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Exhaustive exercise-induced tissue hypoxia does not change endothelin and big endothelin plasma levels in normal volunteers
AJH
1998;11:1028 –1031
Exhaustive Exercise-induced Tissue Hypoxia Does Not Change Endothelin and Big Endothelin Plasma Levels in Normal Volunteers Tomas Lenz, Markus Nadansky, Jan Gossmann, Gerhard Oremek, and Helmut Geiger
Chronic hypoxia has been shown to increase plasma endothelin levels. The current study was undertaken to examine the effect of exerciseinduced tissue hypoxia on plasma levels of endothelin-1 (ET-1) and its precursor big endothelin-1 (Big-ET-1). After approval by the local ethical committee an incremental dynamic exercise test was performed in 12 physically trained volunteers (aged 20 to 40 years), using an electrically braked bicycle ergometer. The protocol included a step-wise increase of the workload until a heart rate of 130/min was reached, followed by a maintenance period of 25 min, and a further stepwise increase until exhaustion. Blood was drawn before, at several time points during, and 5 min after termination of the study for determination of ET-1, Big-ET-1, plasma renin activity (PRA), angiotensin converting enzyme (ACE), norepinephrine, epinephrine, and lactate. Lactate levels at baseline were 14.5 6 1.6 mg/dL (mean 6
SEM), which increased to 76.5 6 4.8 mg/dL at the time of exhaustion (P < .01). Baseline values for ET-1 and Big-ET-1 were 0.264 6 0.061 and 0.637 6 0.130 fmol/ml, respectively, which remained essentially unaltered throughout the exercise test. PRA was 1.46 6 0.45 ng/mL/h before exercise and increased to 3.55 6 0.96 ng/mL/h at exhaustion (P < .001). Norepinephrine and epinephrine were also increased at exhaustion. The study demonstrates that exhaustive physical exercise with acute development of pronounced tissue hypoxia— in contrast to chronic hypoxia— does not influence the release of ET-1 or Big-ET-1 or the conversion of the precursor to the active compound. Unlike endothelin, circulating renin and the catecholamines were markedly stimulated by this maneuver. Am J Hypertens 1998;11:1028 –1031 © 1998 American Journal of Hypertension, Ltd.
ndothelin-1 (ET-1) belongs to a gene familiy of 21-amino-acid peptides. ET-1 has strong vasoconstrictor properties, binds to specific receptors, and is cleaved from the precursor big endothelin-1 (Big-ET-1) by endothelin converting
E
enzyme, which has 1:100 the potency of ET-1.1,2 Various clinical situations, for example, chronic renal failure,3 chronic heart failure,4 and acute myocardial infarction,5 occur coincidently with elevated ET-1 plasma levels.
Received December 17, 1997. Accepted March 9, 1998. From the Division of Nephrology, Medical Clinic IV (TL, MN, JG, HG), and Central Laboratory, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. Parts of this article were presented in abstract form at the 21st Annual Meeting of the German Hypertension League, Lu¨beck, Germany, 1997.
Address correspondence and reprint requests to Tomas Lenz, MD, Division of Nephrology, Medical Clinic IV, Johann Wolfgang Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
© 1998 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
KEY WORDS:
Exercise, hypoxia, endothelin.
0895-7061/98/$19.00 PII S0895-7061(98)00086-7
AJH–AUGUST 1998 –VOL. 11, NO. 8, PART 1
EXHAUSTIVE EXERCISE AND ENDOTHELIN
1029
FIGURE 1. Endothelin and big endothelin plasma levels before and during exercise, at exhaustion, and 5 min after termination in 12 healthy volunteers.
