Published online before print July 1, 2002, doi: 10.1161/01.HYP.0000024218.04872.F3
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2002;40:202.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Endogenous Endothelin-1 Limits Exercise-Induced Vasodilation in Hypertensive Humans
From the Clinical Pharmacology Unit and Research Centre, University of Endinburgh, Western General Hospital (C.M.M., I.B.W., D.J.W.), United Kingdom; and School of Human Movement Studies (D.G.J.), The University of Queensland, Queensland, Australia. The present address for Drs McEniery and Wilkinson is Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom.
Correspondence to Dr CM McEniery, Clinical Pharmacology Unit, Addenbrooke’s Hospital, Box 110, Cambridge CB2 2QQ, United Kingdom. E-mail cmm41{at}cam.ac.uk
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Essential hypertension is a common disorder, associated with increased endothelin-1–mediated vasoconstrictor tone at rest. We hypothesized that increased vasoconstrictor activity of endothelin-1 might explain why the normal decrease in peripheral vascular resistance in response to exercise is attenuated in hypertensive patients. Therefore, we investigated the effect of endothelin A (ETA) receptor blockade on the vasodilator response to handgrip exercise. Forearm blood flow responses to handgrip exercise (15%, 30%, and 45% of maximum voluntary contraction) were assessed in hypertensive patients and matched normotensive subjects, before and after intra-arterial infusions of the ETA receptor antagonist BQ-123; a control dilator, hydralazine; and placebo (saline). Preinfusion (baseline) vasodilation in response to exercise was significantly attenuated at each workload in hypertensive patients compared with normotensive subjects. Intra-arterial infusions of hydralazine and saline did not increase the vasodilator response to exercise in either hypertensives or normotensives at any workload. The vasodilator response to exercise was markedly enhanced after BQ-123 at the 2 higher workloads in hypertensives (157±48%, P<0.01; 203±58%, P<0.01) but not in normotensives. This suggests that the impaired vasodilator response to exercise in hypertensive patients is, at least in part, a functional limitation caused by endogenous ETA receptor–mediated vasoconstriction. Treatment with endothelin receptor antagonists may, therefore, increase exercise capacity in essential hypertension.
Key Words: endothelin • exercise • vasodilation • hypertension, essential • blood flow
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Essential hypertension, in its established form, is characterized by increased peripheral vascular resistance. Moreover, the ‘normal‘ decrease in peripheral vascular resistance during physical exercise is markedly impaired in hypertensive patients1 and may, in part, contribute to the reduced exercise capacity that is evident in these patients compared with age-matched normotensive subjects.2–5
Endothelin-1 (ET-1) is an endothelium-derived 21-amino-acid peptide that exerts its actions on vascular smooth muscle through binding to at least 2 specific subtypes of receptors.6,7 The endothelin A (ETA) receptor is highly expressed on vascular smooth muscle cells and appears to be the major receptor subtype that causes vasoconstriction in human arteries.8 In contrast, the endothelin B (ETB) receptor is expressed on vascular smooth muscle cells, mediating vasoconstriction, and on endothelial cells, producing vasodilation through the production and release of NO and prostacyclin.9 Recent data demonstrate that infusion of ET-1 reduces vasodilation during handgrip exercise in normotensive subjects,10 suggesting that endogenous ET-1 may limit exercise-induced vasodilation in conditions in which the vasoconstrictor activity of this mediator is increased, such as essential hypertension.11,12
We hypothesized that endogenously produced ET-1, acting via the ETA receptor, limits peripheral vasodilation in response to exercise in patients with essential hypertension compared with normotensive subjects. The aim of this study was to test this hypothesis in vivo, by assessing the effect of the ETA receptor antagonist BQ-123 on forearm blood flow (FBF) during a previously validated handgrip exercise task.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
Eight male hypertensive patients, defined by a sustained systolic blood pressure >160 mm Hg and/or diastolic blood pressure >100 mm Hg and aged between 18 and 65 years, were recruited from the Cardiovascular Risk Clinic, Western General Hospital, Edinburgh, United Kingdom. Patients were newly diagnosed with essential hypertension, having never received antihypertensive medication. Those with evidence of a secondary form of hypertension were excluded. At the same time, 8 normotensive men, systolic blood pressure <135 mm Hg and diastolic blood pressure <85 mm Hg, were recruited from the community and matched to the hypertensive patients for age and total cholesterol. Cigarette smokers and subjects with diabetes mellitus or hypercholesterolemia (total cholesterol >6.0 mmol/L) were excluded. Approval for the study was obtained from the local Research Ethics Committee, and written informed consent was given by each subject. Subjects abstained from alcohol for 24 hours and from caffeine-containing food and beverages for at least 5 hours before each study.
