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Department of Sports Medicine, Heidelberg University, 69115 Heidelberg, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We studied the contributions of hypoxemia, hypocapnia, and hyperpnea to the acute hypoxic diuretic response (HDR) in humans and evaluated the role of peripheral O2 chemosensitivity and renal hormones in HDR. Thirteen healthy male subjects (age 19-38 yr) were examined after sodium equilibration (intake: 120 mmol/day) during 90 min of normoxia (NO), poikilocapnic hypoxia (PH), and isocapnic hypoxia (IH) (days 1-3, random order, double blind), as well as normoxic voluntary hyperpnea (HP; day 4), matching ventilation during IH. O2 saturation during PH and IH was kept equal to a mean level measured between 30 and 90 min of breathing 12% O2 in a pretest. Urine flow during PH and IH (1.81 ± 0.92 and 1.94 ± 1.03 ml/min, respectively) but not during HP (1.64 ± 0.96 ml/min) significantly exceeded that during NO (control, 1.38 ± 0.71 ml/min). Urine flow increases vs. each test day's baseline were significant with PH, IH, and HP. Differences in glomerular filtration rate, fractional sodium clearance, urodilatin, systemic blood pressure, or leg venous compliance were excluded as factors of HDR. However, slight increases in plasma and urinary endothelin-1 and epinephrine with PH and IH could play a role. In conclusion, the early HDR in humans is mainly due to hypoxia and hypocapnia. It occurs without natriuresis and is unrelated to O2 chemosensitivity (hypoxic ventilatory response).
diuresis; urodilatin; endothelin; peripheral arterial chemoreceptor
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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DIURESIS AND NATRIURESIS HAVE long been reported to occur in response to acute hypoxic exposure. Since its first report by Stämpfli and Eberle (37), a hypoxic diuretic response (HDR) has been demonstrated to occur often between 16 and 10% of inspired oxygen or hypobaric equivalents (13, 16, 21, 30, 40). HDR is assumed to be a transient phenomenon in early adaptation to hypoxia that increases blood O2 capacity before hypoxia-induced erythropoiesis becomes effective (13). Whereas the role of volume-regulating hormones in mediating HDR is still contentious, it is believed that hypoxemia, as well as factors inherent in the hypoxic ventilatory response (HVR), i.e., hypocapnia and alkalosis as well as hyperpnea (HP)-related intrathoracic pressure changes, may contribute to diuresis (3, 7, 9, 11, 13, 42, 43).
Hypoxia itself appears to be the main stimulus of HDR, as demonstrated by Honig (13). Isolated hypoxic perfusion of the carotid body causes hypoxic diuresis and natriuresis by inhibition of renal tubular sodium reabsorption (13, 14, 17, 33), whereas carotid body denervation abolishes HDR. Selective peripheral chemostimulation with almitrine bismesylate in animals (13, 15) and in humans (22, 24) also elicits HDR. The diuretic effects of increased central venous or arterial pressure have been excluded as a cause for HDR (2, 13, 40, 41). Because renal denervation augments the diuretic response, the link between renal water and sodium excretion and peripheral chemoreceptors must involve a humoral factor.
Under laboratory conditions of acute hypoxic exposure in sedentary subjects, Swenson et al. (41) demonstrated that diuresis and natriuresis caused by 6 h of normobaric hypoxia are related to the isocapnic HVR (HVRiso). There was no correlation between plasma levels of atrial natriuretic factor (ANF), antidiuretic hormone (ADH), or aldosterone with diuresis or natriuresis as also found in field studies (1, 2). Because the hypoxic exposure in that approach (41) was poikilocapnic, any renal effects of hypocapnia or HP could not be separated from the hypoxic effects.
The present study, therefore, was undertaken to further analyze mechanisms of HDR in humans 1) by comparing the diuretic effects of hypocapnic hypoxia and isocapnic HP with isocapnic hypoxia (IH) to isolate and quantitate the hypoxia-induced diuresis and evaluate its relation to the O2 chemosensitivity as assessed by HVRiso testing; 2) by measuring salt- and water-regulating hormones, which have potential relevance to HDR but have not yet been studied in the renal response to hypoxia [endothelin-1 (ET-1), urodilatin]; and 3) by measuring venous compliance, a determinant of central blood pooling during hypoxia, which may affect renal function via low-pressure stretch responses (4, 6, 13).