Furthermore, chronic hypoxia is a condition with elevated ET-1 plasma levels6 and in a rat model of chronic hypoxia enhanced ET-1 and endothelin receptor expression was found.7 Conflicting data, however, exist on the effect of acute hypoxia on the release of ET-1. In most studies exercise tests were used to induce tissue hypoxia in humans. Several investigators reported that with prolonged exercise ET-1 levels were markedly increased in healthy volunteers without8 –10 or with dehydration11 as well as in patients with coronary artery disease.12,13 The increase was found to be augmented by alveolar hypoxia in healthy subjects.14 Others, however, reported no change during exercise compared to resting values in normal volunteers under normoxic3,12,13,15 or hypobaric conditions,16 or in patients with coronary heart disease17 or congestive heart failure.4,18 These discrepancies may partly be attributable to different exercise protocols, in particular with regard to the duration and the workload increments (ie, aerobic v anaerobic conditions). No published data exist on the release of Big-ET with exercise, which conceivably could be different from that of ET-1. Therefore, in the current study the effect of acute tissue hypoxia with exhaustive physical exercise on the release of ET-1 and its precursor Big-ET-1 was examined in healthy volunteers. SUBJECTS AND METHODS After approval by the local ethical committee 12 healthy physically well-trained volunteers (3 women, 9 men; aged 20 to 40 years, mean age 28.3 years) were enrolled after informed consent. An electrically braked bicycle ergometry was started with an initial workload of 50 W, which was increased by 10 W every min until the heart rate was 130/min. The workload was kept at this level for another 25 min, followed by
increases of 20 W every 2 min until exhaustion. Blood pressure and heart rate were continously monitored by an automatic device. Blood was drawn before, at the end of the initial and maintenance phase, at exhaustion, and 5 min after termination of the exercise for determination of ET-1/2 (the commercial ELISA has a 100% cross-reactivity for ET-1 and ET-2) and Big-ET-1 (ELISA) (Immundiagnostic, Bensheim, Germany), plasma renin activity (radioimmunoassay) (Isotex, Friendswood, TX), angiotensin converting enzyme (ACE) (sphectrophotometrically), norepinephrine, and epinephrine (radioimmunoassay) (IBL, Hamburg, Germany), and lactate (enzymatically). Wilcoxon tests were used for statistical analysis. RESULTS All 12 volunteers completed the study according to the protocol. Serum lactate increased from a baseline value of 14.5 6 1.6 mg/dL to a maximum of 76.5 6 4.8 mg/dL at the time of exhaustion (P , .01). ET-1 and Big-ET plasma levels during and immediately after exercise were not statistically different from baseline values (Figure 1). PRA at baseline amounted to 1.46 6 0.45 ng/mL/h and increased to 3.55 6 0.96 ng/mL/h at the time of exhaustion (P , .001), whereas at the same time serum ACE decreased from 24.9 6 2.9 to 15.8 6 3.5 U/L (P , .01). Norepinephrine and epinephrine (measured in 5 of the subjects) increased from a baseline value of 153 6 71.2 and 29.1 6 15.9 ng/L to 327 6 169 and 76.7 6 43.0 ng/L at exhaustion. Systolic/diastolic blood pressure changed from a baseline value of 121 6 2.7/79.2 6 3.6 mm Hg to 181 6 5.9 (P 5 .002) /72.7 6 2.6 (P 5 .12) mm Hg at exhaustion, respectively. Heart rate amounted to 78.8 6 4.2 per min at baseline and increased to 167 6 5.0 per min at exhaustion (P 5 .001).
1030
AJH–AUGUST 1998 –VOL. 11, NO. 8, PART 1
LENZ ET AL
DISCUSSION This study demonstrates that under normoxic conditions exhaustive exercise with the development of pronounced tissue hypoxia (demonstrated by markedly increased lactate levels) did not alter the release of ET-1 or its precursor Big-ET-1. Furthermore, the conversion of Big-ET-1 to the biologically active compound was apparently not enhanced under this condition, suggesting that acute strenous exercise had no effect on the activity or expression of endothelin converting enzyme. The activity of the enzyme, however, was not measured in this study. The only other, albeit unlikely, explanation would be that release and uptake/degradation of the endothelins were enhanced to a similar degree, leading to unaltered plasma levels of the peptides during and after exercise. The absence of an effect of exercise on ET-1 release in normal subjects is in agreement with previous studies.3,12,13,15 At variance with our results, however, Rocker et al9 showed that plasma endothelin levels increased by about 50% immediately after short-term exercise at maximal capacity. Maeda et al8 reported that plasma ET-1 levels increased in parallel with exercise intensity with a peak at 30 min after termination of exercise. A similar approach was used by Kullmer et al14 who also found increased plasma levels of ET-1 during exhaustive exercise. This stimulatory effect, however, was only seen