Handgrip Exercise
The handgrip exercise task consisted of subjects squeezing an electronic handgrip dynamometer with the nondominant arm for 5 seconds, followed by a 10-second relaxation period. Exercise was performed for 5 minutes at 15%, 30%, and 45% of maximum voluntary contraction (MVC), which was determined in each subject at the start of the study.
Drugs
The brachial artery of the nondominant arm was cannulated with a 27-SWG cannula under local anesthesia (0.1% lignocaine; Antigen Pharmaceuticals) for drug infusions. The ETA receptor antagonist BQ-123 (Clinalfa) was infused at 50 nmol/min for 5 minutes. The endothelium-independent arterial vasodilator hydralazine (Alliance Pharmaceuticals) was infused as a control for BQ-123 at 40 µg/min for 5 minutes. Saline was infused for 5 minutes in a third, nonvasodilating control study. The doses of BQ-123 and hydralazine were selected on the basis of published literature,13–15 and were confirmed by pilot studies conducted in 4 healthy volunteers (data not shown), to produce similar increases in FBF.
Measurements
Blood flow was measured simultaneously in both arms by use of a dual-channel strain gauge plethysmograph (Hokanson), as described previously.16 Data were collected using a computer-based, R wave–triggered system for online semicontinuous data processing, as described previously.17 Blood pressure was monitored in the noninfused, nonexercised arm by use of a validated oscillometric sphygmomanometer (HEM-705CP, Omron Corporation).18
General Study Design
A randomized, single-blind, placebo-controlled, crossover study was conducted. The experimental protocol is shown in Figure 1. Subjects were studied on 3 occasions separated by 1 week. Subjects rested quietly for 30 minutes in a temperature-controlled room (22° to 24.5°C), and baseline FBF measurements were made. Handgrip exercise (baseline) was then performed with FBF assessed in the final 3 minutes of each exercise step, during each of the 10-second relaxation periods between contractions. The brachial artery of the exercised arm was then cannulated, and subjects received a 5-minute intra-arterial infusion of BQ-123, hydralazine, or placebo (saline). After the infusion, the cannula was removed and FBF assessed at 6-minute intervals over the next 30 minutes. Handgrip exercise and FBF recordings were then repeated.
|
Statistical Analyses
Results are expressed as mean±SEM. FBF data are presented as the percent change in the ratio of blood flow between the infused and noninfused arms (or exercised and nonexercised arms). To determine the effect of the intra-arterial infusions on exercise-induced vasodilation, the percent change from preinfusion (baseline) exercise blood flow was calculated and compared between the 3 infusion conditions.16 Data were analyzed using paired 2-tailed Student t tests and repeated measures ANOVA, with a priori comparisons when appropriate. A value of P<0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The clinical characteristics of the 2 groups are shown in Table 1.
|
Resting (preinfusion) FBF was similar in hypertensives and normotensives on each study day (Table 2). The effect of exercise on FBF before each drug infusion is shown in Figure 2. In both groups, FBF progressively increased with each exercise workload. However, responses in hypertensive patients were significantly lower at each workload (15% MVC, P<0.05; 30% MVC, P<0.01; 45% MVC, P<0.001).
|
|
), and BQ-123 (
). Open symbols indicate normotensives; closed symbols, hypertensives. Data are mean±SEM. *P<0.05, **P<0.01, ***P<0.001 vs hypertensives.The effects of the 3 intra-arterial infusions on resting FBF are shown in Figure 3. There was no significant change in the FBF ratio in either group after infusion of saline. However, in both groups, hydralazine and BQ-123 caused progressive significant vasodilation in the infused arm by 30 minutes (P<0.05). In the normotensive subjects (Figure 3A), hydralazine caused significantly more vasodilation at 30 minutes than did BQ-123 (P<0.05). In hypertensive patients (Figure 3B), the extent of vasodilation was similar between the 2 treatments. Blood pressure did not change after any infusion.
