Am. J. Respir. Crit. Care Med., Volume 164, Number 7, October 2001, 1282-1287

Pathogenic Role of Endothelin 1 in Hemodynamic Dysfunction in Experimental Acute Pulmonary Thromboembolism

JI-HYUN LEE, YONG-GAM CHUN, IN-CHUL LEE, RUBIN M. TUDER, SANG-BUM HONG, TAE-SUN SHIM, CHAE-MAN LIM, YOUNSUCK KOH, WOO-SUNG KIM, DONG-SOON KIM, WON-DONG KIM, and SANG-DO LEE

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, Seoul, Korea; College of Medicine, Ulsan University, Seoul, Korea; Asan Life Science Institute, Seoul, Korea; Department of Diagnostic Pathology, Asan Medical Center, Seoul, Korea; and Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado

The plasma endothelin-1 (ET-1) level is elevated in patients with acute pulmonary thromboembolism (APE). Whether ET-1 is a pathogenic mediator or a simple marker of APE is not known. We investigated the role of ET-1 in hemodynamic dysfunction in APE through evaluating the effects of ET_A receptor antagonist in an experimental APE model. We also examined ET-1 expression in embolized lungs. In a canine autologous blood clot pulmonary embolism model, ET_A receptor antagonist ZD2574 (10 mg/kg, intravenous; ZD2574 group; n = 6) or vehicle (control group; n = 5) was administered. Hemodynamic and gas exchange parameters and plasma levels of ET-1 were serially measured. Prepro-ET-1 mRNA expression and the distribution of ET-1 peptide in lung tissues were also examined. With ZD2574 pulmonary arterial pressure and pulmonary vascular resistance significantly decreased, and were lower compared with the control group. The decrease in cardiac output was also less in the ZD2574 group. Plasma ET-1 levels increased after embolization. Prepro-ET-1 mRNA expression increased in embolized lungs and ET-1 peptide expression also increased in embolized lungs, particularly in the muscular pulmonary arteries, compared with normal lungs. These findings suggest that ET-1 partially contributes to hemodynamic derangements of APE, and that ET_A receptor antagonists might constitute a useful therapeutic tool for APE.

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