The separate contributions of hypoxia, HP, and hypocapnia to HDR were studied by the following four experimental conditions applied on 4 consecutive days over 90 min each: normoxia (NO), poikilocapnic hypoxia (PH), and isocapnic hypoxia (IH) were randomly assigned to days 1-3 and studied in a double-blind fashion; voluntary normoxic isocapnic HP at a level matching ventilation during IH was studied on day 4. We considered urine flow the primary efficacy variable and its increase of 1 SD (e.g., from ~1.00 to 1.50 ml/min) sufficient to explain hypoxic diuresis, as a volume loss of an additional 30 ml/h or 720 ml/day would be in line with the hypoxic diuresis observed during comparable hypoxia under normobaric (41) or high-altitude field conditions (2, 3). To assess such an increase in urine flow with P < 0.05, the number of subjects (n = 13) in the present study was sufficient (26). The investigations were carried out under conditions of sodium balance and postural volume equilibration. As this study addresses several hypotheses on the mediation of HDR, it is considered to be a pilot study.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Thirteen healthy male subjects volunteered for the study, which was approved by the ethics committee of the Medical Faculty of the University of Heidelberg. Their age, body weight, body height, and body mass index are given in Table 1. All subjects had been familiarized with the laboratory facilities, especially with breathing through a mouthpiece while wearing a noseclip. Subjects were nonsmokers and had abstained from alcohol, caffeine, and any medication. They had not been above an altitude of 2,000 m within 6 mo before the study nor were they involved in competitive sports during the study. All measurements were carried out in a quiet environment with calming music provided by earphones. The ambient room temperature was maintained between 22 and 25°C.
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Study Procedure
Sodium equilibration. Four days before and throughout the 4 consecutive test days, the subjects adhered to a fixed sodium diet (120 mmol/day). During the same time, their 24-h urine production was measured to determine daily sodium excretion and the resulting sodium balance. The subjects' fluid and food intake, urine output, as well as body weight and daily physical activity, were documented in an individual diary.
Pretests. Within 2 wk before the 4 consecutive test days, all subjects underwent measurement of their HVR under HVRiso and poikilocapnic (HVRpoi) conditions and their hypercapnic ventilatory response (HCVR). These tests were performed with the subjects in a semireclined, comfortable sitting position. In addition, a 90-min period of breathing 12% inspiratory O2 fraction (FIO2) was performed to determine individual mean arterial O2 saturation (SaO2) between 30 and 90 min of PH exposure for use as matched controlled targets during IH and PH.
Test conditions for the diuretic response. The following four test conditions, which lasted 90 min each, were investigated on 4 consecutive days in sodium-equilibrated subjects: 1) NO (control), 2) PH, 3) IH, and 4) voluntary normoxic (isocapnic) HP.
The test conditions of NO, PH, and IH were studied in random order on days 1, 2, and 3, whereas HP was performed on day 4 with HP matching minute ventilation (
E) during IH (Table
2, Fig.
1A).
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Time protocol. On the morning of each test day, the subject drank 400 ml of water at 7:00 AM. On arrival at the laboratory at 8:00 AM, he was asked to empty his bladder. Thereafter, he resumed a supine position in which complete emptying of the bladder was immediately determined by three-dimensional (3D) ultrasonic volumetry (see below). This supine rest position was maintained for 55 min to reach postural volume equilibration. After 45 min in this position, venous compliance was recorded in duplicate at two calf circumferences. After 55 min, venous blood samples were drawn for normoxic daily baseline measurements of Hb, hematocrit (Hct), plasma creatinine, electrolytes, osmolality, and ET-1. Thereafter, the subject emptied his bladder again for determination of normoxic baseline urine flow during this 55-min supine rest interval. Bladder emptying was again verified by the 3D ultrasonic volumetry.
The subject then was attached to a mouthpiece for a 5-min normoxic baseline recording ofE and end-tidal
and inspiratory PO2 and
PCO2. Thereafter, one of the four
test conditions, NO, PH, IH, or HP, was applied, and recordings of E, end-tidal and inspiratory
PO2 and
PCO2, and
SaO2 (pulse oximetry) were performed
breath by breath, while heart rate (HR) (electrocardiogram) and finger
arterial pressure (Finapres) were stored continuously. Capillary
blood-gas samples were obtained after 30 and 88 min, and venous
compliance and calf fluid volume were determined in duplicate after
80-88 min. Venous blood samples for Hb, Hct, plasma creatinine,
electrolytes, osmolality, and ET-1 were drawn, and the urine volume was
measured after 90 min.
Measurements and Equipment
Ventilation and respiratory gas analysis. Ventilation as well as inspiratory and end-tidal PO2 and PCO2 were measured breath by breath by the respiratory monitoring system Oxyconbeta (Mijnhardt, Bunnik, The Netherlands) by using the software version 3.12 with elimination of gliding averages. Subjects wore a noseclip and breathed through a mouthpiece connected to the flowmeter (TripleV) with an integrated gas-sampling capillary. The flowmeter was attached to a low-resistance T-shape valve system (Haward, Edenridge, UK) with a deadspace of 95 ml. The inspiratory side was connected to a 110-cm tube (inner diameter 4.5 cm) through which room air, compressed normoxic air, or hypoxic mixtures were breathed.
