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Am J Physiol Regul Integr Comp Physiol 280: R481-R487, 2001;
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Vol. 280, Issue 2, R481-R487, February 2001

Physicochemical analysis of phasic menstrual cycle effects on acid-base balance

Robert J. Preston, Aaron P. Heenan, and Larry A. Wolfe

Department of Physiology and School of Physical and Health Education, Queen's University, Kingston, Ontario K7L 3N6, Canada


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

In accordance with Stewart's physicochemical approach, the three independent determinants of plasma hydrogen ion concentration ([H+]) were measured at rest and during exercise in the follicular (FP) and luteal phase (LP) of the human menstrual cycle. Healthy, physically active women with similar physical characteristics were tested during either the FP (n = 14) or LP (n = 14). Arterialized blood samples were obtained at rest and after 5 min of upright cycling at both 70 and 110% of the ventilatory threshold (TVent). Measurements included plasma [H+], arterial carbon dioxide tension (PaCO2), total weak acid ([ATot]) as reflected by total protein, and the strong-ion difference ([SID]). The transition from rest to exercise in both groups resulted in a significant increase in [H+] at 70% TVent versus rest and at 110% TVent versus both rest and 70% TVent. No significant between-group differences were observed for [H+] at rest or in response to exercise. At rest in the LP, [ATot] and PaCO2 were significantly lower (acts to decrease [H+]) compared with the FP. This effect was offset by a reduction in [SID] (acts to increase [H+]). After the transition from rest to exercise, significantly lower [ATot] during the LP was again observed. Although the [SID] and PaCO2 were not significantly different between groups, trends for changes in these two variables were similar to changes in the resting state. In conclusion, mechanisms regulating [H+] exhibit phase-related differences to ensure [H+] is relatively constant regardless of progesterone-mediated ventilatory changes during the LP.

hydrogen ion; strong-ion difference; total weak acid; carbon dioxide tension; exercise


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

HYDROGEN ION CONCENTRATION ([H+]) remains constant throughout a normal human menstrual cycle despite a ventilatory-induced reduction in arterial carbon dioxide tension (PaCO2) acting to reduce [H+]. This study tested the hypothesis that changes in the hormonal milieu during a normal human menstrual cycle cause alterations in plasma electrolyte composition and plasma protein concentration. It is proposed that changes in these two variables comprise the mechanism to offset the tendency of a ventilatory-induced reduction in PaCO2 to reduce [H+].

The human menstrual cycle is divided into two phases differing with respect to the concentration of reproductive hormones. The follicular phase (FP) extends from the first day of menstruation until ovulation (preovulatory) and the luteal phase (LP) begins with ovulation and ends on the first day of the subsequent menstrual period (postovulatory). The LP is associated with a cascade of events causing ventilatory changes and alterations in alveolar PCO2 and PaCO2 at rest. Progesterone, a known respiratory stimulant, rises during the LP to ~10-fold its FP level (1). High concentrations of progesterone cause increased minute ventilation (VE) (2) and result in significantly lower PaCO2 during the LP (7, 25, 26).

Others have confirmed the link between circulating progesterone and ventilatory changes. Schoene et al. (29) found that the LP was associated with an increased hypercapnic ventilatory response (HVR), increased VE, and a reduction in PaCO2 at rest. Furthermore, increases in resting HVR and subsequent reductions in PaCO2 were observed in men after administration of the progesterone analog medroxyprogesterone acetate (MPA) (5). In response to cycle ergometry, Dombovy et al. (6) found a lower PaCO2 and a higher ventilatory equivalent for CO2 (VE/VCO2) during the LP versus FP. Similar results were obtained in exercising subjects administered MPA versus controls (5). These studies confirm that high concentrations of progesterone, either administered or naturally produced, cause respiratory stimulation leading to decreased PaCO2 at rest and during exercise.

The recent development of Stewart's physicochemical approach provides a useful tool to assess the quantitative relationships determining [H+] in any ionic solution (30, 31). All variables in solution are defined as being either independent or dependent. If the values of the three independent variables, PCO2, the strong-ion difference ([SID]), and total weak acid concentration ([ATot]), and dissociation constants are known, values for dependent variables (which include [H+], [HCO3-], [A-], [HA], [CO32-], and [OH-]) may be determined mathematically.

