Journal of Applied Physiology Ad Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 95: 336-341, 2003. First published February 28, 2003; doi:10.1152/japplphysiol.01016.2002
8750-7587/03 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
95/1/336    most recent
01016.2002v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (38)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Maeda, S.
Right arrow Articles by Matsuda, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Maeda, S.
Right arrow Articles by Matsuda, M.

Aerobic exercise training reduces plasma endothelin-1 concentration in older women

Seiji Maeda ,1,2 Takumi Tanabe,2 Takashi Miyauchi,1,3 Takeshi Otsuki,2 Jun Sugawara,1 Motoyuki Iemitsu,3 Shinya Kuno,2 Ryuichi Ajisaka,2 Iwao Yamaguchi,3 and Mitsuo Matsuda2

1Center for Tsukuba Advanced Research Alliance, 2Institute of Health and Sport Sciences, and 3Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-0006, Japan

Submitted 5 November 2002 ; accepted in final form 24 February 2003


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Endothelial function deteriorates with aging. On the other hand, exercise training improves the function of vascular endothelial cells. Endothelin-1 (ET-1), which is produced by vascular endothelial cells, has potent constrictor and proliferative activity in vascular smooth muscle cells and, therefore, has been implicated in regulation of vascular tonus and progression of atherosclerosis. We previously reported significantly higher plasma ET-1 concentration in middle-aged than in young humans, and recently we showed that plasma ET-1 concentration was significantly decreased by aerobic exercise training in healthy young humans. We hypothesized that plasma ET-1 concentration increases with age, even in healthy adults, and that lifestyle modification (i.e., exercise) can reduce plasma ET-1 concentration in previously sedentary older adults. We measured plasma ET-1 concentration in healthy young women (21–28 yr old), healthy middle-aged women (31–47 yr old), and healthy older women (61–69 yr old). The plasma level of ET-1 significantly increased with aging (1.02 ± 0.08, 1.33 ± 0.11, and 2.90 ± 0.20 pg/ml in young, middle-aged, and older women, respectively). Thus plasma ET-1 concentration was markedly higher in healthy older women than in healthy young or middle-aged women (by ~3- and 2-fold, respectively). In healthy older women, we also measured plasma ET-1 concentration after 3 mo of aerobic exercise (cycling on a leg ergometer at 80% of ventilatory threshold for 30 min, 5 days/wk). Regular exercise significantly decreased plasma ET-1 concentration in the healthy older women (2.22 ± 0.16 pg/ml, P < 0.01) and also significantly reduced their blood pressure. The present study suggests that regular aerobic-endurance exercise reduces plasma ET-1 concentration in older humans, and this reduction in plasma ET-1 concentration may have beneficial effects on the cardiovascular system (i.e., prevention of progression of hypertension and/or atherosclerosis by endogenous ET-1).

regular exercise; vascular endothelium; endothelial function

IT IS GENERALLY ACCEPTED that loss of endothelial function not only is characteristic of diseases such as essential or secondary hypertension (35, 43), hypercholesterolemia (6, 54), and atherosclerosis (54) but also has been associated with advancing age (42). It has been reported that, independent of the presence of other pathological states, aging impairs endothelial function in the aorta and small resistance arteries (9, 12, 23, 33, 38). The alteration of endothelial function with aging may have important clinical implications in the pathogenesis of cardiovascular disease.

Vascular endothelial cells play an important role in the regulation of vascular activity by producing vasoactive substances, e.g., endothelin-1 (ET-1) and nitric oxide (27, 32, 50). ET-1 is a potent vasoconstrictor peptide produced by vascular endothelial cells (22, 27, 36, 50); in human vascular endothelial cells, it has a potent vasoconstrictor effect (27, 29). It has also been reported that systemic administration of an endothelin receptor antagonist significantly decreased systemic blood pressure and peripheral vascular resistance in healthy humans, strongly suggesting that endogenously generated ET-1 contributes to basal vascular tonus in humans (10). Furthermore, ET-1 has potent proliferative activity in vascular smooth muscle cells; therefore, ET-1 has been implicated in the progression of atherosclerosis (16, 18, 27, 36). Our laboratory previously reported that plasma ET-1 concentration is increased in some human diseases (28, 31), e.g., chronic heart failure (11, 24, 39), acute myocardial infarction (31), and acute renal failure (47). Furthermore, pulmonary hypertension is associated with increased plasma ET-1 levels (5), and plasma ET-1 concentration correlates with disease severity (3, 13, 51). Therefore, the increase in plasma ET-1 level may have important clinical significance in the pathophysiology of some diseases. Furthermore, our laboratory also reported that plasma ET-1 concentration was significantly higher in middle-aged than in young humans (30), although plasma ET-1 concentration in older humans remains to be investigated. On the other hand, exercise training improves the function of vascular endothelial cells (8). Our laboratory recently showed that plasma ET-1 concentration was significantly decreased by aerobic exercise training in healthy young humans (21). It is of great interest and importance to study whether exercise training causes a decrease in plasma ET-1 concentration in older humans.