Blood-gas analysis and pulse oximetry. Blood-gas analysis was carried out in duplicate from 50-µl samples taken from the ear lobe that was made hyperemic by Finalgon (Thomea, Biberach, Germany). Capillary blood samples were analyzed for PO2, PCO2, pH, and bicarbonate by using the 845 blood-gas CO-oximeter system (Ciba Corning Diagnostics, Dietlikon, Switzerland). SaO2 was measured continuously by a pulse oximeter (3740 Biox Pulse Oximeter, Ohmeda Biox, Louisville, KY) by using the finger probe placed at heart level.
Chemosensitivity.
HVR was determined by the method of Weil et al. (44). The
FIO2 was progressively
lowered by admixture of N2 to an inspiratory air reservoir
initially containing 35%
FIO2 such that
SaO2 fell in a linear fashion to 80%
within 6-10 min. The slope of the ventilatory response
(
E/SaO2;
ml · min
1 · %1)
was calculated by linear regression of breath-by-breath values. For
HVRiso measurement, CO2 was added to the
inspiratory air to maintain
PETCO2 at the individual
level observed for 1 min during normoxic baseline before progressive
hypoxia. The HVRpoi was determined without CO2
addition. All HVRs were determined in duplicate and are presented as
the mean of both values. In case of a deviation of both HVR values of
>50% of the higher value, the measurement was repeated.
E (l/min) per 1-Torr increase in
PETCO2 by linear regression.
Venous blood sampling and analysis.
Venous blood samples of 33 ml were drawn from an antecubital vein
through a 19-gauge needle and the Sarstedt System (Sarstedt, Nümbrecht, Germany). Blood was immediately placed in ice water for 10 min and centrifuged at 2,000 g and 4°C for 30 min
within 10 min after sampling. Aliquots of plasma were stored at
80°C for analysis of ET-1.
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Urine and renal functional analysis. Urine flow (ml/min) was determined from urine samples taken after 90 min of NO, PH, IH, and HP and after 55 min of normoxic baselines. Emptying of the bladder was verified, or any remaining urine volume determined, by 3D computersonography (Combison 530, Kretz, Wiesbaden, Germany). The 3D phased annular 3.5-MHz scanner (VWP3.5) covers a 60° angle and a volume of 2.5 liters within a sway of 4 s at a resolution of <1 mm. This urine volume measurement was validated beforehand by direct comparison to urine sample volumes in the range of 5 to 100 ml. The volume of urinary output was corrected for remaining bladder urine volumes (the maximum value being 15 ml) as detected by this computersonographic method.
Urine samples were analyzed for pH directly after sampling by using a glass electrode pH meter (ion analyzer 250, Ciba Corning Diagnostic, Sudbury, UK). Urine samples were frozen at 20°C for later measurements of sodium concentration, osmolality, and creatinine. Samples for urodilatin, ET-1, epinephrine, norepinephrine, and dopamine measurements were frozen at80°C. Glomerular filtration rate
(GFR) was obtained by calculation of creatinine clearance and
fractional urine flow, and sodium excretion was calculated in
percentage of GFR. Free water clearance
(CH2O) was determined by
subtraction of osmotic clearance from urine flow.
The urinary concentrations of catecholamines, i.e., epinephrine,
norepinephrine, and dopamine, in the urine samples covering the 90-min
interval of each condition were determined by high-pressure liquid
chromatography with electrochemical detection. Urodilatin was measured
by the urodilatin ELISA (Immundiagnostic). Urinary ET-1 was analyzed as
described for plasma ET-1 (see Venous blood sampling and
analysis).
Cardiovascular parameters. HR was recorded beat by beat by an electrocardiogram monitor (Hellige, Freiburg, Germany) by using the R-wave interval of a standard precordial bipolar lead.
Arterial blood pressure (BP) was recorded continuously by the Finapres monitor (Ohmeda 2300, Englewood, NJ) on the left middle finger placed at heart level. Venous compliance was determined at maximal right calf circumference and 10 cm distally by two-channel venous occlusion plethysmography using two mercury-filled silicon tube strain-gauge systems (Gutman, Eurasburg, Germany). As a further development of the traditional Whitney strain gauge, the silicon tube sensor in this system is embedded in sliding plastic links, which minimizes friction, superficial tissue compression, and thermal effects. For venous occlusion, a 14-cm-wide cuff was placed above the knee. The automated device applied occlusion pressures of 40, 60, and 80 mmHg after 1, 2, and 3 min, respectively, and calculated the mean volume increase per 100 ml calf tissue and per 1 mmHg occlusion pressure. This value represents venous compliance in a calf segment of 1 cm width. The measurements were performed in duplicate and in both locations. The mean of all four measurements is reported. The calf was placed ~15 cm above heart level in a padded splint, avoiding venous occlusion. Calf fluid volume changes were recorded in a 20-cm segment of the right calf (enclosing maximal circumference) by means of a 40-MHz (0.4-mA) tetrapolar electrical impedance plethysmograph (Cardiodynagraph, Diefenbach, Frankfurt, Germany). This technique has been validated in vivo and in vitro (39) for intraindividual comparison by using circular gel-coated silver electrodes (6 cm width) as presently done. Because the calf was placed and fixed 15 cm above heart level with support of the heel and the knee, volume changes detected by impedance plethysmography can be attributed to the extravascular compartment, because venous vascular volume was assumed to be constant and small because of postural venous collapse (12). This calf position was maintained for 55 min before and throughout the 90 min of each test condition. Absolute fluid volume changes were calculated according to Ref. 39 with the specific resistance of the fluid added or subtracted to the calf segment volume being 65.5
/cm.