The ability of Stewart's approach to accurately predict acid-base behavior and quantify the relationships of the independent variables determining [H+] has been proven in animals (28), men at rest and during exercise recovery (19-22, 24), and in pregnant and nonpregnant women (9, 17). Therefore, Stewart's physicochemical approach is useful to examine individual changes in each of the three independent variables at rest and during exercise. In the context of Stewart's physicochemical approach, it was hypothesized that hypocapnea during the LP (acts to reduce [H+]) is offset by changes in one or both of the other independent variables ([SID] and [ATot]) such that [H+] remains constant regardless of menstrual cycle phase.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects. Subjects were 28 healthy, nonsmoking, physically active women not using oral contraceptives tested during either the FP (n = 14) or LP (n = 14) of the menstrual cycle. Prospective subjects responded to newspaper advertisements, posters, flyers, radio programs, and television news programs within Kingston and the surrounding area. Written informed consent was obtained from all subjects before study entry. The study protocol was approved by the Research Ethics Board, Queen's University, and the US Army Medical Research and Materiel Command, Human Subjects Protection Branch. All subjects completed the revised Physical Activity Readiness Questionnaire.

Minimum sample size calculation. A conventional unpaired subject formula for comparison of means was used to estimate the minimum sample size per group for this study, assuming 80% power and a confidence level of P < 0.05. The variables considered most important were VE (l/min), PaCO2 (mmHg), and [H+] (neq/l). Standard deviations for these variables from healthy women were available from a recent publication from this laboratory (9). Sample sizes capable of detecting between-group differences of 1.0 l/min, 1.5 mmHg, and 1.5 neq/l were calculated for VE, PaCO2, and [H+], respectively. Differences less than these were considered to be within the normal range of physiological variability. The resulting minimum sample size estimates were 11, 12, and 11 per group for VE, PaCO2, and [H+]. Therefore, a sample size of 14 subjects per group was considered sufficient.

Experimental procedures. Subjects participated in exercise testing sessions on two occasions, with at least 48 h between sessions. Subjects consumed a standard meal (350 kcal, 40% carbohydrate, 40% fat, 20% protein) 1-2 h before each testing session and refrained from caffeine intake and strenuous physical activity on the day of testing. Menstrual status at the time of testing was calculated using the first day and average length of the last menstrual cycle and was verified by plasma progesterone measurements. Physical measurements included body height, body mass, and resting blood pressure. Body mass index (BMI) was calculated as body mass (kg) divided by body height (m2).

Exercise testing protocol. Subjects performed two exercise tests on a Sensor Medics (model 800S) constant work rate cycle ergometer. Heart rate was monitored by a Marquette Max-1 electrocardiograph and, additionally, a Polar Vantage monitor. The first test was used to determine the ventilatory threshold (TVent) using the V-slope method (4). The protocol involved 5 min resting data collection preceding a 4-min warm-up at 20 W. This was followed by a 20 W/min ramp increase in work rate until a heart rate of at least 170 beats/min was recorded (9, 35). Alveolar gas exchange was measured on a breath-by-breath basis using a computerized system that integrates a respiratory mass spectrometer (Perkin-Elmer, MGA 1100) and a volume turbine (VMM-1100) (10). Metabolic and respiratory variables were calculated using the algorithm of Beaver et al. (3).

The second exercise test consisted of 10 min resting data collection preceding a 3-min warm-up at 0 W, followed by a ramp increase in work rate from 0 W to a level corresponding to 70% TVent (9). After 20-min rest, subjects again warmed up for 3 min at 0 W, followed by a ramp increase in work rate from 0 W to a level corresponding to 110% TVent. Both work rates were sustained for 7 min (9).

Biochemistry analyses. The second exercise test involved the insertion of an indwelling catheter into a dorsal hand vein situated as far from the thumb as possible. The hand and lower arm were soaked in a warm water bath and heated by warm circulating air to promote vasodilation. Arterialized blood samples were collected at rest and during the 6th min of exercise at work rates corresponding to 70 and 110% TVent (9).