when the healthy volunteers were exposed to simulated high altitude conditions with acute alveolar hypoxia. Therefore, it appears that tissue hypoxia alone, as in our study, is not always sufficient to induce endothelin release but that hypoxemia is required. In vitro data suggest that the production of ET-1 is regulated by multiple factors, including endogeneous substances such as catecholamines and arginine vasopressin.19,20 In our study and the ones of many others it was shown that the plasma catecholamine levels markedly increased during exhaustive exercise.21 Because there was no change in the plasma concentration of the endothelins in our and other studies, the physiologic role of catecholamines for the release of these peptides remains unclear. It was previously shown that exercise in combination with inspiring hypoxic gas mixtures induced lactate accumulation. which correlated with the release of catecholamines, suggesting a relationship between glycogen metabolism and sympathoadrenal activity.22 Another interesting hypothesis claims that nonworking muscles produce and release more ET-1 than the working muscles, thereby shifting the blood flow to the working muscles.23 However, the markedly elevated serum lactate levels in our study were not paralleled by changes in endothelin release. There is a possibility that we did not wait long enough after exercise to observe such an
effect, as changes may occur as late as 30 to 60 min after termination of exercise.8 It is very likely that short-term maneuvers may not be suitable to induce ET-1 release, as the peptide does not appear to be stored in vesicles. Thus, ET-1 secretion may largely depend on the levels of transcription and translation, processes that usually require more time.1 The increased sympathoadrenal acitivity may partly explain the stimulated renin release, which depends on b1-receptor activation.24 However, another compound of the renin angiotensin system, the endothelium-derived angiotensin converting enzyme, decreased in plasma during exercise. It appears, therefore, justified to conclude that this vasoregulating system is more variable with exercise than the endothelin system. Whether these changes are physiologically important or are merely reactive remains to be answered. In summary, this study demonstrates that exhaustive physical exercise with acute development of pronounced tissue hypoxia—in contrast to chronic hypoxia—influenced neither the release of ET-1/BigET-1 nor the conversion of the precursor to the active compound. Unlike the endothelins, circulating renin and the catecholamines were markedly stimulated by this maneuver. This study supports the view that storage vesicles for endothelin may not exist in vivo. REFERENCES 1.
Kohan DE: Endothelins in the kidney: physiology and pathophysiology. Am J Kidney Dis 1993;22:493–510.
2.
Levin ER: Endothelins. N Engl J Med 1995;333:356 – 363.
3.
Predel HG, Meyer-Lehnert H, Backer A, et al: Plasma concentrations of endothelin in patients with abnormal vascular reactivity. Effects of ergometric exercise and acute saline loading. Life Sci 1990;47:1837–1843.
4.
McMurray JJ, Ray SG, Abdullah I, et al: Plasma endothelin in chronic heart failure. Circulation 1992;85: 1374 –1379.
5.
Miyauchi T, Yanagisawa M, Tomizawa T, et al: Increased plasma concentrations of endothelin-1 and big endothelin-1 in acute myocardial infarction. Lancet 1989;2:53–54.
6.
Ferri C, Bellini C, De Angelis C, et al: Circulating endothelin concentrations in patients with chronic hypoxia. J Clin Pathol 1995;48:519 –524.
7.
Li H, Chen SJ, Chen YF, et al: Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. J Appl Physiol 1994;77:1451–1459.
8.
Maeda S, Miyauchi T, Goto K, Matsuda M: Alteration of plasma endothelin-1 by exercise at intensities lower and higher than ventilatory threshold. J Appl Physiol 1994;77:1399 –1402.
9.
Rocker L, Mockel M, Westpfahl KP, Gunga HC: Influence of maximal ergometric exercise on endothelin concentrations in relation to molecular markers of the hemostatic system. Throm Haemost 1996;75:612– 616.
AJH–AUGUST 1998 –VOL. 11, NO. 8, PART 1
EXHAUSTIVE EXERCISE AND ENDOTHELIN
1031
10.
Cozenzi A, Sacerdote A, Bocin E, et al: Neither physical exercise nor alpha-1- and b-adrenergic blockade affect plasma endothelin concentrations. Am J Hypertens 1996;9:819 – 822.
17.
Letizia C, Barilla F, Cerci S, et al: Plasma endothelin-1 concentrations in patients with coronary artery disease during stress test before and after nisoldipine administration. Acta Cardiol 1996;51:165–172.
11.
Maeda S, Miyauchi T, Waku T, et al: Plasma endothelin-1 level in athletes after exercise in a hot environment: exercise-induced dehydration contributes to increase in plasma endothelin-1. Life Sci 1996;58:1259 – 1268.
18.
de Groote P, Maillaire A, Racadot A, et al: Plasma levels of endothelin-1 at rest and after exercise in patients with moderate congestive heart failure. Int J Cardiol 1995;51:267–272.