Statistics. All statistical procedures were performed by SPSS for Windows (version 6.1, 1995). Results are presented as means ± SD. All variables were analyzed for normal distribution by the Kolmogorov-Smirnov test before applying ANOVA models. The 24-h sodium balance during the 4 equilibration days (days 1-4 of diet) and during the 4 test days (days 5-8 of diet) was examined by comparison of means and time courses between the groups' sodium input and sodium output by a two-way ANOVA for repeated measures and post hoc test (Student-Newman-Keuls t-test). The primary efficacy variable urine flow, as well as venous compliance and plasma ET-1, was compared among PH, IH, HP, and NO by ANOVA for repeated measures by using each condition's baseline as a covariate for multiple and single comparison (analysis of covariance). Additionally, changes in urine flow, venous compliance, and plasma ET-1 vs. baseline were examined by the paired Student's t-test. All other parameters were compared among PH, IH, HP, and NO, and comparison between HVRiso and HVRpoi was performed by a one-factorial ANOVA for repeated measures and post hoc test (paired Student's t-test). Simple linear regression analysis was used to determine correlations between HVR or HCVR and the renal functional parameter. A statistically significant difference was accepted with P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hypoxic and Hypercapnic Chemosensitivity
The individual values and means ± SD of HVRiso, HVRpoi, and HCVR are given in Table 1. HVRiso ranged between 0.10 and 2.71 and HVRpoi between 0.06 and 0.40 l · min1 · %1.
HVRiso was significantly higher than HVRpoi
(P < 0.05) and correlated with HVRpoi (r = 0.65, P < 0.05). HCVR ranged between 0.76 and 2.39 l · min1 · mmHg1
and was unrelated to HVRiso or
HVRpoi.
Sodium Balance
Fig. 2 provides sodium balance data during the 4 days of pretest equilibration and during the four test conditions, NO, PH, IH, and HP. All subjects revealed an initial sodium loss and reached sodium balance at day 5, defined as a sodium excretion between <150 and >50 mmol/day. No statistically significant difference was found between sodium intake and urinary excretion after day 2 of the diet. The 24-h sodium excretion did not differ among the four different test conditions (nor the 4 consecutive test days, to which these test conditions had been randomly assigned).
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E,
PETCO2, and
SaO2
E,
FIO2,
PETCO2, and
SaO2, respectively, during the 90 min of
NO, PH, IH, and HP. Mean values covering the last 80 min (means ± SD)
of each of these four conditions are given for
E, PETCO2, and
SaO2 in Table 2. During NO (control),
E was 8.8 l/min, and
PETCO2 was 41.2 Torr, which
are normal resting values. During PH with a controlled
SaO2 around 76.2%, E transiently increased to 12 l/min,
paralleled by a mean drop in
PETCO2 of 4.3 Torr
relative to mean PETCO2 during NO. E during PH leveled off just
below 10 l/min after 15-20 min and thereafter remained slightly
but significantly above control E during
NO (Fig. 1A, Table 2). The initial adjustment of
FIO2 for this ventilatory
response to maintain the target SaO2 can
be seen in Fig. 1B. IH was induced at virtually the same
SaO2 as PH (77.0 vs. 76.2%;
Table 2, Fig. 1D). Whereas E
during IH increased markedly to ~16.3 l/min, isocapnia was successfully maintained over 90 min (Fig. 1C, Table 2) during this hypoxic condition. This required a lower
FIO2, ranging <10% as
opposed to ~12% in PH (Fig. 1B). Voluntary HP on test day 4 was closely matched to the
E observed during the IH test day (Fig.
1A, Table 2). This led to a slight but significant increase in
SaO2 (Fig. 1D, Table 2).
PETCO2 during HP was
maintained at the baseline level by CO2 admixture (Fig.
1C, Table 2); however, mean
PETCO2 was 0.7 Torr below
that of NO (P = 0.04).