Blood samples for determination of oxygen tension (PO2), PaCO2, [HCO3-], and [H+] were collected using a syringe containing lyophilized heparin and analyzed immediately using a Radiometer ABL 30 acid-base analyzer at a standard temperature of 37°C. Quality control using four control liquids was done on testing days to ensure the analyzer was functioning properly. Blood for determination of plasma osmolality was collected using a syringe containing lithium heparin. The blood was centrifuged for 10 min at 2,500 rpm, and the plasma was used for osmolality analysis. Plasma osmolality was determined using an automated analyzer (Precision Systems, "Osmette A") that uses the freezing-point depression technique. The remaining blood from the lyophilized heparin syringe was centrifuged for 10 min at 2,500 rpm, and the plasma was frozen for later analysis of total protein ([TP]), albumin ([Alb]), and electrolytes. [TP] was measured using the Biuret method. [Alb] was determined using a conventional dye-binding method. Globulin concentration ([Glob]) was calculated by subtracting [Alb] from [TP] to allow calculation of the albumin to globulin ratio. Total Pi concentration ([Pi Tot]) was determined using phosphomolybdate complex. Plasma concentrations of sodium ([Na+]), potassium ([K+]), calcium ([Ca2+]), and chloride ([Cl-]) were measured using ion-selective electrodes.

Lactate ([La-]) was determined by treating samples with potassium oxalate (antiglycolytic agent) and sodium fluoride (anticoagulant). Samples were then centrifuged for 10 min at 2,500 rpm, and the plasma was frozen for later analysis using an automated analyzer (Yellow Springs Instruments, model 2300). The [SID] was calculated as ([Na+]+[K+]+2[Ca2+]) - ([Cl-]+[La-]).

To ensure that measured [SID] was representative of "effective" [SID] ([SID]e), the strong-ion gap (SIG) (16) was determined using the formula SIG = [SID] - [SID]e - ionic contributions of lactate and urates, where [SID]e = 2.46 × 10-8 × (10-pH)+10 × [Alb] × (0.123 × pH - 0.631)+[PO43-] × (0.309 × pH - 0.469) (15).

The interassay coefficient of variability was less than 3% for all of the procedures listed above. Stewart's physicochemical equation (30, 31) was used to calculate [H+] from plasma measurements of PCO2, [SID], and [ATot] (represented by [TP]) (17, 22).

Statistical analyses. Physical characteristics and responses to graded exercise tests of LP and FP subjects were compared between groups using Student's t-statistics for independent samples. Data at rest and during exercise at 70% TVent and 110% TVent were compared within and between subjects using a two-way (group vs. rest/exercise level) ANOVA with repeated measures on the second factor. When a significant between-group main effect was observed, separate independent Student's t-statistics were used to identify significant differences between group means at rest, at 70% TVent, and 110% TVent. When a significant within-group main effect was observed, paired Student's t-statistics were used to detect significant differences between rest, 70%, and 110% TVent.

At rest and in response to cycling at 70% TVent and 110% TVent, measured and predicted [H+] were compared within and between groups using a two-way ANOVA (group vs. measured/calculated values) with repeated measures on the second factor. When a significant between-group main effect was observed, independent Student's t-statistics were used to identify significant differences between the LP and FP. When a significant within-group main effect was observed, paired Student's t-statistics were used to detect significant differences between measured and calculated [H+].

Results of all tests were considered significant if P < 0.05. Because post hoc comparisons within and between groups were planned and the number of comparisons was small in each case, the critical alpha level for significance was maintained at P < 0.05 (18).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Physical characteristics and progesterone. Subjects in both groups were closely matched for age, height, body mass, BMI, parity, and TVent (Table 1). No significant between-group differences were observed for these variables. Progesterone was significantly greater in the LP. A resting level >16.0 nmol/l was considered confirmation of a test conducted during the LP (23).

