PA, achieving maximal values at 16 h (AA 6.44 ± 0.73 pg/ml, PA 8.67 ± 0.90 pg/ml). At the completion of the WDT, AA values had returned to the baseline level, whereas PA PAVP measurements were still significantly higher than baseline measures. No changes in PAVP were seen during the SL trial.

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Fig. 2. Plasma arginine vasopressin (AVP) levels (PAVP; group means ± SE) during the 3 WDTs. *Significant difference from corresponding SL value and a significant within-group difference from preceding time point; **significant difference from corresponding SL value; significant difference from corresponding SL and AA values, and a significant within-group difference from preceding time point.
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Figure 3 displays PAVP as a function of Posm for each treatment. The best fit curve describing this relation changed from linear (SL) to slightly nonlinear (AA) to strongly curved (PA) with progressive altitude exposure.

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Fig. 3. Best fit curve estimations of the relation between Posm and PAVP for SL (A), AA (B), and PA (C).
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The mathematical nature of the power model representing AA and PA, however, precludes the analysis of a physiologically relevant osmolality threshold for AVP release (i.e., the x-intercept of the regression line). To visualize this threshold, Fig. 4 again details the relation between Posm and PAVP, forcing the regression curve into a linear model. From these estimations, the osmolality threshold for AVP release was calculated at 275.6, 276.5, and 288.3 mosmol/kgH2O for SL, AA, and PA, respectively.