12.
Letizia C, Barilla F, Cerci S, et al: Dynamic exercise induces elevation of plasma levels of endothelin-1 in patients with coronary artery disease. Angiology 1995; 46:819 – 826.
19.
Emori T, Hirata Y, Ohta K, et al: Cellular mechanism of endothelin-1 release by angiotensin and vasopressin. Hypertension 1991;18:165–170.
20.
Yanagisawa M, Kurihara H, Kimura S, et al: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411– 415.
21.
Haller H, Lenz T, Thiede HM, et al: Platelet intracellular free calcium during dynamic exercise. Am J Nephrol 1986;6(suppl 1):57–59.
13.
Predel HG, Knigge H, Prinz U, et al: The exerciseinduced increase in plasma levels of endothelin-1 is enhanced in patients with atherosclerotic coronary artery disease. Modulation by PETN. Agents Actions 1995;45:219 –225.
14.
Kullmer T, Jungmann E, Haak T, Usadel KH: Modification of the response of endothelin-1 to exhaustive physical exercise under simulated high altitude conditions with acute hypoxia. Metabolism 1995;44:8 –9.
22.
Takahashi H, Irizawa M, Komura T, et al: Relationship among blood lactate and plasma catecholamine levels during exercise in acute hypoxia. Appl Human Sci 1995;14:49 –53.
15.
Richter EA, Emmeluth C, Bie P, et al: Biphasic response of plasma endothelin-1 concentration to exhaustive submaximal exercise in man. Clin Physiol 1994;14:379 – 384.
23.
Maeda S, Miyauchi T, Sakane M, et al: Does endothelin-1 participate in the exercise-induced changes of blood flow distribution of muscles in humans? J Appl Physiol 1997;82:1107–1111.
16.
Vuolteenaho O, Koistinen P, Martikkala V, et al: Effect of physical exercise in hypobaric conditions on atrial natriuretic peptide secretion. Am J Physiol 1992;263: R647–R652.
24.
Lenz T, Thiede HM, Nussberger J, et al: Hyperreninemia and secondary hyperaldosteronism in a patient with pheochromocytoma and von Hippel Lindau disease. Nephron 1992;62:345–350.
1998;11:1028 –1031
Exhaustive Exercise-induced Tissue Hypoxia Does Not Change Endothelin and Big Endothelin Plasma Levels in Normal Volunteers Tomas Lenz, Markus Nadansky, Jan Gossmann, Gerhard Oremek, and Helmut Geiger
Chronic hypoxia has been shown to increase plasma endothelin levels. The current study was undertaken to examine the effect of exerciseinduced tissue hypoxia on plasma levels of endothelin-1 (ET-1) and its precursor big endothelin-1 (Big-ET-1). After approval by the local ethical committee an incremental dynamic exercise test was performed in 12 physically trained volunteers (aged 20 to 40 years), using an electrically braked bicycle ergometer. The protocol included a step-wise increase of the workload until a heart rate of 130/min was reached, followed by a maintenance period of 25 min, and a further stepwise increase until exhaustion. Blood was drawn before, at several time points during, and 5 min after termination of the study for determination of ET-1, Big-ET-1, plasma renin activity (PRA), angiotensin converting enzyme (ACE), norepinephrine, epinephrine, and lactate. Lactate levels at baseline were 14.5 6 1.6 mg/dL (mean 6
SEM), which increased to 76.5 6 4.8 mg/dL at the time of exhaustion (P < .01). Baseline values for ET-1 and Big-ET-1 were 0.264 6 0.061 and 0.637 6 0.130 fmol/ml, respectively, which remained essentially unaltered throughout the exercise test. PRA was 1.46 6 0.45 ng/mL/h before exercise and increased to 3.55 6 0.96 ng/mL/h at exhaustion (P < .001). Norepinephrine and epinephrine were also increased at exhaustion. The study demonstrates that exhaustive physical exercise with acute development of pronounced tissue hypoxia— in contrast to chronic hypoxia— does not influence the release of ET-1 or Big-ET-1 or the conversion of the precursor to the active compound. Unlike endothelin, circulating renin and the catecholamines were markedly stimulated by this maneuver. Am J Hypertens 1998;11:1028 –1031 © 1998 American Journal of Hypertension, Ltd.
ndothelin-1 (ET-1) belongs to a gene familiy of 21-amino-acid peptides. ET-1 has strong vasoconstrictor properties, binds to specific receptors, and is cleaved from the precursor big endothelin-1 (Big-ET-1) by endothelin converting
E
enzyme, which has 1:100 the potency of ET-1.1,2 Various clinical situations, for example, chronic renal failure,3 chronic heart failure,4 and acute myocardial infarction,5 occur coincidently with elevated ET-1 plasma levels.