                              
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  		Table 1.   Physical characteristics and plasma progesterone concentration

Metabolic and cardiorespiratory responses. No significant between-group differences for any variable were found at any measurement time, and similar within-group changes were observed in response to exercise in both groups (Table 2). The following observations were applicable to both groups: mean values for heart rate, VE, tidal volume (VT), breathing frequency (f), oxygen uptake (VO2), carbon dioxide output (VCO2), and respiratory exchange ratio (RER) were significantly greater at 70% TVent versus rest; VE/VCO2 was significantly lower at 70% TVent compared with rest; mean values for heart rate, VE, VT, f, VO2, VCO2, and RER were significantly greater at 110% TVent relative to both 70% TVent and rest; and the ventilatory equivalent for oxygen (VE/VO2) and VE/VCO2 were greater at 110% TVent compared with 70% TVent. Within the FP, VE/VO2 was significantly greater at 110% TVent versus rest, and VE/VCO2 was significantly lower at 110% TVent versus rest.

                              
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  		Table 2.   Heart rate and ventilatory variables

Acid-base variables. No significant between-group differences were observed at rest or during exercise for mean [H+] measured (Table 3). In both groups, mean [H+] measured was significantly increased at 70% TVent versus rest, and at 110% TVent versus both 70% TVent and rest. No significant between-group differences were observed at rest or during exercise for mean [H+] calculated using Stewart's physicochemical approach (Table 3). In both groups, mean [H+] calculated was significantly increased at 70% TVent versus rest and at 110% TVent versus both 70% TVent and rest. No significant differences were observed between mean [H+] measured and mean [H+] calculated in either group at any measurement time.

                              
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  		Table 3.   Comparison of mean [H+] measured and mean [H+] calculated using Stewart's physicochemical approach

PaCO2 was significantly lower in the LP at rest (Fig. 1). No between-group differences were observed after the transition from rest to either exercise intensity. Within the FP, PaCO2 was significantly reduced at 110% TVent versus 70% TVent. No within-group differences existed in the LP.


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  		Fig. 1.   Arterialized plasma carbon dioxide tension (PaCO2) at rest (filled bars) and at 2 work rates (70%, open bars; 110%, hatched bars). *Significant difference between groups. §Significant change within group from cycling at 70% ventilatory threshold (TVent) to cycling at 110% TVent. PaCO2, partial pressure of carbon dioxide in arterialized blood.

[Cl-] was significantly greater in the LP at all measurement times (Table 4). No between-group differences were observed at any measurement time for other electrolytes or osmolality. Within the FP, osmolality, [Na+], [K+], [Cl-], and [La-] were significantly greater at 70% TVent relative to resting values and significantly greater at 110% TVent versus 70% TVent and rest. Within the LP, osmolality and [La-] were significantly increased at 70% TVent compared with rest and at 110% TVent compared with both rest and 70% TVent. [Na+], [Ca2+], and [Cl-] were significantly greater at 70% TVent versus rest and at 110% TVent versus rest. [K+] was significantly greater at 110% TVent versus both rest and 70% TVent.

                              
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  		Table 4.   Osmolality, plasma strong ions, and [SID] at rest and in response to cycling at 70% TVent and 110% TVent

[SID] was significantly lower in the LP at rest (Table 4 and Fig. 2). No between-group differences were observed during cycling at either intensity. Within both groups, [SID] was significantly lower at 110% TVent versus 70% TVent and rest. The SIG approximated zero in both groups at all measurement times.


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  		Fig. 2.   Calculated plasma strong ion difference ([SID]) at rest (filled bars) and at 2 work rates (70%, open bars; 110%, hatched bars). *Significant difference between groups. dagger Significant change within group from rest. §Significant change within group from cycling at 70% TVent to cycling at 110% TVent.

At rest, [TP] and [Alb] were significantly less during the LP versus FP (Table 5). After the transition from rest to cycling at 70% TVent, [TP], [Alb], and [Glob] were significantly lower during the LP versus FP. At 110% TVent, [Alb] was significantly lower in the LP.

                              
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  		Table 5.   Plasma protein and total phosphate at rest and in response to cycling at 70% TVent and 110% TVent

Within the FP, [TP] was significantly greater at both cycling intensities compared with rest. [Alb] was significantly greater at 70% TVent versus rest and at 110% TVent relative to both 70% TVent and rest. [Glob] was significantly higher at 70% versus rest. [Pi Tot] was significantly greater at 110% TVent compared with both 70% TVent and rest. Within the LP, [TP], [Alb], [Glob], and [Pi Tot] were significantly greater after cycling at either intensity relative to rest and greater at 110% TVent versus 70% TVent.

