(Circulation. 1999;99:3266-3271.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Continuous Infusion of Epoprostenol Improves the Net Balance Between Pulmonary Endothelin-1 Clearance and Release in Primary Pulmonary Hypertension
From the Division of Cardiology, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Canada (D.L., E.S.); College of Physicians and Surgeons, Columbia University, New York, NY (R.J.B.); University of Colorado Health Sciences Center, Denver, Colo (D.B., B.M.G.); Duke University Medical Center, Durham, NC (V.F.T.); Presbyterian University Hospital, Pittsburgh, Pa (S.M.); University of Alabama, Birmingham, Ala (R.C.B.); Washington University, St. Louis, Mo (N.E.); Glaxo Wellcome Inc, Research Triangle Park, NC (L.M.C., M.M.J.); United Therapeutics Inc, Research Triangle Park, NC (S.D.B., J.W.C.); University of Toronto, Toronto, Canada (D.J.S.); and University of North Carolina, Chapel Hill, NC (W.L.).
Correspondence to Dr David Langleben, Room E-258, Jewish General Hospital, 3755 Cote Ste. Catherine, Montreal, Quebec, Canada H3T 1E2. E-mail mddl{at}musica.mcgill.ca
Background—Primary pulmonary hypertension results from progressive narrowing of the precapillary pulmonary vasculature. A variety of endothelial abnormalities have been identified, including a net reduction in pulmonary clearance of the vasoconstrictor and smooth muscle mitogen endothelin-1. In many patients, net pulmonary release of endothelin-1 is observed. Chronic infusions of epoprostenol (prostacyclin) improve functional capacity, survival, and hemodynamics in patients with advanced primary pulmonary hypertension. We hypothesized that the epoprostenol infusions, as compared with conventional therapy, might alter the abnormal pulmonary endothelin-1 homeostasis.
Methods and Results—Using a subset of patients from a larger randomized study comparing epoprostenol plus conventional therapy (n=11 in the present study) with conventional therapy alone (n=7 in the present study), we determined the ratio of plasma endothelin-1 levels in systemic arterial blood leaving the lung to levels in mixed venous blood entering the lung both before randomization and after 88 days of continuous therapy. There were no differences between the 2 groups before therapy, but by day 88, the epoprostenol-treated group had a greater proportion of patients (82%) with an arterial/venous ratio <1 than did the conventional therapy group, in which only 29% of patients had a ratio <1 (P<0.05).
Conclusions—These results suggest that continuous epoprostenol therapy may have a beneficial effect on the balance between endothelin-1 clearance and release in many patients with primary pulmonary hypertension and may provide one explanation for the salutary effect of epoprostenol in this disease.
Key Words: hypertension, pulmonary • endothelin • epoprostenol • prostaglandins
This article has been cited by other articles:
 |
|
 |
|
  L. De Franceschi, O. S. Platt, G. Malpeli, A. Janin, A. Scarpa, C. Leboeuf, Y. Beuzard, E. Payen, and C. Brugnara Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice FASEB J, June 1, 2008; 22(6): 1849 - 1860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Fredenburgh, O. D. Liang, A. A. Macias, T. R. Polte, X. Liu, D. F. Riascos, S. W. Chung, S. L. Schissel, D. E. Ingber, S. A. Mitsialis, et al. Absence of Cyclooxygenase-2 Exacerbates Hypoxia-Induced Pulmonary Hypertension and Enhances Contractility of Vascular Smooth Muscle Cells Circulation, April 22, 2008; 117(16): 2114 - 2122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Merkus, B. Houweling, V. J. de Beer, Z. Everon, and D. J. Duncker Alterations in endothelial control of the pulmonary circulation in exercising swine with secondary pulmonary hypertension after myocardial infarction J. Physiol., May 1, 2007; 580(3): 907 - 923. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Peacock, R. Naeije, N. Galie, and J.T. Reeves End points in pulmonary arterial hypertension: the way forward Eur. Respir. J., June 1, 2004; 23(6): 947 - 953. [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]
|
|
|
|
|
|
R. Budhiraja, R. M. Tuder, and P. M. Hassoun Endothelial Dysfunction in Pulmonary Hypertension Circulation, January 20, 2004; 109(2): 159 - 165. [Full Text] [PDF]
|
|
|
|
 |
|
 N. H. Kim, R. N. Channick, and L. J. Rubin Successful Withdrawal of Long-term Epoprostenol Therapy for Pulmonary Arterial Hypertension Chest, October 1, 2003; 124(4): 1612 - 1615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wilkens, M. Bauer, N. Forestier, J. Konig, A. Eichler, S. Schneider, H.J. Schafers, and G.W. Sybrecht Influence of Inhaled Iloprost on Transpulmonary Gradient of Big Endothelin in Patients With Pulmonary Hypertension Circulation, March 25, 2003; 107(11): 1509 - 1513. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Wort, M. Woods, T. D. Warner, T. W. Evans, and J. A. Mitchell Cyclooxygenase-2 Acts as an Endogenous Brake on Endothelin-1 Release by Human Pulmonary Artery Smooth Muscle Cells: Implications for Pulmonary Hypertension Mol. Pharmacol., November 1, 2002; 62(5): 1147 - 1153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Suhara, Y. Sawa, N. Fukushima, K. Kagisaki, C. Yokoyama, T. Tanabe, S. Ohtake, and H. Matsuda Gene transfer of human prostacyclin synthase into the liver is effective for the treatment of pulmonary hypertension in rats J. Thorac. Cardiovasc. Surg., May 1, 2002; 123(5): 855 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Beghetti, G. Reber, P. de Moerloose, L. Vadas, A. Chiappe, I. Spahr-Schopfer, and P.C. Rimensberger Aerosolized iloprost induces a mild but sustained inhibition of platelet aggregation Eur. Respir. J., March 1, 2002; 19(3): 518 - 524. [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]
|
|
|
|
|
|
C. Rubens, R. Ewert, M. Halank, R. Wensel, H.-D. Orzechowski, H.-P. Schultheiss, and G. Hoeffken Big Endothelin-1 and Endothelin-1 Plasma Levels Are Correlated With the Severity of Primary Pulmonary Hypertension Chest, November 1, 2001; 120(5): 1562 - 1569. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Wort, M. Woods, T. D. Warner, T. W. Evans, and J. A. Mitchell Endogenously Released Endothelin-1 from Human Pulmonary Artery Smooth Muscle Promotes Cellular Proliferation . Relevance to Pathogenesis of Pulmonary Hypertension and Vascular Remodeling Am. J. Respir. Cell Mol. Biol., July 1, 2001; 25(1): 104 - 110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-D. Lee, D.-S. Kim, T.-S. Shim, C.-M. Lim, Y. Koh, W.-S. Kim, and W.-D. Kim Nitric Oxide and Molsidomine in the Management of Pulmonary Hypertension in Takayasu's Arteritis Chest, January 1, 2001; 119(1): 302 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wharton, N. Davie, P. D. Upton, M. H. Yacoub, J. M. Polak, and N. W. Morrell Prostacyclin Analogues Differentially Inhibit Growth of Distal and Proximal Human Pulmonary Artery Smooth Muscle Cells Circulation, December 19, 2000; 102(25): 3130 - 3136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Archer and S. Rich Primary Pulmonary Hypertension : A Vascular Biology and Translational Research "Work in Progress" Circulation, November 28, 2000; 102(22): 2781 - 2791. [Abstract] [Full Text] [PDF]
|
|