|
, and BQ-123 (50 nmol/min; 
P<0.05 vs hydralazine.In normotensive subjects, vasodilator responses to exercise after the 3 infusions did not differ significantly from those at baseline (Figure 4A). Similarly, the vasodilator response to exercise was not significantly different after hydralazine or saline in the hypertensive patients (Figure 4B). However, after BQ-123, there was a markedly greater exercise-induced vasodilation at 30% and 45% MVC compared with baseline (P<0.01 for both) and also compared with the responses to both saline and hydralazine (P<0.01 for both). Furthermore, absolute FBF responses in the exercised arm of hypertensive patients were similar after BQ-123 to baseline exercise FBF in normotensive subjects at the 2 higher exercise workloads (Figure 5).
|
|
) and hypertensive patients ( |
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We have demonstrated, for the first time, that hypertensive patients exhibit a reduced vasodilator response to handgrip exercise. Moreover, blockade of endogenous, ET-1–mediated vasoconstriction via the ETA receptor with BQ-123 resulted in a markedly enhanced vasodilator response to moderate intensity handgrip exercise in hypertensive patients. Furthermore, the response to exercise in hypertensive patients during ETA receptor antagonism was comparable to that in matched normotensive subjects at baseline. These data suggest that the impaired exercise-induced vasodilation observed in patients with essential hypertension is, at least in part, a functional limitation, caused by endogenous ETA receptor–mediated vasoconstriction.
Vascular Responses to Intra-Arterial Infusions
The increase in resting FBF after BQ-123 in normotensive subjects is consistent with previous data from our own and other groups, demonstrating both local13,19,20 and systemic21 vasodilation in response to BQ-123 in healthy normotensive subjects. Hydralazine was infused as a control vasodilator because of its similar pharmacodynamic action in the forearm vascular bed.14,15 In the normotensive subjects, hydralazine increased FBF more than did BQ-123. In contrast, although resting FBF at baseline was similar between the 2 subject groups, in the hypertensive patients, hydralazine and BQ-123 produced a similar increase in FBF. These data indicate that vasodilation in response to BQ-123, relative to hydralazine, was greater in hypertensive subjects. Although this is consistent with previous findings of increased vasoconstrictor activity of ET-1 in essential hypertension,11,12 recent data are conflicting.22,23 Therefore, evidence of an enhanced contribution of ET-1 to basal vascular tone in essential hypertension is not conclusive.
Vasodilator Responses to Exercise
On each study day, vasodilator responses to the baseline handgrip exercise were significantly reduced at each workload in hypertensive patients compared with normotensive subjects (Figure 2), demonstrating that exercise-induced vasodilation is impaired in the forearm in patients with essential hypertension. After saline and hydralazine, exercise-induced vasodilation did not differ significantly from the baseline response in either group (Figure 4), despite resting FBF increasing after hydralazine. This demonstrates that a modest increase in FBF per se does not influence the subsequent vasodilator response to exercise in normotensive or hypertensive subjects.
After BQ-123, the extent of vasodilation during exercise was markedly increased from baseline at the 2 higher workloads in hypertensive patients but not in normotensive subjects. Importantly, the effect of BQ-123 on exercise-induced vasodilation was significantly greater than that observed after saline or hydralazine. Moreover, after BQ-123, the vasodilator responses to exercise at the 2 higher workloads in hypertensive patients were similar to the baseline exercise responses in normotensive subjects. This suggests a functional impairment in the vasodilator response to moderate-intensity handgrip exercise in hypertensive patients, which is caused by ETA receptor–mediated vasoconstriction. Indeed, exercise-induced vasodilation can be normalized by ETA receptor antagonism in these patients, suggesting that treatment with endothelin receptor antagonists may increase exercise capacity in essential hypertension.
