(Circulation. 1996;94:1578-1584.)
© 1996 American Heart Association, Inc.
Articles |
Human Pulmonary Circulation Is an Important Site for Both Clearance and Production of Endothelin-1
the Department of Medicine, Montreal Heart Institute, St. Michael's Hospital, Toronto, and the Royal Victoria Hospital, Montreal, Canada.
Correspondence to Jocelyn Dupuis, MD, Montreal Heart Institute, 5000 Belanger St, Montreal, Quebec H1T 1C8, Canada.
Background Animal studies suggest a major role of the pulmonary circulation in the clearance of circulating endothelin-1 (ET-1). The contribution of the human pulmonary circulation to plasma ET-1 clearance, however, has never been quantified. The absence of an AV gradient in plasma ET-1 has previously been interpreted as evidence that the lungs do not have a role in modulating circulating ET-1 levels. This study was designed to quantify and discern between pulmonary ET-1 clearance and production in humans.
Methods and Results We studied 13 subjects by combining the multiple indicator-dilution technique with the measurement of immunoreactive ET-1 (irET-1). All patients had normal left ventricular ejection fractions (61±7%, mean±SD) and baseline hemodynamics. Mean pulmonary ET-1 extraction was 47±7%. The ET-1 extracted does not return to circulation and can be characterized by a sequestration rate constant: Kseq=0.048±0.019 s-1. There was no significant difference between irET-1 levels from the pulmonary artery and aorta (0.61±0.29 and 0.68±0.33 pg/mL, respectively; P=.22); the normal lung consequently produces an amount of ET-1 that is quantitatively similar to the amount that has been extracted.
Conclusions The human lung is an important site for both clearance and production of ET-1. There is a normal physiological balance of ET-1 across the pulmonary circulation, which explains the absence of difference in AV ET-1 levels despite a 47±7% clearance. Reduced pulmonary clearance or increased production of this peptide may contribute to the increase in circulating levels found in various cardiovascular conditions.
Key Words: endothelin • circulation • metabolism • endothelium
This article has been cited by other articles:
 |
|
 |
|
  H. J. Bogaard, R. Natarajan, S. C. Henderson, C. S. Long, D. Kraskauskas, L. Smithson, R. Ockaili, J. M. McCord, and N. F. Voelkel Chronic Pulmonary Artery Pressure Elevation Is Insufficient to Explain Right Heart Failure Circulation, November 17, 2009; 120(20): 1951 - 1960. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P Wexberg, W Sperker, N G Morgenthaler, H Heinzl, C Adlbrecht, C Plass, H D Glogar, I M Lang, and T Neunteufl Inhomogeneous vasomotor effects of moderate selective and non-selective endothelin-receptor blockade in stable coronary artery disease Heart, August 1, 2009; 95(15): 1258 - 1264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. G. Julian, H. L. Galan, M. J. Wilson, W. DeSilva, D. Cioffi-Ragan, J. Schwartz, and L. G. Moore Lower uterine artery blood flow and higher endothelin relative to nitric oxide metabolite levels are associated with reductions in birth weight at high altitude Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2008; 295(3): R906 - R915. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. de Frutos, L. Duling, D. Alo, T. Berry, O. Jackson-Weaver, M. Walker, N. Kanagy, and L. Gonzalez Bosc NFATc3 is required for intermittent hypoxia-induced hypertension Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2382 - H2390. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dupuis and M. M. Hoeper Endothelin receptor antagonists in pulmonary arterial hypertension Eur. Respir. J., February 1, 2008; 31(2): 407 - 415. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Houweling, D. Merkus, O. Sorop, F. Boomsma, and D. J. Duncker Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction J. Physiol., July 15, 2006; 574(2): 615 - 626. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sauvageau, E. Thorin, A. Caron, and J. Dupuis Evaluation of endothelin-1-induced pulmonary vasoconstriction following myocardial infarction. Experimental Biology and Medicine, June 1, 2006; 231(6): 840 - 846. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Barst, D. Langleben, D. Badesch, A. Frost, E. C. Lawrence, S. Shapiro, R. Naeije, N. Galie, and on behalf of the STRIDE-2 Study Group Treatment of Pulmonary Arterial Hypertension With the Selective Endothelin-A Receptor Antagonist Sitaxsentan J. Am. Coll. Cardiol., May 16, 2006; 47(10): 2049 - 2056. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Langleben, J. Dupuis, I. Langleben, A. M. Hirsch, M. Baron, J.-L. Senecal, and M. Giovinazzo Etiology-Specific Endothelin-1 Clearance in Human Precapillary Pulmonary Hypertension Chest, March 1, 2006; 129(3): 689 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kubanek, I. Malek, J. Kautzner, M. Hegarova, M. Wiendl, P. Lupinek, L. Karasova, and V. Lanska The value of B-type natriuretic peptide and big endothelin-1 for detection of severe pulmonary hypertension in heart transplant candidates Eur J Heart Fail, December 1, 2005; 7(7): 1149 - 1155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Thomson, P. Kumarathasan, P. Goegan, R. A. Aubin, and R. Vincent Differential Regulation of the Lung Endothelin System by Urban Particulate Matter and Ozone Toxicol. Sci., November 1, 2005; 88(1): 103 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Migneault, S. Sauvageau, L. Villeneuve, E. Thorin, A. Fournier, N. Leblanc, and J. Dupuis Chronically Elevated Endothelin Levels Reduce Pulmonary Vascular Reactivity to Nitric Oxide Am. J. Respir. Crit. Care Med., March 1, 2005; 171(5): 506 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, A. F. Chen, S. W. Watts, J. J. Galligan, and G. D. Fink Endothelin in the splanchnic vascular bed of DOCA-salt hypertensive rats Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H729 - H736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dupuis Increased endothelin levels in congestive heart failure: does it come from the lungs? Does it matter? Cardiovasc Res, July 1, 2004; 63(1): 5 - 7. [Full Text] [PDF]
|
|
|
|
|
|
T. G von Lueder, H. Kjekshus, T. Edvardsen, E. Oie, S. Urheim, L. E. Vinge, M. S. Ahmed, O. A Smiseth, and H. Attramadal Mechanisms of elevated plasma endothelin-1 in CHF: congestion increases pulmonary synthesis and secretion of endothelin-1 Cardiovasc Res, July 1, 2004; 63(1): 41 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Galie, A. Manes, and A. Branzi The endothelin system in pulmonary arterial hypertension Cardiovasc Res, February 1, 2004; 61(2): 227 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S C Apostolopoulou, S Rammos, Z S Kyriakides, D J Webb, N R Johnston, D V Cokkinos, and D T. Kremastinos Acute endothelin A receptor antagonism improves pulmonary and systemic haemodynamics in patients with pulmonary arterial hypertension that is primary or autoimmune and related to congenital heart disease Heart, October 1, 2003; 89(10): 1221 - 1226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. D. Wagner, S. Buz, C. Knosalla, R. Hetzer, and B. Hocher Modulation of Circulating Endothelin-1 and Big Endothelin by Nitric Oxide Inhalation Following Left Ventricular Assist Device Implantation Circulation, September 9, 2003; 108(90101): II-278 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F S Benjaminov, M Prentice, K W Sniderman, S Siu, P Liu, and F Wong Portopulmonary hypertension in decompensated cirrhosis with refractory ascites Gut, September 1, 2003; 52(9): 1355 - 1362. [Abstract] [Full Text]
|
|
|
|
 |
|
 P. Massoudy, J. A. Piotrowski, H. C.J.M. van de Wal, R. Giebler, G. Marggraf, J. Peters, and H. G. Jakob Perfusing and ventilating the patient's lungs during bypass ameliorates the increase in extravascular thermal volume after coronary bypass grafting Ann. Thorac. Surg., August 1, 2003; 76(2): 516 - 521. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. F. Luscher, F. Enseleit, R. Pacher, V. Mitrovic, M. R. Schulze, R. Willenbrock, R. Dietz, V. Rousson, D. Hurlimann, S. Philipp, et al. Hemodynamic and Neurohumoral Effects of Selective Endothelin A (ETA) Receptor Blockade in Chronic Heart Failure: The Heart Failure ETA Receptor Blockade Trial (HEAT) Circulation, November 19, 2002; 106(21): 2666 - 2672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Schulze-Neick, J. Li, J. A. Reader, L. Shekerdemian, A. N. Redington, and D. J. Penny The endothelin antagonist BQ123 reduces pulmonary vascular resistance after surgical intervention for congenital heart disease J. Thorac. Cardiovasc. Surg., September 1, 2002; 124(3): 435 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. K. Oktar, M. A. Gulpinar, A. Bozkurt, S. Ghandour, S. Cetinel, H. Moini, B. C. Yegen, S. Bilsel, D. N. Granger, and H. Kurtel Endothelin receptor blockers reduce I/R-induced intestinal mucosal injury: role of blood flow Am J Physiol Gastrointest Liver Physiol, April 1, 2002; 282(4): G647 - G655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bauer, H. Wilkens, F. Langer, S. O. Schneider, H. Lausberg, and H.