Received December 17, 1997. Accepted March 9, 1998. From the Division of Nephrology, Medical Clinic IV (TL, MN, JG, HG), and Central Laboratory, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. Parts of this article were presented in abstract form at the 21st Annual Meeting of the German Hypertension League, Lu¨beck, Germany, 1997.
Address correspondence and reprint requests to Tomas Lenz, MD, Division of Nephrology, Medical Clinic IV, Johann Wolfgang Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
© 1998 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
KEY WORDS:
Exercise, hypoxia, endothelin.
0895-7061/98/$19.00 PII S0895-7061(98)00086-7
AJH–AUGUST 1998 –VOL. 11, NO. 8, PART 1
EXHAUSTIVE EXERCISE AND ENDOTHELIN
1029
FIGURE 1. Endothelin and big endothelin plasma levels before and during exercise, at exhaustion, and 5 min after termination in 12 healthy volunteers.
Furthermore, chronic hypoxia is a condition with elevated ET-1 plasma levels6 and in a rat model of chronic hypoxia enhanced ET-1 and endothelin receptor expression was found.7 Conflicting data, however, exist on the effect of acute hypoxia on the release of ET-1. In most studies exercise tests were used to induce tissue hypoxia in humans. Several investigators reported that with prolonged exercise ET-1 levels were markedly increased in healthy volunteers without8 –10 or with dehydration11 as well as in patients with coronary artery disease.12,13 The increase was found to be augmented by alveolar hypoxia in healthy subjects.14 Others, however, reported no change during exercise compared to resting values in normal volunteers under normoxic3,12,13,15 or hypobaric conditions,16 or in patients with coronary heart disease17 or congestive heart failure.4,18 These discrepancies may partly be attributable to different exercise protocols, in particular with regard to the duration and the workload increments (ie, aerobic v anaerobic conditions). No published data exist on the release of Big-ET with exercise, which conceivably could be different from that of ET-1. Therefore, in the current study the effect of acute tissue hypoxia with exhaustive physical exercise on the release of ET-1 and its precursor Big-ET-1 was examined in healthy volunteers. SUBJECTS AND METHODS After approval by the local ethical committee 12 healthy physically well-trained volunteers (3 women, 9 men; aged 20 to 40 years, mean age 28.3 years) were enrolled after informed consent. An electrically braked bicycle ergometry was started with an initial workload of 50 W, which was increased by 10 W every min until the heart rate was 130/min. The workload was kept at this level for another 25 min, followed by
increases of 20 W every 2 min until exhaustion. Blood pressure and heart rate were continously monitored by an automatic device. Blood was drawn before, at the end of the initial and maintenance phase, at exhaustion, and 5 min after termination of the exercise for determination of ET-1/2 (the commercial ELISA has a 100% cross-reactivity for ET-1 and ET-2) and Big-ET-1 (ELISA) (Immundiagnostic, Bensheim, Germany), plasma renin activity (radioimmunoassay) (Isotex, Friendswood, TX), angiotensin converting enzyme (ACE) (sphectrophotometrically), norepinephrine, and epinephrine (radioimmunoassay) (IBL, Hamburg, Germany), and lactate (enzymatically). Wilcoxon tests were used for statistical analysis. RESULTS All 12 volunteers completed the study according to the protocol. Serum lactate increased from a baseline value of 14.5 6 1.6 mg/dL to a maximum of 76.5 6 4.8 mg/dL at the time of exhaustion (P , .01). ET-1 and Big-ET plasma levels during and immediately after exercise were not statistically different from baseline values (Figure 1). PRA at baseline amounted to 1.46 6 0.45 ng/mL/h and increased to 3.55 6 0.96 ng/mL/h at the time of exhaustion (P , .001), whereas at the same time serum ACE decreased from 24.9 6 2.9 to 15.8 6 3.5 U/L (P , .01). Norepinephrine and epinephrine (measured in 5 of the subjects) increased from a baseline value of 153 6 71.2 and 29.1 6 15.9 ng/L to 327 6 169 and 76.7 6 43.0 ng/L at exhaustion. Systolic/diastolic blood pressure changed from a baseline value of 121 6 2.7/79.2 6 3.6 mm Hg to 181 6 5.9 (P 5 .002) /72.7 6 2.6 (P 5 .12) mm Hg at exhaustion, respectively. Heart rate amounted to 78.8 6 4.2 per min at baseline and increased to 167 6 5.0 per min at exhaustion (P 5 .001).