The purpose of the present study was to examine whether plasma ET-1 concentration increases with aging, especially in older humans, and is decreased by exercise training, even in older humans. We hypothesized that plasma ET-1 concentration increases with age, even in healthy adults, and that lifestyle modification (i.e., exercise) can reduce plasma ET-1 concentration in previously sedentary older adults. First, we measured plasma ET-1 concentration in healthy young women, healthy middle-aged women, and healthy older women. Second, in the healthy older women, we also measured plasma ET-1 concentration after 3 mo of aerobic exercise [cycling on a leg ergometer at 80% of ventilatory threshold (VT) for 30 min, 5 days/wk].


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects. For experiment I, 39 healthy and untrained women (21–69 yr old) participated in a cross-sectional study. They were grouped into young (21–28 yr old, n = 16), middle-aged (31–47 yr old, n = 16), and older (61–69 yr old, n = 7) subjects. All subjects were normotensive (<140/90 mmHg). None of the women was taking medication on a regular basis at the time of the study. For experiment II, the older subjects performed an exercise intervention study. All seven older women were studied before and after 3 mo of aerobic exercise training.

The study was approved by the Ethical Committees of the Institute of Health and Sport Sciences and the Institute of Clinical Medicine of the University of Tsukuba. The study conformed with the principles outlined in the Helsinki Declaration, and all subjects gave their written informed consent before inclusion in the study.

Experimental design. In experiment I, systolic blood pressure, diastolic blood pressure, and venous plasma ET-1 concentration at rest were measured in the young, middle-aged, and older groups. All participants were instructed to stop oral intake, including water, overnight 12 h before blood pressure measurement and ET-1 sampling in plasma. Blood pressure at rest was measured in duplicate, with subjects in the upright sitting position. All measurements were performed at a constant room temperature (25°C).

In experiment II, the older women completed an exercise intervention study. VT, resting systolic blood pressure, resting diastolic blood pressure, resting heart rate, and resting venous plasma ET-1 concentration were measured before and after 3 mo of aerobic exercise training in the older women. Before they were tested, subjects fasted for 12 h. Resting blood pressure and resting heart rate were measured in duplicate, with subjects in the upright sitting position. The measurements after the exercise training program were performed after ≥1 day of rest to rule out an acute effect from the most recent bout of exercise. All measurements were performed at a constant room temperature (25°C). Thus we controlled conditions preceding the measurements.

Exercise test and exercise training in older subjects. In experiment II, the older subjects performed symptom-limited ramp-fashion cycling exercise (after 2 min at 20 W, with 15-W increases every 1 min) until they felt exhausted or reached 85% of the age-predicted maximal heart rate, before and after the exercise training program. Their individual VT was calculated by using regression analysis of the slopes of CO2 production, O2 uptake, and minute ventilation plot (2, 7, 34). The older subjects submitted to a 3-mo exercise training program on a cycle ergometer for 30 min/day, 5 days/wk, at 80% of their individual VT.

Measurement of plasma ET-1 concentration by sandwich-enzyme immunoassay. Each blood sample was placed in a chilled tube containing aprotinin (300 kallikrein-inactivating units/ml) and EDTA (2 mg/ml) and then centrifuged at 2,000 g for 15 min at 4°C. The plasma was stored at -80°C until use. Plasma (1 ml) was acidified with 3 ml of 4% acetic acid, and immunoreactive ET-1 was extracted with a Sep-Pak C-18 cartridge (Waters, Milford, MA) as previously described (20, 21). The eluates were reconstituted with 0.25 ml of assay buffer and subjected to sandwich-enzyme immunoassay. The sandwich-enzyme immunoassay for ET-1 was carried out as previously described using immobilized mouse monoclonal antibody AwETN40, which recognizes the NH2-terminal portion of ET-1, and peroxidase-labeled rabbit anti-ET-1 COOH-terminal peptide-(15–25) Fab' (20, 21). The Fab' fragment of this rabbit antibody was used as an enzyme-labeled detector antibody after being coupled with horseradish peroxidase. The intra- and interassay coefficients of variation of the ET-1 assay were 11 and 13%, respectively (25). Our laboratory previously reported that the lowest detection limit of this assay was 0.4 pg/ml for ET-1 (28). The plasma ET-1 levels in the present study were far beyond the lowest limit of detection with this assay (0.4 pg/ml) in all subjects.

