a-192621 and Respiratory-Distress-Syndrome

The receptors underlying the endothelin-dependent component of lung plasma extravasation and leucocyte infiltration induced by oleic acid were assessed in mice. Oleic acid (1 mg.kg(-1) intravenously), but not endothelin-1 (up to 1 nmol.kg(-1) intravenously), increased accumulation of Evans blue in the lungs (excluding the trachea and main bronchi) from 11.8+/-3.9 to 98.6+/-10.7 microg 1 h after injection. Bosentan, the antagonist of endothelin receptors (ET(A) and ET(B)) or the selective ET(B) receptor antagonists Ro 46-8443 or A-192621 (administered 1 h before oleic acid at doses of 30, 10 and 30 mg x kg(-1) respectively) reduced the effect of oleic acid by 71%, 58% and 79% respectively. However, the selective ET(A) receptor antagonist A-127722.5 (10 mg x kg(-1)) was inactive. Oleic acid (2 mg xkg(-1), intravenously) raised the number of total leucocytes, mononuclear cells and neutrophils in broncho-alveolar lavage fluid 4 h after injection. Bosentan and Ro 46-8443 (at doses of 30 and 10 mg x kg(-1) respectively) inhibited the neutrophil infiltration induced by oleic acid by approx. 80%. None of the antagonists modified control (basal) pulmonary microvascular permeability or total and differential cell counts. Thus, endogenous endothelins, acting via ET(B) receptor-dependent mechanisms, play a major role in oleic acid-induced lung injury in the mouse by promoting infiltration of circulating neutrophils and enhancement of pulmonary microvascular plasma extravasation. These findings suggest that either ET(B) or mixed ET(A)/ET(B) receptor antagonists might be beneficial in the treatment of the adult respiratory distress syndrome.

Topics: Acute Disease; Analysis of Variance; Animals; Atrasentan; Bosentan; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Evans Blue; Lung; Male; Mice; Mice, Inbred Strains; Neutrophil Infiltration; Oleic Acid; Pyrimidines; Pyrrolidines; Receptor, Endothelin A; Receptor, Endothelin B; Respiratory Distress Syndrome; Sulfonamides