-J. Schafers Selective Upregulation of Endothelin B Receptor Gene Expression in Severe Pulmonary Hypertension Circulation, March 5, 2002; 105(9): 1034 - 1036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. DAVIE, S. J. HALEEN, P. D. UPTON, J. M. POLAK, M. H. YACOUB, N. W. MORRELL, and J. WHARTON ETA and ETB Receptors Modulate the Proliferation of Human Pulmonary Artery Smooth Muscle Cells Am. J. Respir. Crit. Care Med., February 1, 2002; 165(3): 398 - 405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Egidy, E. Baviera, G. Ciuffo, P. Corvol, and F. Pinet Localization of the Endothelin System in Aldosterone-Producing Adenomas Hypertension, November 1, 2001; 38(5): 1137 - 1142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.J. Cowburn and J.G.F. Cleland Endothelin antagonists for chronic heart failure: do they have a role? Eur. Heart J., October 1, 2001; 22(19): 1772 - 1784. [PDF]
|
|
|
|
|
|
B. R. Bond, B. H. Dorman, M. J. Clair, C. A. Walker, M. L. Pinosky, S. T. Reeves, S. Walton, J. M. Kratz, J. L. Zellner, A. J. Crumbley III, et al. Endothelin-1 during and after cardiopulmonary bypass: Association to graft sensitivity and postoperative recovery J. Thorac. Cardiovasc. Surg., August 1, 2001; 122(2): 358 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Mathieu, J. Dupuis, M. Carrier, P. Cernacek, M. Pellerin, L. P. Perrault, R. Cartier, J. Taillefer, and L. C. Pelletier Pulmonary metabolism of endothelin 1 during on-pump and beating heart coronary artery bypass operations J. Thorac. Cardiovasc. Surg., June 1, 2001; 121(6): 1137 - 1142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Spieker, G. Noll, F. T. Ruschitzka, and T. F. Luscher Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future? J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1493 - 1505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Lepailleur-Enouf, G. Egidy, M. Philippe, L. Louedec, J.-P. Henry, P. Mulder, and J.-B. Michel Pulmonary endothelinergic system in experimental congestive heart failure Cardiovasc Res, February 1, 2001; 49(2): 330 - 339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-F. Jasmin, M. Lucas, P. Cernacek, and J. Dupuis Effectiveness of a Nonselective ETA/B and a Selective ETA Antagonist in Rats With Monocrotaline-Induced Pulmonary Hypertension Circulation, January 16, 2001; 103(2): 314 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Moraes, W. S. Colucci, and M. M. Givertz Secondary Pulmonary Hypertension in Chronic Heart Failure : The Role of the Endothelium in Pathophysiology and Management Circulation, October 3, 2000; 102(14): 1718 - 1723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Stangl, T. Dschietzig, C. Richter, M. Laule, V. Stangl, E. Tanis, G. Baumann, and S. B. Felix Pulmonary Release and Coronary and Peripheral Consumption of Big Endothelin and Endothelin-1 in Severe Heart Failure : Acute Effects of Vasodilator Therapy Circulation, September 5, 2000; 102(10): 1132 - 1138. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Spieker, V. Mitrovic, G. Noll, R. Pacher, M. R. Schulze, J.o. Muntwyler, C. Schalcher, W. Kiowski, T. F. Luscher, and on behalf of the ET 003 Investigators Acute hemodynamic and neurohumoral effects of selective ETA receptor blockade in patients with congestive heart failure J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1745 - 1752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ergul, C. A. Walker, A. Goldberg, S. C. Baicu, J. W. Hendrick, M. K. King, and F. G. Spinale ET-1 in the myocardial interstitium: relation to myocyte ECE activity and expression Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H2050 - H2056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kjekshus, O. A. Smiseth, R. Klinge, E. Oie, M. E. Hystad, and H. Attramadal Regulation of ET: pulmonary release of ET contributes to increased plasma ET levels and vasoconstriction in CHF Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1299 - H1310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Dupuis, A. J. Schwab, A. Simard, P. Cernacek, D. J. Stewart, and C. A. Goresky Kinetics of endothelin-1 binding in the dog liver microcirculation in vivo Am J Physiol Gastrointest Liver Physiol, October 1, 1999; 277(4): G905 - G914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B Prendergast, D E Newby, L E Wilson, D J Webb, and P S Mankad Early therapeutic experience with the endothelin antagonist BQ-123 in pulmonary hypertension after congenital heart surgery Heart, October 1, 1999; 82(4): 505 - 508. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Battistelli, M. Billi, G. Manasse, A. Vittoria, F. Roviello, and S. Forconi Behavior of Circulating Endothelin-1 in a Group of Patients with Acute Myocardial Infarction Angiology, August 1, 1999; 50(8): 629 - 638. [Abstract] [PDF]
|
|
|
|
|
|
J. Dupuis, J.-C. Tardif, P. Cernacek, and P. Theroux Cholesterol Reduction Rapidly Improves Endothelial Function After Acute Coronary Syndromes : The RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) Trial Circulation, June 29, 1999; 99(25): 3227 - 3233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Langleben, R. J. Barst, D. Badesch, B. M. Groves, V. F. Tapson, S. Murali, R. C. Bourge, N. Ettinger, E. Shalit, L. M. Clayton, et al. Continuous Infusion of Epoprostenol Improves the Net Balance Between Pulmonary Endothelin-1 Clearance and Release in Primary Pulmonary Hypertension Circulation, June 29, 1999; 99(25): 3266 - 3271. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Parker, J. J. Thiessen, R. Reilly, J. H. Tong, D. J. Stewart, and A. S. Pandey Human Endothelin-1 Clearance Kinetics Revealed by a Radiotracer Technique J. Pharmacol. Exp. Ther., April 1, 1999; 289(1): 261 - 265. [Abstract] [Full Text]
|
|
|
|
|
|
S. E. Orfanos, D. Langleben, J. Khoury, R. D. Schlesinger, L. Dragatakis, C. Roussos, J. W. Ryan, and J. D. Catravas Pulmonary Capillary Endothelium-Bound Angiotensin-Converting Enzyme Activity in Humans Circulation, March 30, 1999; 99(12): 1593 - 1599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M Mundhenke, B Schwartzkopff, M Köstering, U Deska, R M Klein, and B E Strauer Endogenous plasma endothelin concentrations and coronary circulation in patients with mild dilated cardiomyopathy Heart, March 1, 1999; 81(3): 278 - 284. [Abstract] [Full Text]
|
|
|
|
|
|
T. Tsutamoto, A. Wada, T. Hisanaga, K. Maeda, M. Ohnishi, N. Mabuchi, M. Sawaki, M. Hayashi, M. Fujii, and M. Kinoshita Relationship between endothelin-1 extraction in the peripheral circulation and systemic vascular resistance in patients with severe congestive heart failure J. Am. Coll. Cardiol., February 1, 1999; 33(2): 530 - 537. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dupuis and S. Prie The ETA-Receptor Antagonist LU 135252 Prevents the Progression of Established Pulmonary Hypertension Induced by Monocrotaline in Rats Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1999; 4(1): 33 - 39. [Abstract] [PDF]
|
|
|
|
|
|
J. Dupuis, J.-L. Rouleau, and P. Cernacek Reduced Pulmonary Clearance of Endothelin-1 Contributes to the Increase of Circulating Levels in Heart Failure Secondary to Myocardial Infarction Circulation, October 20, 1998; 98(16): 1684 - 1687. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Cowburn, J. G.F. Cleland, J. D. McArthur, M. R. MacLean, H. J. Dargie, J. J.V. McMurray, and J. J. Morton Endothelin-1 has haemodynamic effects at pathophysiological concentrations in patients with left ventricular dysfunction Cardiovasc Res, September 1, 1998; 39(3): 563 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Dupuis, G. W Moe, and P. Cernacek Reduced pulmonary metabolism of endothelin-1 in canine tachycardia-induced heart failure Cardiovasc Res, September 1, 1998; 39(3): 609 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Prie, D. J. Stewart, and J. Dupuis EndothelinA Receptor Blockade Improves Nitric Oxide–Mediated Vasodilation in Monocrotaline-Induced Pulmonary Hypertension Circulation, June 2, 1998; 97(21): 2169 - 2174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Shi, P. Cernacek, F. Hu, and R. P. Michel Endothelin reactivity and receptor profile of pulmonary vessels in postobstructive pulmonary vasculopathy Am J Physiol Heart Circ Physiol, December 1, 1997; 273(6): H2558 - H2564. [Abstract] [Full Text] [PDF]
|
|