Statistics. Values are means ± SE. To evaluate differences among young, middle-aged, and older women, statistical analysis was carried out by analysis of variance followed by Fisher's protected least significant difference test for multiple comparisons. To evaluate differences in the levels before and after exercise training in older women, Student's t-test for paired values was used. P < 0.05 was accepted as significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Experiment I. Table 1 shows the age and resting blood pressure of healthy young, middle-aged, and older women for the cross-sectional study. Systolic and diastolic blood pressures generally increased with aging (Table 1). Plasma ET-1 concentration significantly increased with aging (1.02 ± 0.08, 1.33 ± 0.11, and 2.90 ± 0.20 pg/ml in young, middle-aged, and older women, respectively; Fig. 1). Plasma ET-1 concentration was markedly higher in healthy older women than in healthy young or middle-aged women (Fig. 1). Plasma ET-1 concentration was significantly higher in middle-aged than in young women (Fig. 1). Indeed, plasma ET-1 concentration in older women was about threefold higher than in young women and about twofold higher than in middle-aged women. There was a significant positive correlation between systolic or diastolic blood pressure and plasma ET-1 concentration in the cross-sectional groups (systolic blood pressure vs. ET-1: r = 0.490, P < 0.05; diastolic blood pressure vs. ET-1: r = 0.488, P < 0.05).


View this table:
[in this window]
[in a new window]
  		Table 1. Age and blood pressure in healthy young, middle-aged, and older women

 


View larger version (22K):
[in this window]
[in a new window]
  		Fig. 1. Plasma concentration of endothelin-1 in healthy young (Young, n = 16), middle-aged (Middle, n = 16), and older (Older, n = 7) women. Values are means ± SE. Significantly different from Young: *P < 0.05 and **P < 0.01. Significantly different from Middle: {dagger}{dagger}P < 0.01.

 

Experiment II. All seven older women completed the exercise intervention study. Table 2 shows the physiological parameters in the older women before and after 3 mo of aerobic exercise training. There were no significant differences in body weight and body mass index before and after exercise training (Table 2). Systolic and diastolic blood pressures at rest significantly decreased after exercise training, whereas heart rate at rest was not different (Table 2). After exercise training, individual VT during the exercise test significantly increased (Fig. 2). These results suggest that 3 mo of exercise training in the older women caused physiological effects, i.e., effects of exercise training, as evidenced by the decrease in blood pressure at rest and the increase in individual VT during the cycle exercise test. Figure 3 shows the resting plasma ET-1 concentration in the older women before and after exercise training. The plasma concentration of ET-1 significantly decreased after exercise training (2.90 ± 0.20 vs. 2.22 ± 0.16 pg/ml, P < 0.01; Fig. 3). There was a tendency for a positive correlation between the changes in systolic or diastolic blood pressure and the changes in ET-1 after exercise training (systolic blood pressure vs. ET-1: r = 0.479; diastolic blood pressure vs. ET-1: r = 0.590), but the correlation was not statistically significant.


View this table:
[in this window]
[in a new window]
  		Table 2. Effects of exercise training in older women

 


View larger version (16K):
[in this window]
[in a new window]
  		Fig. 2. Individual ventilatory threshold during cycle exercise test before and after 3 mo of exercise training in healthy older women (n = 7). Values are means ± SE.

 


View larger version (17K):
[in this window]
[in a new window]
  		Fig. 3. Venous plasma concentration of endothelin-1 before and after 3 mo of exercise training in healthy older women (n = 7). Values are means ± SE.

 


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
In the present study, we measured plasma ET-1 concentration in healthy young women, healthy middle-aged women, and healthy older women. Furthermore, the older women participated in an exercise intervention study, and we also measured the plasma ET-1 concentration after 3 mo of exercise. The plasma ET-1 concentration significantly increased with aging; i.e., plasma ET-1 concentration was markedly higher in healthy older women than in healthy young or middle-aged women (by ~3- and 2-fold, respectively). We also demonstrated that regular exercise in the older subjects significantly decreased plasma ET-1 concentration. Because it is considered that circulating plasma ET-1 may mainly originate from vascular endothelial cells (27), it is possible that the increased production of ET-1 in vascular endothelial cells of older humans is decreased by regular aerobic exercise; therefore, this phenomenon as a result of regular aerobic exercise may produce beneficial effects on the cardiovascular system (i.e., prevention of progression of hypertension and/or atherosclerosis by endogenous ET-1).