[ATot] was significantly lower during the LP at each measurement time (Fig. 3). Within the FP, [ATot] was significantly greater at both cycling intensities compared with rest. Within the LP, [ATot] was significantly higher after cycling at both intensities versus rest and at 110% TVent versus 70% TVent.


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  		Fig. 3.   Total weak acid ([ATot]) as reflected by total protein ([TP]) at rest (filled bars) and at 2 work rates (70%, open bars; 110%, hatched bars). *Significant difference between groups. dagger Significant change within group from rest. §Significant change within group from cycling at 70% TVent to cycling at 110% TVent.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

To our knowledge, Stewart's physicochemical approach to acid-base analysis has never been employed to compare mechanisms of acid-base regulation during different phases of the menstrual cycle in healthy women at rest or in response to exercise. This study tested the hypothesis that the independent variables constituting the underlying mechanisms regulating [H+] exhibit phase-related differences at rest and in response to exercise during a normal menstrual cycle to ensure relative constancy of [H+] regardless of menstrual cycle phase. In addition, two work rates were chosen to confirm that [H+] is accurately predicted using Stewart's approach above and below TVent and to determine if the independent variables behave differently in response to exercise above versus below TVent.

In general, metabolic and cardiorespiratory responses at rest were similar to previous studies. It is well established that respiratory sensitivity is augmented during the LP due to higher circulating levels of progesterone, and others have reported significantly higher values for VE and VE/VCO2 as a result (6, 25, 26). Although no significant between-group differences for these variables were found, between-group trends for higher VE and VE/VCO2 in the LP were evident at rest. The lack of any discernable between-group trends after the transition from rest to cycling may reflect the increased flux associated with exercise. Alternatively, exercise-induced changes in ventilatory drive may far exceed, thus masking, any progesterone-mediated ventilatory effects.

Previously, Stewart's physicochemical approach has been applied to the study of acid-base regulation at rest and during recovery from exercise in men (19-22, 24, 32) and pregnant women (9, 17). In men, mean [H+] measured and mean [H+] calculated using Stewart's physicochemical method of analysis were similar in arterial and venous blood at rest and during recovery from 30 s of maximal exercise on a cycle ergometer (20) and in venous blood before and immediately after a maximal exercise test on a treadmill (32). In pregnant women, mean [H+] calculated was found to be an accurate reflection of mean [H+] measured in venous (17) and arterial (9) blood at rest and after cycle ergometry above and below TVent. Comparisons of mean [H+] measured and mean [H+] calculated were in close agreement at rest and during exercise above and below TVent. Thus the validity of Stewart's physicochemical approach may now be extended to include normal healthy women, regardless of menstrual cycle phase.

Changes in [H+] during the transition from rest to either exercise intensity were similar in both phases, and no between-group differences for [H+] were observed at any measurement time. This is consistent with reports that menstrual cycle phase does not have a significant effect on [H+] at rest or in response to exercise (5, 6, 14, 26). Note that because [H+] is the cumulative result of all three independent variables, constant [H+] regardless of menstrual cycle phase does not preclude the existence of phase-related differences in the underlying mechanisms that determine [H+]. Such differences are important because the independent variables impact the electrostatic state of plasma proteins. Altering the electrostatic state of a protein can cause subsequent changes in conformational structure, potentially compromising functionality within the biological system (11, 13, 27).

Lower PaCO2 values during the LP at rest and similar trends after the transition to exercise are the result of increased respiratory sensitivity to PCO2 (2). Others have attributed augmented respiratory sensitivity to the effects of increased progesterone and estrogen, but other factors may be involved. Changes in plasma osmolality, [SID], and ANG II have recently been implicated in ventilatory control (9, 11-13, 34) and may play a role here. As discussed below, phase-related differences in [SID] were observed but osmolality remained unchanged. Future studies should attempt to further address the roles of these and other factors in ventilatory control.