1030
AJH–AUGUST 1998 –VOL. 11, NO. 8, PART 1
LENZ ET AL
DISCUSSION This study demonstrates that under normoxic conditions exhaustive exercise with the development of pronounced tissue hypoxia (demonstrated by markedly increased lactate levels) did not alter the release of ET-1 or its precursor Big-ET-1. Furthermore, the conversion of Big-ET-1 to the biologically active compound was apparently not enhanced under this condition, suggesting that acute strenous exercise had no effect on the activity or expression of endothelin converting enzyme. The activity of the enzyme, however, was not measured in this study. The only other, albeit unlikely, explanation would be that release and uptake/degradation of the endothelins were enhanced to a similar degree, leading to unaltered plasma levels of the peptides during and after exercise. The absence of an effect of exercise on ET-1 release in normal subjects is in agreement with previous studies.3,12,13,15 At variance with our results, however, Rocker et al9 showed that plasma endothelin levels increased by about 50% immediately after short-term exercise at maximal capacity. Maeda et al8 reported that plasma ET-1 levels increased in parallel with exercise intensity with a peak at 30 min after termination of exercise. A similar approach was used by Kullmer et al14 who also found increased plasma levels of ET-1 during exhaustive exercise. This stimulatory effect, however, was only seen when the healthy volunteers were exposed to simulated high altitude conditions with acute alveolar hypoxia. Therefore, it appears that tissue hypoxia alone, as in our study, is not always sufficient to induce endothelin release but that hypoxemia is required. In vitro data suggest that the production of ET-1 is regulated by multiple factors, including endogeneous substances such as catecholamines and arginine vasopressin.19,20 In our study and the ones of many others it was shown that the plasma catecholamine levels markedly increased during exhaustive exercise.21 Because there was no change in the plasma concentration of the endothelins in our and other studies, the physiologic role of catecholamines for the release of these peptides remains unclear. It was previously shown that exercise in combination with inspiring hypoxic gas mixtures induced lactate accumulation. which correlated with the release of catecholamines, suggesting a relationship between glycogen metabolism and sympathoadrenal activity.22 Another interesting hypothesis claims that nonworking muscles produce and release more ET-1 than the working muscles, thereby shifting the blood flow to the working muscles.23 However, the markedly elevated serum lactate levels in our study were not paralleled by changes in endothelin release. There is a possibility that we did not wait long enough after exercise to observe such an
effect, as changes may occur as late as 30 to 60 min after termination of exercise.8 It is very likely that short-term maneuvers may not be suitable to induce ET-1 release, as the peptide does not appear to be stored in vesicles. Thus, ET-1 secretion may largely depend on the levels of transcription and translation, processes that usually require more time.1 The increased sympathoadrenal acitivity may partly explain the stimulated renin release, which depends on b1-receptor activation.24 However, another compound of the renin angiotensin system, the endothelium-derived angiotensin converting enzyme, decreased in plasma during exercise. It appears, therefore, justified to conclude that this vasoregulating system is more variable with exercise than the endothelin system. Whether these changes are physiologically important or are merely reactive remains to be answered. In summary, this study demonstrates that exhaustive physical exercise with acute development of pronounced tissue hypoxia—in contrast to chronic hypoxia—influenced neither the release of ET-1/BigET-1 nor the conversion of the precursor to the active compound. Unlike the endothelins, circulating renin and the catecholamines were markedly stimulated by this maneuver. This study supports the view that storage vesicles for endothelin may not exist in vivo. REFERENCES 1.
Kohan DE: Endothelins in the kidney: physiology and pathophysiology. Am J Kidney Dis 1993;22:493–510.
2.
Levin ER: Endothelins. N Engl J Med 1995;333:356 – 363.
3.
Predel HG, Meyer-Lehnert H, Backer A, et al: Plasma concentrations of endothelin in patients with abnormal vascular reactivity. Effects of ergometric exercise and acute saline loading. Life Sci 1990;47:1837–1843.
