Effect of physical exercise in hypobaric on atria1 natriuretic peptide secretion OLLI TIM0
VUOLTEENAHO, PENTTI KOISTINEN, TAKALA, AND JUHANI LEPPALUOTO
conditions
VESA MARTIKKALA,
Department of Physiology, University of Oulu, Health Center Hospital of Oulu; Deaconess Institute of Oulu, Oulu, Finland Vuolteenaho, Timo Takala,
Olli, Pentti and Juhani
Koistinen, LeppLiluoto.
Vesa Martikkala,
Effect of physical exercise in hypobaric conditions on atria1 natriuretic peptide secretion. Am. J. Physiol. 263 (Regulatory Integrative Cornp. Physiol. 32): R647-R652, 1992.-To evaluate the role of atria1 natriuretic peptide (ANP) in exercise-related cardiovascular and hormonal adjustments in hypobaric conditions, 14 young athletes performed a maximal ergometer test in a hypobaric chamberadjustedto simulatethe altitudes of sealevel and 3,000 m. Plasmaimmunoreactive ANP levels rose from 5.89 to 35.1 pmol/l at sealevel and rose significantly less(P < 0.05), from 5.36 to 22.3 pmol/l, at simulated 3,000m. Plasmaimmunoreactive amino-terminal peptide of proANP (NT-proANP) levels increasedto the sameextent at sealevel and at simulated3,000 m (from 240 to 481 pmol/l and from 257 to 539 pmol/l, respectively). Plasma immunoreactive aldosteroneincreasedsignificantly lessat simulated 3,000m (P < 0.05), but the changesin plasma renin were similar in both conditions. Plasma immunoreactive endothelin- 1 and serum erythropoietin levels remained unchanged. In conclusion, we found a blunted ANP responseto maximal exerciseof ANP in acute hypobaric exposure comparedwith that in normobaric conditions, but no significant difference in the NT-proANP responsesbetween the two conditions. The divergencemay be due to stimulation of the elimination mechanismof ANP. aldosterone; cortisol; endothelin; ergometer; erythropoietin; heart rate; high altitude; hypoxemia; renin; work load
(ANP) has diuretic, natriuretic, and vasorelaxant properties (8). The concentration of plasma ANP has been shown to increase in response to physical exercise in a dose-dependent manner. Increased cardiac filling and sympathetic tone as well as vasopressor hormones are believed to be the main factors causing the increased release of ANP (9, 12, 13, 22, 26, 29, 31-33). ANP has been reported to increase water conductivity at the capillary level (15), thus having the potential to cause fluid shift from the intravascular to the extravascular space. It also inhibits the secretion of renin and aldosterone (18). Recent studies have indicated that ANP may have a physiological role in the adaptation to hypoxia. Normobaric hypoxia has been reported to raise plasma ANP and to lower plasma aldosterone secretion (20, 27). Elevated plasma ANP levels have been observed in subjects suffering from acute mountain sickness (3). Thus both physical exercise and hypoxia appear to be capable of elevating plasma ANP levels. Exercise after a &day stay at high altitude was shown to result in reduced plasma aldosterone and renin responses when compared with sea level conditions, but the ANP response was unchanged (5). Submaximal exercise in normobaric hypoxic conditions was recently reported to result in higher plasma ANP elevation than similar exercise in normoxic conditions (19). ATRIAL
NATRIURETIC
PEPTIDE
0363-6119/92
$2.00
Copyright
The amino-terminal peptide (l-98) of proANP (NTproANP) is secreted to the circulation in equimolar quantities with ANP. It does not have any known biological activity, and it differs from ANP in that its halflife in circulation is longer and therefore its plasma levels are higher (17). Whole body immersion in water, which produces central hypervolemia, has been reported to elevate plasma ANP and NT-proANP in a parallel manner (14). Endothelin-1, a peptide derived from vascular endothelium, is a very potent vasoconstrictor and appears to be an important regulator for the secretion of ANP (16, 24). The role of endothelin during physical exercise and hypoxia is not known. We are interested in learning more about the physiological function of ANP in the adaptation to exercise. We have now compared the acute effects of maximal physical exercise at sea level and in hypobaric conditions simulating the altitude of 3,000 m on hemodynamics, circulating ANP, NT-proANP, aldosterone, and renin in young athletes. We are