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Fig. 4. Regression analysis describing Posm vs. PAVP forced into a linear model. Solid regression line, SL; dotted regression line, AA; dashed regression line, PA.
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DISCUSSION
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The primary purpose of this study was to assess the effects of high-altitude exposure on plasma AVP before, during, and after 24 h of water deprivation. The significantly enhanced AVP response to a similar osmotic challenge (Fig. 2) and the altered relationship between Posm and PAVP observed at AA and PA compared with SL (Figs. 3 and 4) indicate that altitude acclimatization dynamically changed AVP regulation. Early acclimatization increased AVP sensitivity to changes in Posm, whereas more complete acclimatization enhanced both the threshold and responsiveness of AVP release.
Fluid restriction during WDTs resulted in physiological and biochemical changes consistent with progressive dehydration. The significant WDT-induced weight loss (mean of all three trials -1.78%) was indicative of mild dehydration capable of increasing Posm (1). Body weights (Table 1) and 24-h urinary volumes were similar throughout each trial, suggesting that altitude exposure had no effect on the rate of water loss during the WDT.
Resting Posm was significantly higher after 2 and 20 days at 4,300 m than at SL (Fig. 1). This response has been noted by previous researchers (3-5) and is consistent with a normal altitude-induced loss of plasma volume and resultant diuresis (7, 12, 25). Although plasma volumes were not directly measured, the subjects' good health, diet, and exercise restriction preclude any conclusion other than that augmented baseline Posm resulted from altitude-induced reductions in plasma volume. During SL and PA WDTs, a significantly increased Posm may be attributed to water deprivation-induced declines in plasma volume. During AA, however, no significant changes were seen in Posm, although a trend existed for increased tonicity. The osmolar effects of dehydration may have been overshadowed during AA by altitude-induced decreases in plasma volume. During PA, plasma volume gradually and partially reexpands (7, 12, 25); although subjects' PA fluid balance may not have mirrored that of SL, it was most likely normalized to a point at which water deprivation could significantly alter Posm.
Unlike Posm, altitude exposure did not affect resting PAVP, as baseline PAVP values were similar for all conditions (Fig. 2). This apparently paradoxical maintenance in PAVP despite altitude-induced increases in Posm has been previously observed (3-5) and constitutes one of the main questions regarding the relationships among altitude exposure, AMS, and AVP. In response to water deprivation, AA and PA significantly increased PAVP, whereas no changes were seen during SL. These responses may seem inappropriate when we consider the strong relation between Posm and PAVP and the observed changes, or lack thereof, in Posm. Posm is, however, one of only a number of physiological influences on PAVP; fluctuations in plasma volume and blood pressure are also capable of altering PAVP response (23, 27, 29). When all three primary stimuli are considered, a clearer view of the observed PAVP response emerges.
At SL, water deprivation from a euvolemic state may have reduced plasma volume sufficiently to disturb Posm (stimulating AVP release) but not enough to stimulate a dehydration-induced AVP release (thereby maintaining PAVP at basal levels). Blood pressure, stable throughout most of SL WDT, would also have limited PAVP release. The sum of all three factors would result in no AVP response, as seen in the present study. Alternately, the novel WDT may have stimulated significant cortisol release, in turn limiting PAVP response despite increased Posm (15). At AA, water deprivation amplified PAVP despite unchanged Posm. As stated above, significant altitude-induced decreases in plasma volume may have raised Posm such that the effects of the WDT were eclipsed. The increased baseline Posm, without supplementation by other factors, was unable to induce an AVP response, as indicated by the similar AA and SL baseline PAVP values. The combined stimulation of an altitude-induced increase in baseline Posm, a dehydration-induced decrease in plasma volume, and an altitude-induced increase in blood pressure was capable of enhancing PAVP. At PA, water deprivation increased PAVP with a concomitant rise in Posm. Although plasma volume would have reexpanded (maintaining AVP), greater blood pressure and Posm may have overpowered any inhibitory influences, resulting in a significant AVP response.
As seen in Figs. 3 and 4, the relation between Posm and PAVP during a WDT was altered by altitude exposure in a time-dependent fashion. Whereas a given Posm elicited a similar PAVP in the low Posm range (276-300 mosmol/kgH2O) regardless of altitude exposure, the PAVP response to Posm measures >300 mosmol/kgH2O dramatically increased as acclimatization progressed. Additionally, linear estimates of the best fit curves indicate that 20 days of altitude exposure enhanced the x-intercept of the regression line, indicating that the Posm threshold of AVP release was substantially changed. Alterations of the Posm threshold for AVP release are well documented from various pharmacological and physiological stimuli: opiates (13), glucocorticoids (2), pregnancy (6), heredity (31), and volemic status (23). Fluctuations in the PAVP "set point" resulting from altitude exposure, although less examined, have been hypothesized by Kelestimur et al. (14) and Bestle et al. (3) to explain results obtained after 28 days of hypoxia in rats and 8 days of exposure to 4,559 m in humans, respectively. To our knowledge, however, this study represents the first comparison between sea level and altitude Posm and PAVP responses before, during, and after 24 h of water deprivation resulting in a defined shift in 1) the nature of the relation between Posm and PAVP, and 2) the Posm threshold of AVP release.
A number of hypotheses explain the changes in the relation between PAVP and Posm and the adjustments of the PAVP set point during and after altitude acclimatization. As previously mentioned, volemic status (7, 22, 25) and blood pressure (5, 21, 28), primary determinants of AVP response, are clearly affected by altitude exposure and may influence AVP responses. Alternately, Ramirez and colleagues (17, 19) have demonstrated renal resistance to physiological quantities of AVP in high-altitude (2,600-3,000 m) natives, indicating that the kidney responds differently to AVP before and after acclimatization. Shifts in the concentrations of K+, modifications to the renal AVP receptor, and alterations in the secondary messenger pathway were all presented as possible mechanisms to explain this result. The current results are best explained by a lack of renal responsiveness to normal PAVP, because greater PAVP responses were seen with similar upper range Posm after AA and PA than at SL. Finally, Rostrup (24) hypothesized that PAVP increased at altitude (7 days of exposure to 4,200 m) to maintain blood pressure in the face of decreased circulating catecholamines. Thus greater AVP (as well as potential AMS) is a precaution against the potentially more harmful results of decreased blood pressure. Unfortunately, no osmotic challenge was incorporated in that study.
Several areas of future research are indicated by the present findings. Foremost, the important influences on PAVP at altitude should be examined. Additionally, the exact time course of changes in the Posm-PAVP relation (i.e., initial 48 h of altitude exposure and beyond 20 days of exposure) requires attention. Finally, despite the small, homogeneous subject cohort of the present study, these results may serve as the basis for similar research with other populations, especially because the hypothesized mechanisms appear to be neither age nor gender specific.
In conclusion, acclimatization to altitude significantly altered the AVP response before, during, and after 24 h of water deprivation. Twenty days of altitude exposure 1) altered the relation between Posm and PAVP, shifting it from linear at SL to exponential at PA, and 2) enhanced the threshold of Posm, causing PAVP release.
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DISCLOSURES
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The views, opinions, and findings contained in this report are those of the authors and should not be construed as an official Department of the Army position, policy, or decision unless so designated by other official documentation.
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ACKNOWLEDGMENTS
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We thank the test subjects who so willingly participated.
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FOOTNOTES
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Address for reprint requests and other correspondence: C. M. Maresh, Dept. of Kinesiology, 2095 Hillside Rd., U-1110, Univ. of Connecticut, Storrs, CT 06269-1110 (E-mail: carl.maresh{at}uconn.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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