Our laboratory previously reported that plasma ET-1 concentration was significantly higher in middle-aged than in young humans (30). The present study demonstrated that plasma ET-1 concentration was markedly increased in older women; i.e., plasma ET-1 concentration significantly increased with age, even in healthy humans. Endothelial function deteriorates with aging (9, 12, 23, 33, 38, 42). Thus, because ET-1 is produced by vascular endothelial cells (22, 27, 36, 50), it is considered that the increase in ET-1 in older women may be a factor in aging-induced loss of endothelial function.

The conclusions drawn in the present study come from plasma ET-1 levels. It has been demonstrated that a twofold increase in plasma ET-1 concentration by the intravenous infusion of exogenous ET-1 significantly increased renal and systemic vascular resistances, suggesting that circulating plasma ET-1 may have biological actions on the cardiovascular system (19). However, it is generally accepted that ET-1 acts predominantly in an autocrine and paracrine manner, and its secretion by endothelial cells is polarized toward the underlying vascular smooth muscle (27, 48). Consequently, plasma levels are largely the results of spillover from vascular endothelium into the blood-stream. Indeed, only ~20% of generated ET-1 is secreted luminally (52). Therefore, because plasma ET-1 concentration is very low and ET-1 is not a circulating hormone, it is considered that tissue ET-1 is more important than circulating ET-1. Thus the present study has the following limitations: 1) it is unclear whether vascular ET-1 content increases with age in humans, and 2) it is unclear whether exercise training reduces vascular ET-1 content in older humans.

Taddei et al. (41) showed that plasma ET-1 levels do not differ between age-matched normotensive and hypertensive subjects, whereas when the biological action of ET-1 was blocked, Taddei et al. noted a greater influence of ET-1 on vascular tone in hypertensive subjects, suggesting a possible role for ET-1 in the pathogenesis of hypertension and/or its complications. On the other hand, pulmonary hypertension is associated with increased plasma ET-1 concentrations (5), and the plasma level of ET-1 correlates with disease severity (3, 13, 51). More recently, it has also been reported that endothelin receptor blockade causes a decrease in mean pulmonary arterial pressure in patients with pulmonary hypertension (1). Therefore, because it is considered that circulating plasma ET-1 mainly originates from vascular endothelial cells (27) and the magnitude of spillover of ET-1 into the plasma reflects the magnitude of ET-1 production originated from the vascular endothelial cells, it is possible that plasma ET-1 levels reflect the tissue ET-1 levels in some pathophysiological conditions. Therefore, in the present study, it is likely that alteration of the circulating ET-1 by exercise training may reflect alteration of ET-1 production by vascular endothelial cells or tissue ET-1 content in the vessels in the older humans.

It has been reported that patients with essential hypertension have increased vascular ET-1 activity, which may be of pathophysiological relevance to their increased vascular tone (4). An increased vascular response to ET-1 has also been reported in an animal model of hypertension (26, 40). Furthermore, ET-1 has potent proliferative activity in vascular smooth muscle cells and has, therefore, been implicated in the progression of atherosclerosis (16, 18, 27, 36). It has also been reported that ET-1 expression increases in human atherosclerotic lesions (18, 49, 53). On the other hand, it is well known that regular exercise produces beneficial effects on the cardiovascular system. Chronic exercise reduces blood pressure in patients with moderate hypertension (37, 45, 46). The aging-induced reduction of arterial compliance causes an increase in systolic blood pressure, whereas exercise training prevents this reduction in arterial compliance (14, 15, 44). It has also been reported that exercise training has a favorable effect on the development of atherosclerosis (17). However, the precise mechanisms by which exercise training reduces blood pressure and the risk of atherosclerosis have not been fully determined. Our present study demonstrated that the aging-related great elevation in endogenous ET-1 significantly decreased after exercise training in older humans. We also observed a reduction of blood pressure after exercise training in the older women with a reduction of plasma ET-1. ET-1 has not only potent constrictor activity, but also proliferative activity, in vascular smooth muscle cells (16, 18, 22, 27, 36, 50). Therefore, it is considered that the decrease in ET-1 production in endothelial cells by exercise training would be partly involved in the exercise training-induced beneficial effects on the cardiovascular system in older humans.

It is well known that exercise training induces an increase in plasma volume in some conditions. In the present study, there was no significant difference in the hematocrit in the older women before and after exercise training (45.7 ± 0.5 vs. 45.2 ± 0.7%). Therefore, it is considered that the reduction in plasma ET-1 levels with the present exercise intervention simply does not represent a dilution relative to an exercise training-induced increase in plasma volume.