Several potential mechanisms may help explain these observations. The enhanced vasoconstrictor response to ET-1 during exercise may be the result of an attenuated release of NO, a potent inhibitor of vascular contractions evoked by ET-1.24 Indeed, endothelial ETB receptor–mediated release of NO is reduced at rest in patients with essential hypertension.12 However, there are no data concerning the role of these receptors during exercise. Alternatively, augmented production of ET-1 in response to exercise may also explain the enhanced vasoconstrictor response in hypertensive patients. Increased expression of the ET-1 gene has been shown by Schiffrin et al in resistance arteries of hypertensive patients at rest,25 and plasma ET-1 increases after handgrip exercise in hypertensive patients26 and in normotensive offspring of hypertensive patients.27 However, ET-1 is released abluminally, where it acts on endothelial and smooth muscle cells, predominantly as an autocrine and paracrine mediator.28 Furthermore, plasma concentrations are likely to reflect a balance between ET-1 production and its clearance. Therefore, it may not be valid to draw conclusions about ET-1 production from plasma concentrations.29 An additional explanation for the enhanced vasoconstrictor response to ET-1 may involve an abnormality in an ET receptor– or postreceptor-mediated mechanism. Although in vitro data demonstrate reduced sensitivity to ET-1 in resistance arteries taken from patients with essential hypertension,30 sensitivity to exogenous ET-1 is increased both in resistance vessels11 and capacitance vessels31 of hypertensive patients in vivo. These latter vessels do not hypertrophy, and therefore, it is possible that the increased vasoconstrictor effect of ET-1 in hypertensive patients may be related to enhanced sensitivity of vascular smooth muscle to the peptide. Finally, it is possible that the different responses between hypertensive and normotensive subjects may be related to underlying factors, such as salt intake or genetic profile, rather than mean pressure differences per se.
There was greater vasodilation after hydralazine than after BQ-123 in normotensive subjects, resulting in different resting FBF before the second bout of exercise. However, changes in resting FBF per se did not appear to influence the subsequent vasodilator response to exercise in either normotensive or hypertensive subjects, and importantly, the responses to BQ-123 and hydralazine were well matched in hypertensive patients.
Perspectives
The current data show, for the first time, decreased vasodilatation in response to exercise in peripheral vessels of patients with essential hypertension. Importantly, reversal of endogenous ETA receptor–mediated vasoconstriction markedly enhanced vasodilation during exercise in hypertensive patients, to the extent that these responses appeared to be ‘normalized’ compared with responses in normotensive subjects. We believe that these data support the hypothesis that increased vascular activity of ET-1 limits the vasodilatory response to exercise in hypertensive patients and may, therefore, contribute to the reduced exercise tolerance that exists in this condition. On the basis of these findings, endothelin receptor antagonists may improve exercise capacity in essential hypertension, and, perhaps, other cardiovascular conditions associated with an activated endothelin system, such as chronic heart failure. Further studies (with ETB and ETA/ETB receptor antagonists) are now needed to more fully characterize the effects of endogenous ET-1 on exercise-induced vasodilation.
|
Acknowledgments |
|---|
Dr McEniery was supported by a Society of St Andrew of Scotland (Queensland) Scholarship. Prof Webb was in receipt of a Research Leave Fellowship from the Wellcome Trust (052633) at the time of this work. We would like to thank Rob Bryant for the design and construction of the electronic handgrip dynamometer and Dr Fiona Strachan and Helen MacCallum for assistance with the studies.
Received March 19, 2002; first decision April 10, 2002; accepted May 20, 2002.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Lund-Johansen P. Haemodynamics in essential hypertension. Clin Sci. 1980; 59: 343S–354S.[Medline] [Order article via Infotrieve]
2. Palatini P. Exercise haemodynamics in the normotensive and the hypertensive subject. Clin Sci. 1994; 87: 275–287.[Medline] [Order article via Infotrieve]
3. Goodman JM, McLaughlin PR, Plyley MJ, Holloway RM, Fell D, Logan AG, Liu PP. Impaired cardiopulmonary response to exercise in moderate hypertension. Can J Cardiol. 1992; 8: 363–371.[Medline] [Order article via Infotrieve]
4. Agostoni P, Doria E, Berti M, Alimento M, Tamborini G, Fiorentini C. Exercise performance in patients with uncomplicated essential hypertension: effects of nifedipine-induced acute blood pressure reduction. Chest. 1992; 101: 1591–1596.[Medline] [Order article via Infotrieve]
5. Montain SJ, Jilka SM, Ehsani AA, Hagberg JM. Altered hemodynamics during exercise in older essential hypertensive subjects. Hypertension. 1988; 12: 479–484.
6. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990; 348: 730–732.[CrossRef][Medline] [Order article via Infotrieve]
7. Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, Masaki T. Cloning of a cDNA encoding a non-isopeptide–selective subtype of the endothelin receptor. Nature. 1990; 348: 732–735.[CrossRef][Medline] [Order article via Infotrieve]
8. Davenport AP, Maguire JJ. Is endothelin-induced vasoconstriction mediated only by ETA receptors in humans? Trends Pharmacol Sci. 1994; 15: 9–11.[CrossRef][Medline] [Order article via Infotrieve]
9. de Nucci G, Thomas R, D’Orleans-Juste P, Antunes E, Walder C, Warner TD, Vane JR. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci U S A. 1988; 85: 9797–9800.
10. Krum H, Katz SD. Effect of endothelin-1 on exercise-induced vasodilation in normal subjects and in patients with heart failure. Am J Cardiol. 1998; 81: 355–358.[CrossRef][Medline] [Order article via Infotrieve]
11. Cardillo C, Kilcoyne CM, Waclawiw M, Cannon RO3rd, Panza JA. Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension. 1999; 33: 753–758.
12. Taddei S, Virdis A, Ghiadoni L, Sudano I, Notari M, Salvetti A. Vasoconstriction to endogenous endothelin-1 is increased in the peripheral circulation of patients with essential hypertension. Circulation. 1999; 100: 1680–1683.
13. Berrazueta JR, Bhagat K, Vallance P, MacAllister RJ. Dose-, and time-dependency of the dilator effects of the endothelin antagonist, BQ-123, in the human forearm. Br J Clin Pharmacol. 1997; 44: 569–571.[CrossRef][Medline] [Order article via Infotrieve]
14. Collier JG, Lorge RE, Robinson BF. Comparison of effects of tolmesoxide (RX71107), diazoxide, hydralazine, prazosin, glyceryl trinitrate and sodium nitroprusside on forearm arteries and dorsal hand veins of man. Br J Clin Pharmacol. 1978; 5: 35–44.[Medline] [Order article via Infotrieve]
15. Davidson NC, Barr CS, Struthers AD. C-type natriuretic peptide: an endogenous inhibitor of vascular angiotensin-converting enzyme activity. Circulation. 1996; 93: 1155–1159.
16. Wilkinson IB, Webb DJ. Venous occlusion plethysmography in cardiovascular research: methodology and clinical applications. Br J Clin Pharmacol. 2001; 52: 631–646.[CrossRef][Medline] [Order article via Infotrieve]
17. Chang PC, Verlinde R, Bruning T, van Brummelen P. A microcomputer-based, R-wave triggered system for hemodynamic measurements in the forearm. Comput Biol Med. 1988; 18: 157–163.[CrossRef][Medline] [Order article via Infotrieve]
18. O’Brien E, Mee F, Atkins N, Thomas M. Evaluation of three devices for self-measurement of blood pressure according to the revised British Hypertension Society Protocol: the Omron HEM-705CP, Philips HP5332, and Nissei DS-175. Blood Press Monit. 1996; 1: 55–61.[Medline] [Order article via Infotrieve]
19. Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet. 1994; 344: 852–854.[CrossRef][Medline] [Order article via Infotrieve]
20. Verhaar MC, Strachan FE, Newby DE, Cruden NL, Koomans HA, Rabelink TJ, Webb DJ. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation. 1998; 97: 752–756.
21. Spratt JC, Goddard J, Patel N, Strachan FE, Rankin AJ, Webb DJ. Systemic ETA receptor antagonism with BQ-123 blocks ET-1–induced forearm vasoconstriction and decreases peripheral vascular resistance in healthy men. Br J Pharmacol. 2001; 134: 648–654.[CrossRef][Medline] [Order article via Infotrieve]
22. Martin P, Ninio D, Krum H. Effect of endothelin blockade on basal and stimulated forearm blood flow in patients with essential hypertension. Hypertension. 2002; 39: 821–824.