also interested in finding out whether circulating endothelin-1 plays a role in the regulation of ANP in these conditions. METHODS Subjects. Fourteen athletes, five male and three femalecrosscountry skiersand six maleice hockey players, aged18-25 years gave their informed consent to participate in this study. The study plan wasapproved by the Ethics Committee of the Medical Faculty, University of Oulu. Experimental protocol. Each subject was studied in random order 2-4 days apart during the maximal electrically braked bicycle ergometertest in the hypobaric chamber of the Department of Physiology. The chamber was maintained either in normobaric conditions or adjustedto hypobaric conditions simulating the altitude of 3,000m (correspondingto pressureof 520 mmHg). The electrodes for ECG monitoring, fingertip pulse oximeter (Pulsox-7, Minolta), and face mask for 0, and CO, monitoring were attached. The subjectsthen sat on the ergometer for 15 min during which time (in the hypobaric experiment) the chamber was adjusted to hypobaric conditions simulating the altitude of 3,000 m. The work load was increasedgradually by 50-W steps at 4-min intervals until exhaustion. Capillary samplesfor the measurementof blood lactate were taken from the fingertips every 5 min. Venous blood samplesfor the hormonal measurementswere taken before the exercise,at the end of it (16-30 min), and after a 30-min resting period following exhaustion. Blood wasdrawn from an antecubital vein into glass tubes for preparing the serum samplesand into polyethylene tubes containing EDTA (1.5 mg/ml blood) for the plasmasamples.The tubes were kept on ice and centrifuged within 60 min at +5”C. Serum and plasmasampleswere stored at -20°C for the assays.The relative plasmavolume changeswere calculated from the hematocrit (34). The blood pressurewas recorded by sphygmomanometer.
0 1992 the American
Physiological
Society
R647
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R648
EXERCISE
IN HYPQBARIC
Chemical anaZyses. Plasma ANP and NT-proANP radioimmunoassayswere carried out using antisera prepared in rabbits against carbodiimide conjugates of bovine thyroglobulin and the respective peptides [rat ANP or human proANP-(79 -98)] as describedpreviously (35). For the ANP radioimmunoassay l-ml plasmasampleswerefirst extracted with Sep-Pak C,, cartridges.The radioimmunoassaywasperformed asdescribed(36) usingantiserum 9-50 (final dilution l/200,000). The antiserum cross-reactsfully with human and rat ANP, but doesnot recognize NT-proANP (CO.1%). NT-proANP wasassayeddirectly from plasmaas follows. Standards [synthetic human proANP(79-98) Peninsula] and samples(25 ~1) in duplicate were incubated with 200 ~1of radioiodinated human Tyr-(O)-proANP(79-98) (Peninsula) and 200 ~1of rabbit antiserum 135 (final dilution l/40,000) overnight at +4”C. The bound and free fractions were separatedby double antibody precipitation in the presenceof polyethylene glycol. The sensitivity of the assaywas 0.5 fmol/tube and the within and between assaycoefficients of variation were 0.05, Fig. 20). Plasma immunoreactive cortisol levels increased significantly from 457 t 42 to 643 t 46 nmol/l in normobaric conditions and from 539 t 48 to 696 t 44 nmol/l in hypobaric conditions (both P < 0.05) in response to exercise. The levels were still elevated 30 min after the exercise (705 t 44 and 663 t 38 nmol/l in normobaric and hypobaric conditions, respectively). The increases in normobaric and hypobaric conditions did not differ significantly from each other (P > 0.05). Plasma endothelin-1 and serum erythropoietin concentrations, and serum electrolytes. Mean plasma immunoreactive endothelin-1 levels did not change significantly (P
> 0.05) during exercise in either normobaric or hypobaric conditions (Fig. 3A). Likewise there was no significant change in the mean serum erythropoietin levels in response to physical exercise (Fig. 3B). Mean serum levels of sodium, potassium, and chloride in normobaric resting conditions were 139 t 0.6, 4.5 t 0.6, and 103 t 1.0 mmol/l, respectively, and levels after the exercise were 140 t 1.0, 4.5 t 0.3, and IO5 t 1.2 mmol/l, respectively. The resting and exercise levels did not differ significantly from each other, nor did the levels differ from those detected in hypobaric conditions (P > 0.05).