In animal studies, endothelin receptor antagonists improve various cardiovascular diseases, such as chronic heart failure, hypertension, and pulmonary hypertension (27). It is of great interest and importance to study whether exercise training causes a decrease in plasma ET-1 concentration in patients with cardiovascular disease, such as hypertension and atherosclerosis. Such studies will provide important information on whether endogenous ET-1 is involved in the exercise training-induced beneficial effects in patients with these cardiovascular diseases.

In conclusion, we demonstrated that plasma ET-1 concentration significantly increased with aging, being markedly higher in older women than in young or middle-aged women (by ~3- and 2-fold, respectively). The present study also demonstrated that regular aerobic-endurance exercise in older humans significantly decreased plasma ET-1 concentration. Because ET-1 has potent constrictor and proliferative activity in vascular smooth muscle cells and has been implicated in the regulation of vascular tonus and the progression of atherosclerosis, we propose that the decrease in production of ET-1 by exercise training may be partly involved in the beneficial effects of chronic exercise on the cardiovascular system in older humans.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
We thank Dr. Wendy Gray for editing the English language of the manuscript.

This work was supported by Grants-in-Aid for Scientific Research 00006781, 11480003, 11557047, 12470147, and 12670646 and Special Coordination Funds of the Ministry of Education, Culture, Sports, Science, and Technology, the Japanese Government, a grant from University of Tsukuba Research Projects, and a grant from the project of Tsukuba Advanced Research Alliance, the University of Tsukuba.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. Matsuda, Institute of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8574, Japan (E-mail: m-matsuda{at}taiiku.tsukuba.ac.jp).

