Pathogenic role of endothelin 1 in hemodynamic dysfunction in experimentalacute pulmonary thromboembolism

The plasma endothelin-1 (ET-1) level is elevated in patients with acute pul monary thromboembolism (APE). Whether ET-1 is a pathogenic mediator or a si mple marker of APE is not known. We investigated the role of ET-1 in hemody namic dysfunction in APE through evaluating the effects of ETA receptor ant agonist in an experimental APE model. We also examined ET-1 expression in e mbolized lungs. In a canine autologous blood clot pulmonary embolism model, ETA receptor antagonist ZD2574 (10 mg/kg, intravenous; ZD2574 group; n = 6 ) or vehicle (control group; n = 5) was administered. Hemodynamic and gas e xchange 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 v ascular resistance significantly decreased, and were lower compared with th e 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 e xpression increased in embolized lungs and ET-1 peptide expression also inc reased in embolized lungs, particularly in the muscular pulmonary arteries, compared with normal lungs. These findings suggest that ET-1 partially con tributes to hemodynamic derangements of APE, and that ETA receptor antagoni sts might constitute a useful therapeutic tool for APE.