Capillary Blood-Gas Analysis
The values of capillary blood-gas analysis, which are given in Table 2, reflected the experimental conditions: PO2 ranged around 40 Torr in the two hypoxic conditions PH and IH, being slightly but nonsignificantly higher in IH than PH. During HP PO2 increased significantly above NO (control). PCO2 was significantly lower during PH than during NO. During HP PCO2 tended to be lower than in NO, corresponding to the 0.7-Torr lower PETCO2 (Table 2). Capillary pH was significantly higher in both hypoxic conditions and in HP than in NO, thereby corresponding to PCO2, whereas bicarbonate was not found to be different from NO. (It should be noted that manipulation for capillary blood sampling may cause ventilatory irritation and thus deviations of blood gases from end-tidal gas measurements, which may better represent resting conditions.)Renal Function and Fluid Shifts
The urine flow (ml/min) before (normoxic baseline) and during each of the four conditions is given in Fig. 3. Whereas NO (control) led to no significant increase in urine flow, a significant diuresis resulted from PH (P < 0.01), IH (P < 0.05), and HP (P < 0.05), compared with each condition's normoxic baseline value. Baseline urine flow was not significantly different among the four experimental conditions. Compared with the NO test day (control), absolute urine flow values (Fig. 3) and percent increases in urine flow relative to baseline (Table 3) were significantly higher in the hypoxic conditions PH and IH.
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As seen in Table 3, there were no differences among the four conditions in GFR, fractional sodium clearance, or in CH2O as calculated for the urine samples collected during 90 min of each test condition. There were urine pH increases vs. baseline with all four conditions (P < 0.05); however, they were significantly greater during PH and HP, compared with NO, whereas no difference was found between IH and NO (Table 3).
ET-1, Urodilatin, and Catecholamines
Plasma ET-1 concentrations were not significantly different among the conditions (Table 4); however, relative to corresponding baselines (which were 0.95 ± 0.86, 0.80 ± 0.81, 0.87 ± 0.96, and 0.67 ± 0.23 pg/ml for NO, PH, IH, and HP, respectively), the plasma ET-1 increased (almost) significantly during PH (P = 0.06) and during IH (P = 0.05), whereas nonsignificant decreases and increases occurred with NO and HP, respectively. (Because of the large variability in ET-1 plasma levels, the increases by 65% with PH and 38% with PH are not well reflected by mean values given in Table 4.) Urinary ET-1 excretion rate (Table 4) was found to be significantly increased during PH compared with NO (P = 0.003), whereas increases during IH and HP did not reach statistical significance. Thereby, urinary ET-1 concentrations tended to increase with greater diuresis (PH, HP) or were unchanged (IH) compared with NO.
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Urinary urodilatin concentration and excretion per time during PH, IH, and HP (Table 4) were not significantly different between conditions.
Among the urinary catecholamines, epinephrine excretion showed a significant increase with IH and PH compared with NO (Table 4). A marginal increase in dopamine excretion with PH compared with NO (Table 4) was significant but not considered to be relevant for discussion.
No significant linear correlations were found between ET-1 or urinary epinephrine excretion and HVRiso, HVRpoi, or SaO2.
Cardiovascular Parameters and Fluid Distribution
Mean HR was significantly higher in the two hypoxic conditions than in NO (control) or during HP, which itself resulted in no HR changes (Table 5). During PH, this HR increase coincided with a small but significant decrease in mean BP compared with NO. Whereas HR was higher in IH than PH, no significant difference was found for mean BP between these two hypoxic conditions. Venous compliance (Table 5) was not significantly different among all conditions (except for a difference between IH and HP, P < 0.01) and showed no significant changes in relation to baseline values, which were 2.22 ± 0.84, 2.28 ± 0.83, 2.23 ± 0.63, and 2.10 ± 0.74 ml · mmHg1 · 100 ml1 for NO, PH, IH, and HP, respectively. The
percent decrease in PV (PV, Table 5) as calculated from Hct and Hb
changes was significantly greater in the two hypoxic conditions. There
was, however, no significant correlation between the diuretic response
and the percent PV change. Mean calf fluid volume changes per unit
tissue volume (Table 5) were small and not significantly different
among the four conditions. The same was true for absolute fluid volume changes, which ranged between 2.6 and 7.4 ml in the total
20-cm calf segment with a mean water displacement volume of 1,820.0 ± 291.7 ml. During NO the calf fluid volume was virtually stable, indicating postural volume equilibration.
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Correlation of O2 Chemosensitivity to Diuresis and Natriuresis
No significant positive linear correlation was found between HDR in terms of absolute urine flow during IH to HVRiso (r = 0.16) or HVRpoi or between HDR during PH to HVRiso or HVRpoi. The same was true for the relation of HDR in terms of absolute changes and percent changes in urine flow (relative to baseline) during IH to HVRiso (r =0.60, P = 0.03, and
r = 0.40, P = 0.17, respectively;
see Fig. 4) and HVRpoi. Also HDR during PH failed to
correlate positively with HVRiso or HVRpoi.