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.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. Apostolopoulou SC, Kourgiannidis G, Manginas A, Kyriakides ZS, Webb DJ, Rammos S, Kremastinos DT, and Cokkinos DV. Differential vasoactive response to endothelin receptor antagonists and prostacyclin in patients with severe pulmonary hypertension. Clin Sci 103, Suppl 48: 298S-301S, 2002.
  2. Beaver WL, Wasserman K, and Whipp BJ. A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol 60: 2020-2027, 1986.
  3. Cacoub P, Dorent R, Maistre G, Nataf P, Carayon A, Piette C, Godeau P, Cabrol C, and Gandjbakhch I. Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome. Am J Cardiol 71: 448-450, 1993.
  4. Cardillo C, Lilcoyne CM, Waclawiw M, Cannon RO III, and Panza JA. Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension 33: 753-758, 1999.
  5. Cernacek P and Stewart DJ. Immunoreactive endothelin in human plasma: marked elevations in patients in cardiogenic shock. Biochem Biophys Res Commun 161: 562-567, 1989.
  6. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, and Dzau VJ. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 86: 228-234, 1990.
  7. Davis JA, Frank MH, Whipp BJ, and Wasserman K. Anaerobic threshold alterations caused by endurance training in middle-aged men. J Appl Physiol 46: 1039-1046, 1979.
  8. Delp MD, McAllister RM, and Laughlin MH. Exercise training alters endothelium-dependent vasoreactivity of rat abdominal aorta. J Appl Physiol 75: 1354-1363, 1993.
  9. Dohi Y, Thiel MA, Büler FR, and Lücher TF. Activation of endothelial L-arginine pathway in resistance arteries: effects of age and hypertension. Hypertension 15: 170-179, 1990.
  10. Haynes WG, Ferro CJ, O'Kane KPJ, Somerville D, Lomax CC, and Webb DJ. Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans. Circulation 93: 1860-1870, 1996.
  11. Hiroe M, Hirata Y, Fujita N, Umezawa S, Ito H, Tsujino M, Koike A, Nogami A, Takamoto T, and Marumo F. Plasma endothelin-1 levels in idiopathic dilated cardiomyopathy. Am J Cardiol 68: 1114-1115, 1991.
  12. Hongo K, Nakagomi T, Kassell NF, Sasaki T, Lehman M, Vollmer DG, Tsukahara T, Ogawa H, and Torner J. Effects of aging and hypertension on endothelium-dependent vascular relaxation in rat carotid artery. Stroke 19: 892-897, 1988.
  13. Ishikawa S, Miyauchi T, Ueno H, Ushinohama H, Sagawa K, Fusazaki N, Sunagawa H, Honda S, Sakai S, Yamaguchi I, Goto K, and Sugishita Y. Influence of pulmonary blood pressure and flow on endothelin-1 production in humans. J Cardiovasc Pharmacol 26, Suppl 3: S429-S433, 1995.
  14. Kakiyama T, Matsuda M, and Koseki S. Effect of physical activity on the distensibility of the aortic wall in healthy males. Angiology 49: 749-757, 1998.
  15. Kingwell BA, Arnold PL, Jennings G, and Dart AM. Spontaneous running increases aortic compliance in Wistar-Kyoto rats. Cardiovasc Res 35: 132-137, 1997.
  16. Komuro I, Kurihara H, Sugiyama T, Yoshizumi M, Takaku F, and Yazaki Y. Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth muscle cells. FEBS Lett 238: 249-252, 1988.
  17. Kramsch DM, Aspen AJ, Abramowitz BM, Kreimendahl T, and Hood WB. Reduction of coronary atherosclerosis by moderate conditioning exercise in monkeys on an atherogenic diet. N Engl J Med 305: 1483-1489, 1981.
  18. Lerman A, Edwards BS, Hallet JW, Heublein DM, Sandberg SM, and Burnett JC Jr. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 325: 997-1001, 1991.
  19. Lerman A, Hildebrand FL, Aarhus LL, and Burnett JC Jr. Endothelin has biological actions at pathophysiological concentrations. Circulation 83: 1808-1814, 1991.
  20. Maeda S, Miyauchi T, Goto K, and Matsuda M. Alteration of plasma endothelin-1 by exercise at intensities lower and higher than ventilatory threshold. J Appl Physiol 77: 1399-1402, 1994.
  21. Maeda S, Miyauchi T, Kakiyama T, Sugawara J, Iemitsu M, Irukayama-Tomobe Y, Murakami H, Kumagai Y, Kuno S, and Matsuda M. Effects of exercise training of 8 wk and detraining on plasma levels of endothelium-derived factors, endothelin-1 and nitric oxide, in healthy young humans. Life Sci 69: 1005-1016, 2001.
  22. Masaki T, Kimura S, Yanagisawa M, and Goto K. Molecular and cellular mechanism of endothelin regulation. Implications for vascular function. Circulation 84: 1457-1468, 1991.
  23. Mayhan WG, Faraci FM, Baumbach GL, and Heistad DD. Effects of aging on responses of cerebral arterioles. Am J Physiol Heart Circ Physiol 258: H1138-H1143, 1990.
  24. McMurray JJ, Ray SG, Abdullah IA, Dargie HJ, and Morton JJ. Plasma endothelin in chronic heart failure. Circulation 85: 1374-1379, 1992.
  25. Miyauchi T, Doi T, Suzuki N, Kakihana M, Yamaguchi I, Sugishita Y, Mitsui T, Hori M, Masaki T, and Goto K. Plasma endothelin-1 concentrations in the coronary sinus in dogs with artificially induced myocardial infarction. Peptides 13: 1013-1015, 1992.
  26. Miyauchi T, Ishikawa T, Tomobe Y, Yanagisawa M, Kimura S, Sugishita Y, Ito I, Goto K, and Masaki T. Characteristics of pressor response to endothelin in spontaneously hypertensive and Wistar-Kyoto rats. Hypertension 14: 427-434, 1989.