4.
McMurray JJ, Ray SG, Abdullah I, et al: Plasma endothelin in chronic heart failure. Circulation 1992;85: 1374 –1379.
5.
Miyauchi T, Yanagisawa M, Tomizawa T, et al: Increased plasma concentrations of endothelin-1 and big endothelin-1 in acute myocardial infarction. Lancet 1989;2:53–54.
6.
Ferri C, Bellini C, De Angelis C, et al: Circulating endothelin concentrations in patients with chronic hypoxia. J Clin Pathol 1995;48:519 –524.
7.
Li H, Chen SJ, Chen YF, et al: Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. J Appl Physiol 1994;77:1451–1459.
8.
Maeda S, Miyauchi T, Goto K, Matsuda M: Alteration of plasma endothelin-1 by exercise at intensities lower and higher than ventilatory threshold. J Appl Physiol 1994;77:1399 –1402.
9.
Rocker L, Mockel M, Westpfahl KP, Gunga HC: Influence of maximal ergometric exercise on endothelin concentrations in relation to molecular markers of the hemostatic system. Throm Haemost 1996;75:612– 616.
AJH–AUGUST 1998 –VOL. 11, NO. 8, PART 1
EXHAUSTIVE EXERCISE AND ENDOTHELIN
1031
10.
Cozenzi A, Sacerdote A, Bocin E, et al: Neither physical exercise nor alpha-1- and b-adrenergic blockade affect plasma endothelin concentrations. Am J Hypertens 1996;9:819 – 822.
17.
Letizia C, Barilla F, Cerci S, et al: Plasma endothelin-1 concentrations in patients with coronary artery disease during stress test before and after nisoldipine administration. Acta Cardiol 1996;51:165–172.
11.
Maeda S, Miyauchi T, Waku T, et al: Plasma endothelin-1 level in athletes after exercise in a hot environment: exercise-induced dehydration contributes to increase in plasma endothelin-1. Life Sci 1996;58:1259 – 1268.
18.
de Groote P, Maillaire A, Racadot A, et al: Plasma levels of endothelin-1 at rest and after exercise in patients with moderate congestive heart failure. Int J Cardiol 1995;51:267–272.
12.
Letizia C, Barilla F, Cerci S, et al: Dynamic exercise induces elevation of plasma levels of endothelin-1 in patients with coronary artery disease. Angiology 1995; 46:819 – 826.
19.
Emori T, Hirata Y, Ohta K, et al: Cellular mechanism of endothelin-1 release by angiotensin and vasopressin. Hypertension 1991;18:165–170.
20.
Yanagisawa M, Kurihara H, Kimura S, et al: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411– 415.
21.
Haller H, Lenz T, Thiede HM, et al: Platelet intracellular free calcium during dynamic exercise. Am J Nephrol 1986;6(suppl 1):57–59.
13.
Predel HG, Knigge H, Prinz U, et al: The exerciseinduced increase in plasma levels of endothelin-1 is enhanced in patients with atherosclerotic coronary artery disease. Modulation by PETN. Agents Actions 1995;45:219 –225.
14.
Kullmer T, Jungmann E, Haak T, Usadel KH: Modification of the response of endothelin-1 to exhaustive physical exercise under simulated high altitude conditions with acute hypoxia. Metabolism 1995;44:8 –9.
22.
Takahashi H, Irizawa M, Komura T, et al: Relationship among blood lactate and plasma catecholamine levels during exercise in acute hypoxia. Appl Human Sci 1995;14:49 –53.
15.
Richter EA, Emmeluth C, Bie P, et al: Biphasic response of plasma endothelin-1 concentration to exhaustive submaximal exercise in man. Clin Physiol 1994;14:379 – 384.
23.
Maeda S, Miyauchi T, Sakane M, et al: Does endothelin-1 participate in the exercise-induced changes of blood flow distribution of muscles in humans? J Appl Physiol 1997;82:1107–1111.
16.
Vuolteenaho O, Koistinen P, Martikkala V, et al: Effect of physical exercise in hypobaric conditions on atrial natriuretic peptide secretion. Am J Physiol 1992;263: R647–R652.
24.
Lenz T, Thiede HM, Nussberger J, et al: Hyperreninemia and secondary hyperaldosteronism in a patient with pheochromocytoma and von Hippel Lindau disease. Nephron 1992;62:345–350.