Correspondence

Endothelin-1 in Pulmonary Hypertension

N Engl J Med 1993; 329:1967-1968December 23, 1993

Article

To the Editor:

Giaid et al. recently reported (June 17 issue)1 increased expression of endothelin-1 in vascular endothelial cells of patients with pulmonary hypertension. We have previously reported that patients with pulmonary hypertension have significantly higher plasma endothelin-1 concentrations than healthy controls2. Together, these results strongly suggest that the pulmonary production of endothelin-1 may contribute to the vascular abnormalities associated with pulmonary hypertension.

To determine the role of the local production of endothelin-1 in the lungs of patients with pulmonary hypertension, we prospectively studied endothelin-1 concentrations in the lungs of six consecutive patients referred for lung or heart-lung transplantation after severe pulmonary hypertension had been diagnosed at cardiac catheterization. Three patients had primary pulmonary hypertension according to the criteria established for the Primary Pulmonary Hypertension Registry of the National Heart, Lung, and Blood Institute,3 and three patients had pulmonary hypertension due to a congenital heart defect (Eisenmenger's syndrome). In addition, lung-biopsy specimens from six patients with lung cancer but without pulmonary hypertension were also analyzed as control samples. Endothelin-1 concentrations were measured by radioimmunoassay with a polyclonal antibody (sensitivity, 0.2 pg per tube). Pulmonary concentrations of endothelin-1 were expressed in picograms per milligram of dry pulmonary tissue.

The characteristics of the patients and controls are shown in Table 1Table 1Characteristics of Patients with Pulmonary Hypertension and Controls.. Pulmonary endothelin-1 concentrations were significantly higher in the patients with pulmonary arterial hypertension, irrespective of its cause, than in the controls (P<0.01). There was a positive association between the endothelin-1 concentration and pulmonary vascular resistance in the patients (P<0.05). Pulmonary endothelin-1 concentrations in the patients with primary pulmonary hypertension were not significantly different from those in the patients with Eisenmenger's syndrome (means ±SE, 18.8 ±1.2 vs. 16.9 ±4.4 pg per milligram).

Our finding of an increase in endothelin-1 concentrations in the lungs provides new evidence in support of the view that excessive local production of endothelin-1 in the lungs contributes to the vascular abnormalities of pulmonary hypertension.

Patrice Cacoub, M.D.
Richard Dorent, M.D.
Patrick Nataf, M.D.
Alain Carayon, M.D.
Hopital Pitie-Salpetriere, 75013 Paris, France

3 References

1. 1

   Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732-1739
   Full Text | Web of Science | Medline

2. 2

   Cacoub P, Dorent R, Maistre G, et al. Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome. Am J Cardiol 1993;71:448-450
   CrossRef | Web of Science | Medline

3. 3

   Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216-223
   Web of Science | Medline

Author/Editor Response

Dr. Giaid replies:

To the Editor: Using a radioimmunoassay, Cacoub et al. found an increase in endothelin-1 concentrations in tissue extracts from a limited number of patients with pulmonary hypertension. Their data are neither sufficient nor necessary to explain the broad spectrum of observations that we made using immunohistochemistry, Northern blotting, and in situ hybridization. Elevated levels of plasma endothelin-1 have previously been reported in patients with primary pulmonary hypertension1 and patients with pulmonary hypertension associated with various disease states, including congenital heart defects2. Elevated levels of endothelin-1 in plasma or tissue provide neither unequivocal evidence of local endothelin-1 production nor evidence of its relation to the genesis of associated pulmonary vascular lesions. Cacoub and colleagues compared the mean values for total tissue endothelin-like immunoreactivity in their patients with primary pulmonary hypertension with the means in patients with secondary pulmonary hypertension (three patients in each group), finding no significant differences, whereas we observed that the endothelin-1-like immunoreactivity was consistently less striking in the muscular pulmonary arteries of our patients with secondary pulmonary hypertension than in those of our patients with primary pulmonary hypertension; the difference between our groups (17 and 11 patients, respectively) was significant (P = 0.016). We may reconcile the two contrary observations by recalling that the data of Cacoub et al. reflect global endothelin-1 concentrations rather than solely those in the tissue compartments of pathophysiologic interest. Moreover, the small size of their sample raises a substantial possibility of wrongly accepting the hypothesis of no difference (i.e., a type II error); a similar comparison of larger groups of patients would be desirable.