  27. Miyauchi T and Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol 61: 391-415, 1999.
  28. Miyauchi T, Suzuki N, Kurihara T, Yamaguchi I, Sugishita Y, Matsumoto K, Goto K, and Masaki T. Endothelin-1 and endothelin-3 play different roles in acute and chronic alterations of blood pressure in patients with chronic hemodialysis. Biochem Biophys Res Commun 178: 276-281, 1991.
  29. Miyauchi T, Tomobe Y, Shiba R, Ishikawa T, Yanagisawa M, Kimura S, Sugishita Y, Ito I, Goto K, and Masaki T. Involvement of endothelin in the regulation of human vascular tonus. Potent vasoconstrictor effect and existence in endothelial cells. Circulation 81: 1874-1880, 1990.
  30. Miyauchi T, Yanagisawa M, Iida K, Ajisaka R, Suzuki N, Fujino M, Goto K, Masaki T, and Sugishita Y. Age- and sex-related variation of plasma endothelin-1 concentration in normal and hypertensive subjects. Am Heart J 123: 1092-1093, 1992.
  31. Miyauchi T, Yanagisawa M, Tomizawa T, Sugishita Y, Suzuki N, Fujino M, Ajisaka R, Goto K, and Masaki T. Increased plasma concentrations of endothelin-1 and big endothelin-1 in acute myocardial infarction. Lancet 2: 53-54, 1989.
  32. Moncada S, Palmer RM, and Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 102-142, 1991.
  33. Moritoki H, Hosoki E, and Ishida Y. Age-related decrease in endothelium-dependent dilator response to histamine in rat mesenteric artery. Eur J Pharmacol 126: 61-67, 1986.
  34. Orr GW, Green HJ, Hughson RL, and Bennett GW. A computer linear regression model to determine ventilatory anaerobic threshold. J Appl Physiol 52: 1349-1352, 1982.
  35. Panza JA, Quyyumi AA, Brush JE Jr, and Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 323: 22-27, 1990.
  36. Rubanyi GM and Polokoff MA. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 46: 325-415, 1994.
  37. Seals DR and Hagberg JM. The effect of exercise training on human hypertension: a review. Med Sci Sports Exerc 16: 207-215, 1984.
  38. Soltis EE. Effect of age on blood pressure and membrane-dependent vascular responses in the rat. Circ Res 61: 889-897, 1987.
  39. Stewart DJ, Cernacek P, Costello KB, and Rouleau JL. Elevated endothelin-1 in heart failure and loss of normal response to postural change. Circulation 85: 510-517, 1992.
  40. Suzuki N, Miyauchi T, Tomobe Y, Matsumoto H, Goto K, Masaki T, and Fujino M. Plasma concentrations of endothelin-1 in spontaneously hypertensive rats and DOCA-salt hypertensive rats. Biochem Biophys Res Commun 167: 941-947, 1990.
  41. Taddei S, Virdis A, Ghiadoni L, Sudano I, Notari M, and Salvetti A. Vasoconstriction to endogenous endothelin-1 is increased in the peripheral circulation of patients with essential hypertension. Circulation 100: 1680-1683, 1999.
  42. Taddei S, Virdis A, Mattei P, Ghiadoni L, Gennari A, Basile Fasolo C, Sudano I, and Salvetti A. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation 91: 1981-1987, 1995.
  43. Taddei S, Virdis A, Mattei P, and Salvetti A. Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension 21: 929-933, 1983.
  44. Tanaka H, Dinenno FA, Monahan KD, Clevenger CM, DeSouza CA, and Seals DR. Aging, habitual exercise, and dynamic arterial compliance. Circulation 102: 1270-1275, 2000.
  45. Tipton CM. Exercise, training and hypertension: an update. Exerc Sports Sci Rev 19: 447-505, 1991.
  46. Tipton CM. Exercise, training, and hypertension. Exerc Sports Sci Rev 12: 245-306, 1984.
  47. Tomita K, Ujiie K, Nakanishi T, Tomura S, Matsuda K, Ando K, Shichiri M, Hirata Y, and Marumo F. Plasma endothelin levels in patients with acute renal failure. N Engl J Med 321: 1127, 1989.
  48. Wagner OF, Christ G, Wojta J, Vierhapper H, Parzer S, Nowotny PJ, Schneider B, Waldäusl W, and Binder BR. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem 267: 16066-16068, 1992.
  49. Winkles JA, Alberts GF, Brogi E, and Libby P. Endothelin-1 and endothelin receptor mRNA expression in normal and atherosclerotic human arteries. Biochem Biophys Res Commun 191: 1081-1088, 1993.
  50. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, and Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411-415, 1988.
  51. Yoshibayashi M, Nishioka K, Nakao K, Saito Y, Matsumura M, Ueda T, Temma S, Shirakami G, Imura H, and Mikawa H. Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects: evidence for increased production of endothelin in pulmonary circulation. Circulation 84: 2280-2285, 1991.
  52. Yoshimoto S, Ishizaki Y, Sasaki T, and Murota S. Effect of carbon dioxide and oxygen on endothelin production by cultured porcine cerebral endothelial cells. Stroke 22: 378-383, 1991.
  53. Zeiher AM, Boebel H, Schachinger V, and Ihling C. Tissue endothelin-1 immunoreactivity in the active coronary atherosclerotic plaque. Circulation 91: 941-947, 1995.
  54. Zeiher AM, Drexter H, Saurbier B, and Just H. Endothelium-mediated coronary blood flow modulation in humans: effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest 92: 652-662, 1993.