Previous studies applying Stewart's physicochemistry to pregnancy revealed reductions in [SID], reportedly due to diminished [Na+] and [K+] secondary to pregnancy-induced expansion of blood volume (9, 17). That [SID] was lower at rest in the LP with a similar trend during exercise was not unexpected given that the LP is often considered to be a "preparatory" stage for pregnancy because many hormonal changes normally associated with pregnancy also occur, albeit to a lesser extent, during the LP. Interestingly, reduced [SID] in the LP was due to significantly higher [Cl-] at each measurement time in the LP, an apparent contrast to the finding of Heenan and Wolfe (9) in late pregnancy. However, in pregnancy the lack of change in [Cl-] despite the pregnancy-induced increase in blood volume also shows that there is an apparent increase in the total circulating amount (not concentration) of this anion so that it does not affect [SID]. The mechanism by which [Cl-] is increased remains elusive, but could be the result of changes in renal absorption of chloride, shifts between fluid compartments, or altered binding of chloride ions by plasma proteins (9). Further studies will be required to clarify this issue.

Significantly lower [Alb] and a general trend for lower [Glob] in the LP explain the lower [TP] in the LP. It is significant that the protein changes occurred in the absence of any appreciable change in osmolality and presumably plasma volume. It is possible that lower [TP] during the LP is due to factors such as "leakage" to the interstitium or a phase-related difference in liver protein production processes and/or protein clearance by the kidney. Alternatively, higher [Cl-] observed during the LP may be responsible for lowering [TP], because strong anions are known to affect dissociation constants.

The cumulative effect of phase-related changes in each independent acid-base variable requires consideration. Owing to significantly lower PaCO2 in the LP at rest, in addition to the trend for lower PaCO2 in the same group after the transition from rest to exercise, a significantly lower [H+] at all measurement times was expected. However, our data and those of others (6, 14, 26) suggest that no significant changes in [H+] occur at rest or in response to exercise. Therefore, changes in other independent variables must at least partially offset the effects of PaCO2 on [H+].

At rest in the LP, significantly lower [ATot] acts to reduce [H+]. Significantly lower [SID], however, acts to increase [H+]. Because the cumulative result produced a prevailing [H+] no different than that observed during the FP, it appears that the effects of a significantly lower PaCO2 and [ATot] were offset by significant reductions in [SID]. It thus appears that the body actively regulates [SID] with chloride ions in response to changes in PCO2 and/or [ATot], not unlike the way PCO2 is changed to compensate for changes in metabolic variables. Similar reports of [SID] being regulated in response to changes in other independent variables exist. Progressive hypercapnia applied acutely resulted in an increased [SID] in ponies (8) attributable to sodium and chloride shifts between plasma and soft tissue red cells (11). In critical care patients, Wilkes (33) reported reduced [SID] as a compensatory response to diminished [ATot] achieved by increases in [Cl-].

During exercise, significantly lower [ATot] and a trend for a lower PaCO2 during the LP coupled with no significant between-group differences for [H+] suggested that these [H+]-reducing effects were offset by a nonsignificant reduction in [SID]. This suggests that phase-related differences in acid-base regulatory mechanisms at rest, necessary to maintain [H+] homeostasis regardless of menstrual cycle phase, persist during exercise.

In conclusion, the validity of Stewart's approach to investigate mechanisms of acid-base regulation is now extended to encompass studies of healthy women regardless of menstrual phase. The original hypothesis that mechanisms regulating [H+] exhibit phase-related differences during a normal menstrual cycle was confirmed. In accordance with Stewart's physicochemical approach, all three of the independent variables, PaCO2, [SID], and [ATot], are significantly lower at rest during the LP. These differences persist during exercise, but are much less pronounced. It appears that phase-related differences in all three independent variables exist to ensure that [H+] is relatively constant regardless of menstrual cycle phase.


    ACKNOWLEDGEMENTS

This study was supported by the Ontario Thoracic Society, the US Army Medical Research and Materiel Command (Contract DAMD17-96-C-6112), and the Natural Sciences and Engineering Research Council of Canada.


    FOOTNOTES

Address for reprint requests and other correspondence: L. A. Wolfe, School of Physical and Health Education, Queen's Univ., Kingston, Ontario K7L 3N6, Canada (E-mail: wolfel{at}post.queensu.ca).

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.

Received 24 January 2000; accepted in final form 9 October 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Regul Integr Comp Physiol 280(2):R481-R487
0363-6119/01 $5.00 Copyright © 2001 the American Physiological Society


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