Endothelin ET(B) receptor-mediated mechanisms involved in oleic acid-induced acute lung injury in mice.
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.
Department of Pharmacology, CCB, Universidade Federal de Santa Catarina, Rua Ferreira Lima, 82, Florianopolis, 88015-420, SC, Brazil.
Cláudio L
CL
Guimarães
Patricia G
PG
Trentin
Giles A
GA
Rae
D000208:Acute Disease; D000704:Analysis of Variance; D000818:Animals; D000077868:Atrasentan; D000077300:Bosentan; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D005070:Evans Blue; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020556:Neutrophil Infiltration; D019301:Oleic Acid / Q000494:pharmacology; D011743:Pyrimidines / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use*; D000096926:Benzenesulfonamides
D000077868:Atrasentan; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D005070:Evans Blue; D019301:Oleic Acid; D011743:Pyrimidines; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; C120508:A 192621; C099180:Ro 46-8443; D000096926:Benzenesulfonamides