Adel Giaid, Ph.D.
Montreal General Hospital, Montreal, QC H3G 1A4, Canada

2 References

1. 1

   Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991;114:464-469
   Web of Science | Medline

2. 2

   Yoshibayashi M, Nishioka K, Nakao K, et al. Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects: evidence for increased production of endothelin in pulmonary circulation. Circulation 1991;84:2280-2285
   Web of Science | Medline

Citing Articles (14)

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   Dongmin Shao, John E.S. Park, Stephen J. Wort. (2011) The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension. Pharmacological Research 63:6, 504-511
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   Tilman Humpl, Ingram Schulze-Neick. 2010. Pulmonary Vascular Disease. , 1147-1161.
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   Steven H. Abman. (2009) Role of Endothelin Receptor Antagonists in the Treatment of Pulmonary Arterial Hypertension. Annual Review of Medicine 60:1, 13-23
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   Robert Tulloh. (2009) Etiology, Diagnosis, and Pharmacologic Treatment of Pediatric Pulmonary Hypertension. Pediatric Drugs 11:2, 115-128
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   Raymond L. Benza. (2008) Pulmonary Hypertension Associated with Sickle Cell Disease: Pathophysiology and Rationale for Treatment. Lung 186:4, 247-254
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   P. Cacoub, Z. Amoura, D. Langleben. (2008) La prise en charge thérapeutique de l’hypertension artérielle pulmonaire par les antagonistes des récepteurs de l’endothéline en 2008. La Revue de Médecine Interne 29:4, 283-289
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   I. Marie, S. Bekri, H. Lévesque. (2008) Endothéline 1 et sélectivité des antagonistes des récepteurs de l’endothéline 1 : to B or not to B ?. La Revue de Médecine Interne 29:4, 263-268
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   M. Beghetti. (2006) Current treatment options in children with pulmonary arterial hypertension and experiences with oral bosentan. European Journal of Clinical Investigation 36:s3, 16-24
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   K. Ahmadi-Simab, W. L. Gross. (2006) Pulmonale arterielle Hypertonie bei Kollagenosen: Klinik, Epidemiologie, Pathogenese, Diagnostik und Therapie. Zeitschrift für Rheumatologie 65:4, 297-305
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    Sophie Motte, Kathleen McEntee, Robert Naeije. (2006) Endothelin receptor antagonists. Pharmacology & Therapeutics 110:3, 386-414
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    Ji-Hyun Lee, Sehyun Kim, Byung-Kyu Park, Woo-Sung Kim, Dong-Soon Kim, Won-Dong Kim, Sang-Do Lee. (2005) The Effect of a Combination of Inhaled Nitric Oxide and an EndothelinA-Receptor Antagonist onHemodynamic Dysfunction in Experimental AcutePulmonary Thromboembolism. Lung 183:2, 139-149
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    Trina K Jeffery, Janet C Wanstall. (2001) Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonary hypertension. Pharmacology & Therapeutics 92:1, 1-20
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    Trina K Jeffery, Janet C Wanstall. (1999) Perindopril, an angiotensin converting enzyme inhibitor, in pulmonary hypertensive rats: comparative effects on pulmonary vascular structure and function. British Journal of Pharmacology 128:7, 1407-1418
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    Joel B. Nelson, Sean P. Hedican, Daniel J. George, A. H. Reddi, Steven Piantadosi, Mario A. Eisenberger, Jonathan W. Simons. (1995) Identification of endothelin–1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nature Medicine 1:9, 944-949
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