DISCUSSION
4-
%
200
R649
formed at the end of the exercise with the plasma immunoreactive ANP levels as the dependent variable and each of the other parameters in turn as the independent variable. The maximal plasma ANP levels correlated weakly but significantly with work load/kg body weight (r = 0.36, P = 0.013), the absolute work load (r = 0.34, P = 0.017), and with diastolic blood pressure (r = 0.33, P = 0.04) but not with any of the other parameters. Whereas the individual immunoreactive NT-proANP and ANP concentrations correlated significantly with each other (r = 0.47, P c 0.001, n = 84), the exercise-induced increments did not (r = 0.20, P = 0.33, n = 28).
10
600
AND ANP
Correlation of maximal plasma ANP levels to other parameters measured. Linear regression analyses were per-
20
B
CONDITIONS
-
0
20
40
60
0 TIME
20
40
60
(mid
Fig. 2 Effect of maximal exercise in normobaric conditions and hypobaric conditions on venous plasma immunoreactive ANP (A), NTproANP (B), aldosterone (C), and renin activity (D). Horizontal bars indicate duration of exercise. Values are given as means t SE. *P < 0.05, **P c 0.01: levels at exhaustion vs. preexercise levels within the normobaric and hypobaric condition groups. +P < 0.05, ++P < 0.01: normobaric vs. hypobaric conditions.
In normobaric conditions, our present exercise protocol resulted in an average maximal work load of 311 W, a systolic blood pressure of 202 mmHg, a heart rate of 186 beats/min, and a blood lactate level of 7.7 mmol/l, demonstrating that the test was intensive. It led to a 5.9-fold increase in plasma ANP, a 2.0-fold increase in plasma NT-proANP, a 4.3-fold increase in renin activity, and a 2.4-fold increase in plasma aldosterone. In earlier studies submaximal exercise has been reported to result in a 1.4to Z&fold increase in plasma ANP (5, 12, 26, 29). An interesting finding in our experiments was the clearly lower relative increase of NT-proANP compared with that of ANP. Plasma molar NT-proANP levels were 40.7
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R650
EXERCISE
IN HYPOBARIC
CONDITIONS
AND ANP
single copies from a common precursor and hence are released to the circulation in equimolar amounts (8). The mean exercise-induced increments in the plasma NT1 proANP levels were similar in our study, 241 pmol/l in normobaric conditions and 282 pmol/l in hypobaric conditions. The respective increments for plasma ANP were 29.2 and 16.9 pmol/l, i.e., 8-17 times smaller than those of NT-proANP. Therefore, it appears that only a fraction of ANP released from the heart remained in the blood circulation so that we were able to pick it up with the radioimmunoassay. In addition, we observed no significant correlation between the plasma ANP and NT-proANP increments. Therefore, it is quite possible that the stimulatory effect of physical exercise on the ANP/NTproANP release was actually the same in both norHypobaria (0) mobaric and hypobaric conditions. The explanation for I Normobaria (0) the observed divergent responses of ANP and NTproANP would then lie in the different fates of the two peptides after secretion. We propose that exercise is somehow able to alter the elimination of circulating ANP (enzymatic degradation or receptor binding) so that it is more efficient in hypobaric than in normobaric conditions. These findings stress the major importance of postsecretory mechanisms in the regulation of the plasma levels of ANP. Even though we did not measure the atria1 pressures it is possible that exercise in hypobaric hypoxic conditions results in lesser degree of atria1 stretch compared with similar exercise in normobaric normoxic conditions. Atria1 stretch is a well-known stimulant of ANP secretion, and therefore this mechanism could explain the smaller increase of plasma ANP in hypobaric conditions observed in the present study. The absence of any significant difference in the NT-proANP responses would, however, still remain without explanation. Moreover, waFig. 