Subtraction of HDR (absolute or relative terms) during HP from that
during IH for isolation of the hypoxic component did not strengthen the relation to HVRiso or HVRpoi. The same was true
for the relation of natriuresis to HVRiso or
HVRpoi. HCVR was unrelated to diuresis and natriuresis or
any hormonal response.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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As a main finding, this study demonstrates that acute IH, as well as PH, induces an early HDR, which, in the first 90 min, is not associated with higher sodium excretion as opposed to the natriuresis induced by 3-6 h of hypoxia (9, 41). Our findings are in line with studies in animals (10, 13) and humans (31), demonstrating that increased volume excretion precedes natriuresis in the first 1-2 h of hypoxia. Whereas hypoxic natriuresis in humans appears to be related to peripheral O2 chemosensitivity (41) as assessed by HVRiso, the early HDR does not bear such a relationship. In addition to hypoxemia, HP and hypocapnia also contribute to HDR. Our data suggest that slight increases in ET-1 or epinephrine may play a role in the diuretic effect of hypoxemia, but that changes in leg venous compliance or urodilatin do not mediate the early HDR. The acute HDR to 90 min of 12% O2 leads to a reduction in PV (6.6% with PH and 7.3% with IH) that amounts to ~50% of the hemoconcentration observed during the first 2 days of an equivalent hypoxic exposure at high altitude (45).
Experimental Considerations
The present study design for evaluation of possible contributors to HDR over 4 consecutive test days required standardization of several factors.Sodium balance. Sodium equilibration was successfully completed by the first test day, and no difference was found in the 24-h sodium output among the 4 test days or among the four experimental conditions.
Sympathetic activity and postural volume adjustment.
Increased sympathetic activity, especially renal sympathetic nerve
activity, is well known to attenuate or even override HDR (13, 14, 18,
33), especially in the presence of (central) hypovolemia or low-cardiac
output and carotid sinus pressure (7, 13, 17, 25). The present study
design minimized and standardized sympathetic stimuli by the supine
test position, comfortable environment, and identical test time of the
day as indicated by equal and low-urinary norepinephrine excretion in
all test conditions. As indicated by absent urine flow changes and a
stable calf fluid and PV during NO (control), the supine rest phase of
55 min before the four test conditions was sufficient for postural
equilibration. This allowed us to study HDR without superimposition of
the volume adjustments to the supine position, i.e., quick central
blood pooling and slow cephalad fluid shifts (4), followed by diuresis and natriuresis via an increase of ANF and decrease of ADH.
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Hypoxemia, hypocapnia, and HP.
To separate the influence of hypocapnia and hypoxia, we studied IH and
PH at equal levels of arterial hypoxemia. These tests were carried out
at the SaO2 assessed during the last 60 min of a 90-min pretest of breathing 12% O2. Because
E was higher in IH than in PH,
FIO2 was lower in IH (~9%
O2) than in PH (~12%; Fig. 1B). As the
contribution of HP to HDR in IH was studied by voluntary increase in
E to a level observed during IH at equal
PETCO2 (HP), the
contribution of hypoxemia to HDR could be estimated by subtraction of
diuresis during HP from that during IH. The contribution of hypocapnia
to HDR may be estimated by comparing this diuretic effect of hypoxemia
alone to that of PH, i.e., hypoxemia and hypocapnia without major
increases in E compared with NO.
Role of Hypoxemia vs. HP and Hypocapnia in Early HDR
HP.
Isocapnic hyperventilation at 
30 l/min is well known to induce a
diuretic response (7). Whereas this effect is associated with
considerable exertion and major intrathoracic pressure oscillations, we
found that HP <20 l/min, which is the level observed during IH of
12% FIO2, may increase
urine volume as well. It should be noted, however, that, unlike the
studies of Curry and Ullmann (7) and Gledhill (9), HP of this level
induced water diuresis but not natriuresis. Although the contribution
of HP may account for a considerable fraction of HDR when hypocapnia is
prevented in hypoxia, the much smaller ventilatory increase in PH
points to a minor role of HP in HDR.
Hypocapnia and alkalosis. These effects of hyperventilation are well known to induce diuresis in humans, as well as increase sodium, potassium, and bicarbonate excretion and decrease total acid excretion (9, 42). Because urine pH significantly increased without an increase in sodium excretion, the present data imply that an increased bicarbonate excretion may be accompanied early by increased potassium excretion rather than sodium excretion, which is observed after longer exposure to hypocapnic hypoxia (41). However, hypocapnia-induced bicarbonate and possibly potassium excretion are not the major factors of early HDR, because urine flow during IH (at unchanged urine pH vs. NO) was not significantly different from that of PH. The separate contribution of hypocapnia may be roughly estimated as follows (given a simplified arithmetic summation of the effects of hypoxia, hypocapnia, and HP on absolute urine flow values): diuresis in IH (1.94 ml/min) minus that in matched normoxic HP (1.64 ml/min) may reflect the hypoxia effect alone (0.3 ml/min). Subtracting this 0.3 ml/min from diuresis in PH (1.81 ml/min) gives 1.51 ml/min, which, compared with NO (1.38 ml/min), leaves an effect of 0.13 ml/min for hypocapnia. During HP, diuresis exceeded that of NO by 0.26 ml/min.