This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
M. Yoshizawa, S. Maeda, A. Miyaki, M. Misono, Y. Choi, N. Shimojo, R. Ajisaka, and H. Tanaka
Additive beneficial effects of lactotripeptides and aerobic exercise on arterial compliance in postmenopausal women
Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1899 - H1903.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Sports. Med.Home page
M Yoshizawa, S Maeda, A Miyaki, M Misono, Y Saito, K Tanabe, S Kuno, and R Ajisaka
Effect of 12 weeks of moderate-intensity resistance training on arterial stiffness: a randomised controlled trial in women aged 32-59 years
Br. J. Sports Med., August 1, 2009; 43(8): 615 - 618.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
A. J. Donato, L. B. Gano, I. Eskurza, A. E. Silver, P. E. Gates, K. Jablonski, and D. R. Seals
Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase
Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H425 - H432.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
R. Coimbra, L. S. Sanchez, J. M. Potenza, L. V. Rossoni, S. L. Amaral, and L. C. Michelini
Is Gender Crucial for Cardiovascular Adjustments Induced by Exercise Training in Female Spontaneously Hypertensive Rats?
Hypertension, September 1, 2008; 52(3): 514 - 521.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
T. Rankinen, T. Church, T. Rice, N. Markward, A. S. Leon, D. C. Rao, J. S. Skinner, S. N. Blair, and C. Bouchard
Effect of Endothelin 1 Genotype on Blood Pressure Is Dependent on Physical Activity or Fitness Levels
Hypertension, December 1, 2007; 50(6): 1120 - 1125.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
D. W. Wray, S. K. Nishiyama, A. J. Donato, M. Sander, P. D. Wagner, and R. S. Richardson
Endothelin-1-mediated vasoconstriction at rest and during dynamic exercise in healthy humans
Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2550 - H2556.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
D. H. J. Thijssen, G. A. Rongen, A. van Dijk, P. Smits, and M. T. E. Hopman
Enhanced endothelin-1-mediated leg vascular tone in healthy older subjects
J Appl Physiol, September 1, 2007; 103(3): 852 - 857.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
G. P. Van Guilder, C. M. Westby, J. J. Greiner, B. L. Stauffer, and C. A. DeSouza
Endothelin-1 Vasoconstrictor Tone Increases With Age in Healthy Men But Can Be Reduced by Regular Aerobic Exercise
Hypertension, August 1, 2007; 50(2): 403 - 409.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
S. Fujita, B. B. Rasmussen, J. G. Cadenas, M. J. Drummond, E. L. Glynn, F. R. Sattler, and E. Volpi
Aerobic Exercise Overcomes the Age-Related Insulin Resistance of Muscle Protein Metabolism by Improving Endothelial Function and Akt/Mammalian Target of Rapamycin Signaling
Diabetes, June 1, 2007; 56(6): 1615 - 1622.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Sports. Med.Home page
S Maeda, T Otsuki, M Iemitsu, M Kamioka, J Sugawara, S Kuno, R Ajisaka, and H Tanaka
Effects of leg resistance training on arterial function in older men
Br. J. Sports Med., October 1, 2006; 40(10): 867 - 869.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
T. Otsuki, S. Maeda, M. Iemitsu, Y. Saito, Y. Tanimura, R. Ajisaka, K. Goto, and T. Miyauchi
Effects of athletic strength and endurance exercise training in young humans on plasma endothelin-1 concentration and arterial distensibility.
Experimental Biology and Medicine, June 1, 2006; 231(6): 789 - 793.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
S. Maeda, S. Jesmin, M. Iemitsu, T. Otsuki, T. Matsuo, K. Ohkawara, Y. Nakata, K. Tanaka, K. Goto, and T. Miyauchi
Weight loss reduces plasma endothelin-1 concentration in obese men.
Experimental Biology and Medicine, June 1, 2006; 231(6): 1044 - 1047.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
M. Iemitsu, S. Maeda, T. Otsuki, J. Sugawara, T. Tanabe, S. Jesmin, S. Kuno, R. Ajisaka, T. Miyauchi, and M. Matsuda
Polymorphism in Endothelin-Related Genes Limits Exercise-Induced Decreases in Arterial Stiffness in Older Subjects
Hypertension, May 1, 2006; 47(5): 928 - 936.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
C. K. Roberts and R. J. Barnard
Effects of exercise and diet on chronic disease
J Appl Physiol, January 1, 2005; 98(1): 3 - 30.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
D. N. Proctor, D. W. Koch, S. C. Newcomer, K. U. Le, and U. A. Leuenberger
Impaired leg vasodilation during dynamic exercise in healthy older women
J Appl Physiol, November 1, 2003; 95(5): 1963 - 1970.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
95/1/336    most recent
01016.2002v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (38)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Maeda, S.
Right arrow Articles by Matsuda, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Maeda, S.
Right arrow Articles by Matsuda, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2003 by the American Physiological Society.