3 Effect of maximal exercise in normobaric conditions and hy- ter immersion, leading to increased atria1 stretch, has pobaric conditions on venous plasma immunoreactive endothelin- 1 (A) been reported to result in parallel increases of plasma and erythropoietin (B). Horizontal bars indicate duration of exercise. ANP and NT-proANP in humans (14). We have also Values are given as means t SE. There were no statistically significant found that in rats both plasma ANP and NT-proANP are differences within or between the groups. elevated following an intravenous volume load (0. Vuolteenaho, Y. Liu, and J. Leppaluoto, unpublished obsertimes higher than those of ANP before the exercise and vations). 13.7 times higher at the point of exhaustion. In previous studies acute normobaric hypoxia (10 to Our finding that the relative ANP response was smaller 12% O2 in ambient air or blood O2 saturation of 90%) was in hypobaric than in normobaric conditions is in agreedemonstrated to increase plasma ANP in resting subjects ment with a recent study in which the plasma ANP re(10, 20, 27). Persons suffering from acute mountain sicksponse to 30-min ergometer exercise was more proness were shown to have elevated plasma ANP, but those nounced at sea level than at the altitude of 4,350 m (5). without symptoms had unchanged plasma ANP even at The fact that in our study the maximal work load was, as the altitude of 4,559 m (3). In animal studies normobaric expected, significantly lower in hypobaric conditions compared with normobaric conditions could explain the hypoxia has reproducibly been found to result in augmenlower ANP response. The progressively increased exer- tation of plasma ANP levels (1, 2, 21), which correlate especially well with the increases of pulmonary arterial cise was, however, continued to ex .haustion and should pressure (2). Thus, previous results demonstrate that in therefore have been equally stressful to the cardiovascular resting healthy subjects and in different animal species and other systems in both conditions. An interesting finding in our study was that the NT-proANP responses, hypoxia leads to elevated plasma ANP levels in norin contrast to ANP, did not differ from each other in the mobaric conditions. A recent study reported enhanced elevation of plasma two conditions. This is unexpected, considering the comANP in response to submaximal exercise in normobaric mon origin of the two peptides. What-is the mechanism behind the divergent responses hypoxic conditions as compared with normobaric norof ANP and NT-proANP? The peptides are derived as moxie conditions (19). Our present results and those of A
5
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EXERCISE
IN HYPOBARIC
Bouissou et al. (5), however, showed that physical exercise in hypobaric conditions leads to lower plasma ANP responses than the same stimulus in normobaric conditions. O2 saturation does not seem to be responsible for the difference, since comparable blood O2 saturation has been observed in normobaric hypoxemia (20) as in hypobaric hypoxemia (this study). Apart from the facts that our study was performed in hypobaric conditions and that we used maximal exercise, a possible factor explaining the conflicting results with the study of Lawrence and Shenker (19) may be the clearly less intensive hypoxic stimulus in the latter. Moreover, their study subjects were untrained, whereas we studied well-trained athletes. Another important variable might be the length of the hypobaric exposure. However, in both our study and that of Lawrence and Shenker (19) the exposure was acute, a fact that was reflected in our study by the presence of a significant difference in the preexercise values between the normobaric and hypobaric exposures only in the case of arterial O2 saturation. In contrast to some previous reports (4,5,30), we found here that plasma renin activity at rest and its responses to exercise were as similar in normobaric conditions as in hypobaric conditions. The responses of aldosterone, however, were more pronounced in normobaric conditions than in hypobaric conditions. The lack of parallel changes in plasma renin activity and aldosterone levels during hypoxia has been reported previously (6,19,20). It has been