Hypoxemia. Hypoxemia thus appeared to be the most important factor in the presently seen HDR compared with HP and hypocapnia. This is in accord with animal studies demonstrating that diuresis and natriuresis occur with isolated hypoxemic stimulation of peripheral chemoreceptors, even in the presence of controlled ventilation and isocapnia (13, 17). Honig (13) and Quies and Ledderhos (31) suggested that, in water-loaded humans, hypotonic diuresis may precede natriuresis, even when peripheral chemoreceptors are stimulated with almitrine and systemic and renal hypoxia are avoided. Moreover, Gledhill (9) demonstrated that normoxic hypocapnia and IH do not cause natriuresis before 3 h, whereas IH increases urine volume within 1 h. Recently, such different time courses of hypoxic water diuresis and natriuresis were also found in chronically instrumented awake rats (10).
Mechanisms of Early HDR
Hypoxia-induced changes in perfusion pressure on GFR may affect HDR to some extent (10); however, in the present study, a pressure diuresis during hypoxia can be ruled out in both IH and PH, because mean arterial BP and GFR failed to increase.Importantly, no change in venous compliance was observed in the leg,
suggesting that HDR in the first 90 min may occur without any increase
in venous tone during hypoxia. These data obtained after 80-88 min
of IH or PH are at variance with findings of a decreased venous
compliance in the human forearm after 2 h of a hypobaric hypoxia (6),
which was equivalent to the presently applied normobaric hypoxia. Thus
our data provide evidence against an early hypoxic venoconstriction, at
least in the calves, as a factor of central blood pooling and a renal
response via ADH, ANF (13), or other factors. The observed slight
increase in epinephrine with the two hypoxic conditions (at unchanged
norepinephrine) obviously failed to cause essential 
-adrenergic
venous constriction (4, 28) in the calf. It may well be, however, that
venoconstriction occurs in other areas (e.g., the forearm or splanchnic
vessels) or with prolonged hypoxia and thus plays a role in diuresis
and natriuresis via right atrial blood pooling.
Because GFR was unchanged, the diuretic response appears to be at the level of tubular function, especially with regard to water handling. Within this early phase of HDR, the increased urine flow at unaltered fractional sodium clearance did not lead to a significantly increased CH2O, especially with IH, as was observed with the diuresis of humans induced by almitrine ingestion (13, 31). Although bicarbonate and potassium excretion due to hypocapnia may occur after 1 to several hours and contribute an osmotic component to the observed diuresis, this would not explain an osmotic component with IH.
Many have thought to identify a circulating humoral factor in HDR, which must override increased renal sympathetic nerve activity during peripheral chemoreceptor stimulation and during baroreceptor deactivation (17, 18) as possibly indicated by increased HR and slightly lowered BP in the present study. The absence of increases in fractional sodium excretion in the present study implies that hormones that control natriuresis may not be a driving factor in this early phase of HDR.
The role of ANF in the hypoxic diuresis and natriuresis has not been conclusive in humans and animals, although several mechanisms of an ANF increase during hypoxia certainly exist (13, 16, 40). In humans, diuresis and natriuresis could be induced by selective peripheral chemoreceptor stimulation with almitrine (22) or by 6 h of PH (41) without relevant changes in ANF. In two high-altitude field studies, ANF was not a factor in the hypoxic diuresis or natriuresis, because it was found to be elevated in subjects with antidiuresis and related to the widening of the right atrium (1, 2). Thus ANF may not be a first candidate to mediate acute hypoxic diuresis in humans, especially within the first 90 min.
A more promising candidate to focus on appeared to be urodilatin (21), an analog renal natriuretic hormone, which has not been studied in sodium-equilibrated humans during controlled hypoxemia. Our measurements, obtained under such conditions, however, failed to reveal any increase in urodilatin with acute HDR, whether urodilatin was expressed in terms of urine concentration or excretion rate. In contrast, during 6 h of hypobaric hypoxia, Koller et al. (21) found that the diuretic and natriuretic responses were associated with increased urinary urodilatin excretion. Apart from the much longer time of hypoxic exposure in that study, which compared lowlanders with acclimatized highlanders, the lack of control of sodium balance, postural volume adjustment, and SaO2 may explain some of the differences from our present data on HDR and urodilatin. Thus there is no convincing evidence that the traditional salt- and water-regulating hormones may be involved (13, 15, 40), and, according to the present results, we may now add urodilatin to this list with regard to early HDR.
Our findings and those of others regarding ET-1, however, may suggest that this hormone is involved in mediation of HDR. Both IH and PH caused significant or almost significant small elevations in circulating ET-1, which were absent during HP and NO. The higher rates of urinary endothelin excretion, which were significant with PH, may support some first evidence from animals that local ET-1, which may be also nonvascular and nephron derived, could be involved in HDR (20, 29). ET-1 is a potent vasoconstrictor, especially in the kidney, and can reduce renal blood flow and GFR (20), leading to antidiuresis and antinatriuresis. However, lower ET-1 doses that have little effect on GFR increase water excretion with or without natriuresis (19, 20, 34). This can be attributed to direct ET-1 effects on the nephron, most likely an inhibition of water reabsorption in the collecting duct and differential effects on sodium transport at different sites of the nephron (20). In humans, the site of a reduction in water and sodium reabsorption appears to be the distal tubules, as judged from lithium clearance (36). Hypoxemia has been shown to increase circulating ET-1 in humans (5) and to enhance renal endothelin immunoreactivity, as well as water and sodium excretion, in dogs (29). Therefore, the present finding of a slight increase in plasma and urinary ET-1 combined with a nonnatriuretic diuresis and unchanged GFR with hypoxic conditions may suggest a role of ET-1 in the early HDR via distal tubular inhibition of water reabsorption in humans. A correlation of the ET-1 increase to HDR, however, was not found.