23. Ferro CE, Haynes WG, Hand MF, Webb DJ. Forearm vasoconstriction to endothelin-1 is impaired, but constriction to sarafotoxin 6c and vasodilatation to BQ-123 unaltered, in patients with essential hypertension. Clin Sci. In press.
24. Saijonmaa O, Ristimaki A, Fyhrquist F. Atrial natriuretic peptide, nitroglycerine, and nitroprusside reduce basal and stimulated endothelin production from cultured endothelial cells. Biochem Biophys Res Commun. 1990; 173: 514–520.[CrossRef][Medline] [Order article via Infotrieve]
25. Schiffrin EL, Deng LY, Sventek P, Day R. Enhanced expression of endothelin-1 gene in resistance arteries in severe human essential hypertension. J Hypertens. 1997; 15: 57–63.[CrossRef][Medline] [Order article via Infotrieve]
26. Cottone S, Vella MC, Vadala A, Neri AL, Riccobene R, Cerasola G. Influence of vascular load on plasma endothelin-1, cytokines and catecholamine levels in essential hypertensives. Blood Press. 1998; 7: 144–148.[CrossRef][Medline] [Order article via Infotrieve]
27. Mangieri E, Tanzilli G, Barilla F, Ciavolella M, Puddu PE, De Angelis C, Dell’Italia LJ, Campa PP. Handgrip increases endothelin-1 secretion in normotensive young male offspring of hypertensive parents. J Am Coll Cardiol. 1998; 31: 1362–1366.
28. Wagner OF, Christ G, Wojta J, Vierhapper H, Parzer S, Nowotny PJ, Schneider B, Waldhausl W, Binder BR. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem. 1992; 267: 16066–16068.
29. Goddard J, Webb DJ. Plasma endothelin concentrations in hypertension. J Cardiovasc Pharmacol. 2000; 35 (suppl 2): S25–S31.[Medline] [Order article via Infotrieve]
30. Schiffrin EL, Deng LY, Larochelle P. Morphology of resistance arteries and comparison of effects of vasoconstrictors in mild essential hypertensive patients. Clin Invest Med. 1993; 16: 177–186.[Medline] [Order article via Infotrieve]
31. Haynes WG, Hand MF, Johnstone HA, Padfield PL, Webb DJ. Direct and sympathetically mediated venoconstriction in essential hypertension: enhanced responses to endothelin-1. J Clin Invest. 1994; 94: 1359–1364.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  S. Munir, B. Jiang, A. Guilcher, S. Brett, S. Redwood, M. Marber, and P. Chowienczyk Exercise reduces arterial pressure augmentation through vasodilation of muscular arteries in humans Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1645 - H1650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 R. M. Brothers, M. L. Haslund, D. W. Wray, P. B. Raven, and M. Sander Exercise-induced inhibition of angiotensin II vasoconstriction in human thigh muscle J. Physiol., December 1, 2006; 577(2): 727 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Merkus, O. Sorop, B. Houweling, F. Boomsma, A. H. van den Meiracker, and D. J. Duncker NO and prostanoids blunt endothelin-mediated coronary vasoconstrictor influence in exercising swine Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2075 - H2081. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Boak, A. M. Dart, S. J. Duffy, and J. P. F. Chin-Dusting Responses to neither exogenous nor endogenous endothelin-1 are altered in patients with hypercholesterolemia J. Lipid Res., December 1, 2005; 46(12): 2667 - 2672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Donato, L. A. Lesniewski, and M. D. Delp The effects of aging and exercise training on endothelin-1 vasoconstrictor responses in rat skeletal muscle arterioles Cardiovasc Res, May 1, 2005; 66(2): 393 - 401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Merkus, B. Houweling, A. Mirza, F. Boomsma, A. H van den Meiracker, and D. J Duncker Contribution of endothelin and its receptors to the regulation of vascular tone during exercise is different in the systemic, coronary and pulmonary circulation Cardiovasc Res, September 1, 2003; 59(3): 745 - 754. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||