suggested that ANP is the major factor causing the dissociation (19, 20). However, the secretions of both renin and aldosterone are known to be inhibited by infusions of synthetic ANP, resulting in ANP plasma levels of ~50 pg/ml (7, 28). Our present plasma ANP levels, after exercise, were well over the threshold (69-108 pg/ml). If the decreased aldosterone responses in the hypobaric conditions that we observed were due to ANP, higher plasma ANP levels at hypobaric conditions than at sea level would have been expected. The opposite was actually true; hence ANP appears not to be a major factor responsible for the dissociation of the aldosterone and renin responses during hypobaric hypoxia. On the other hand, the less pronounced decrease in the relative plasma volume observed in hypobaric conditions (Fig. 1B) may be responsible for the smaller elevation of aldosterone in the same condition (Fig. 2C). Speaking against this possibility is the fact that there was not significant difference in the renin responses (Fig. 20). We did not observe any significant increase in plasma potassium in response to exercise. This unexpected finding may be related to the fact that our study subjects were well-trained athletes. Training has been shown to result in the blunting of exercise-induced rises in plasma potassium (23). In addition, our study subjects were not dehydrated or fasting, in contrast to those in earlier studies (13, 19). Moreover, the blood samples in our study were collected after a longer period of exercise. It is possible that these differences and the various superimposed changes in the factors affecting water and electrolyte balance discussed above contributed to the stable potassium levels. ANP has been shown to potentiate the effects of eryth-
CONDITIONS
AND
R651
ANP
ropoietin in stimulating erythroid colony formation (25). Since ANP secretion is increased during normobaric hypoxia (10, 19, 20, 27), it might increase the effectiveness of erythropoietin in increasing the red cell production. Exercise in hypoxic conditions might be an even stronger stimulus. However, we did not observe any changes in serum erythropoietin levels after the exercise with an N70-min stay in the hypobaric chamber. Even though our hypoxemic challenge was quite severe (0, saturation of 76%) the duration of hypoxia was probably too short. It was found in a previous study that exposure (without exercise) to hypobaric conditions simulating the altitude of 3,000 m leads to significantly increased serum erythropoietin levels only after a stay of 114 min or longer (11). In summary, we found a less pronounced elevation of plasma ANP in response to maximal exercise in hypobaric compared with normobaric conditions but identical responses of NT-proANP in both conditions. This is unexpected, since ANP and NT-proANP are produced from a common precursor in equimolar amounts. We propose that exercise in hypobaric conditions is capable of stimulating some aspect of the elimination mechanism of ANP (degradation or receptor binding) leading to divergent changes in the plasma levels of ANP and NTproANP. Circulating endothelin-1 does not appear to have a role in the exercise-induced stimulation of ANP, since its levels did not change in response to exercise. Postexercise plasma renin activity was similar in normobaric and hypobaric conditions, but plasma aldosterone levels were lower in hypobaric conditions. This dissociation between renin and aldosterone does not seem to be caused by ANP. We thank Tuula Lumijarvi, Seija Linnaluoto, Kangas, and Alpo Vanhala for skillful technical This study was supported by a project grant Finland, by The Ministry of Education, and by Committee. Address for reprint requests: 0. Vuolteenaho, Univ. of Oulu, 90220 Oulu, Finland. Received
4 December
1991; accepted
in final
Maria Uusimaki, Auli assistance. from The Academy of The Finnish Olympic
form
Dept.
of Physiology,
11 March
1992.
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R652
EXERCISE
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IN HYPOBARIC
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