There was a small increase in urinary epinephrine excretion during both
hypoxic conditions. Besides unspecified experimental stress, this
response may be attributed to sympathoadrenal activation through
hypoxic chemoreceptor stimulation (27) and to arterial baroreceptor
deactivation (the latter can be derived from the combination of
increased HR and lowered arterial BP with PH and IH). Besides hypoxia,
hypocapnia, but not HP, contributes to this effect, as also
demonstrated by Stäubli et al. (38). The net effect of
epinephrine on renal function, especially on water and sodium handling
via - and 
-receptors of the tubular system and the vasculature,
is complex. Although sympathetic activation is generally known to
reduce renal blood flow and water and sodium excretion (27, 40),
increases in epinephrine without increases in circulating
norepinephrine may induce diuresis and natriuresis, despite increases
in plasma renin activity (23). Thus it remains open whether epinephrine
contributes to early HDR; a relation of epinephrine to diuresis or to
HVR was absent in the present study. This also holds for hormones that
are related to sympathetic activation, such as glucocorticoids and ACTH
(13, 15). It is still undecided whether adrenalectomy prevents diuresis
and natriuresis during hypoxia (13) in animals, especially during acute
hypoxia as presently applied.
Complex effects of local renal hypoxia, such as vasodilatation in the medullary vasculature or other direct tubular effects, may induce diuresis (30, 35). However, we found no relation of HDR to individual levels of SaO2. As further evidence against a role of local renal hypoxemia in HDR, diuresis also occurs with peripheral chemoreceptor stimulation by almitrine in normoxic humans (13, 24, 31).
Relation of Early HDR to Peripheral Chemosensitivity
By separation of the diuretic effects of HP, systemic hypocapnia, and hypoxia, this study confirmed hypoxemia as the major contributor to the early HDR in humans, as shown consistently in animal studies (13). Whereas in animal studies the peripheral chemoreceptors could be established as crucial for HDR by isolated stimulation (hypoxic perfusion, almitrine) or denervation, the evidence in humans for such a role can only be inferred from a correlation of HDR with HVR (41) or from the diuresis through almitrine ingestion (22, 24, 31).However, we found no positive correlation of HDR to HVR within the first 90 min, even when controlling for the interaction of hypocapnia by correlation of HDR during IH with HVRiso or by correlation of HDR during PH with HVRpoi. Isolating the hypoxic factor from hypocapnia and HP by subtraction of HDR during HP from that during IH did not improve the relation to HVRiso. HDR showed no positive relation to HVRiso or HVRpoi, whether expressed in terms of absolute urine flow values or absolute or percent changes relative to normoxic baseline values (Fig. 4). The same was true for natriuresis. This is apparently at variance with the finding of Swenson et al. (41) that hypoxic diuresis and natriuresis after 6 h of PH are closely related to HVRiso (r = 0.87 and 0.76, respectively). The difference to our study may be explained by the greater length of hypoxic exposure (90 min vs. 6 h), which brings into play different diuretic mechanisms.
In summary, the present study demonstrated a major contribution of systemic hypoxemia to the early HDR that occurs at unchanged fractional sodium excretion and GFR and without relation to peripheral O2 chemosensitivity. With regard to effector mechanisms of early HDR, this study provided evidence against a role for increased leg venous tone, pressure diuresis (except for HP), and urodilatin, whereas it pointed at a possible role for ET-1 or epinephrine. Other unrecognized humoral factors arising from peripheral chemoreceptor stimulation, possibly in combination with local renal effects of hypoxemia on vascular or tubular function, remain to be assessed.
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ACKNOWLEDGEMENTS |
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We thank M. Haselmayr for determination of catecholamines. We are also grateful to Dr. W. Fien for determination of electrolytes and to Immundiagnostic (Bensheim, Germany) for supporting the measurement of urodilatin and ET-1. Moreover, we are indebted to Dr. E. Ritz for important advice regarding the study design. We also thank S. Zacharevic-Scherhaufen for careful preparation of the diet.
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: W. Hildebrandt, Institute für Sport und Leistungsmedizin, Universitätspoliklinik Heidelberg, Hospitalstr. 3, 69115 Heidelberg, Germany (E-mail: wulf_hildebrandt{at}med.uni-heidelberg.de).
Received 9 October 1998; accepted in final form 30 September 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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