Mechanism of Endothelin-1—Induced Pulmonary Vasoconstriction

• Published in: Circulation research Vol. 69; no. 1; pp. 157 - 164
• Main Authors: Horgan, Michael J, Pinheiro, Joaquim M.B, Malik, Asrar B
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01-07-1991; Lippincott
• Subjects: Air breathing; Animals; Biological and medical sciences; Dose-Response Relationship, Drug; Endothelins - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Guinea Pigs; Lung - anatomy & histology; Male; Organ Size; Pulmonary Circulation - drug effects; Respiratory system: anatomy, metabolism, gas exchange, ventilatory mechanics, respiratory hemodynamics; Thromboxane B2 - blood; Time Factors; Vascular Resistance - drug effects; Vasoconstriction - drug effects; Vasomotor System - drug effects; Veins; Vertebrates: respiratory system; Vertebrata; Vasomotricity; Mammalia; Guinea pig; Endothelin; Peptides; Pulmonary vessel; Lung; Rodentia; Vasoconstriction; Hemodynamics; Respiratory system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.res.69.1.157

Endothelins are endothelial cell-derived peptides with potent vasoconstrictor properties. We investigated the actions of porcine/human endothelin-1 (ET-1) on the microvasculature of the guinea pig lung perfused at constant flow with Ringers-albumin. We measured the perfusion pressure, distribution of pulmonary vascular resistance (using the double occlusion method), lung weight change, and the pulmonary capillary filtration coefficient. At concentrations of ≥10 M, ET-1 produced dose-dependent increases in mean pulmonary artery pressure (EC50, ∽10 M), which were rapid in onset and biphasic (first phase peaking at 1-2 minutes; second phase peaking at 10-15 minutes) up to 60 minutes of the perfusion period. The vasoconstrictor response was sustained for the 60-minute perfusion period. The pulmonary vasoconstriction was inhibited by pretreatment with indomethacin (10 M), the thromboxane A2 receptor antagonist SQ-29,548 (4×10 M), or papaverine (10 M). Nifedipine (10 or 10 M) had no effect on the first phase but prevented the second phase of the vasoconstriction. The vasoconstriction was primarily the result of a 10-fold increase in pulmonary venous resistance. Pulmonary edema developed after ET-1 challenge because of the venoconstriction and the resultant pulmonary capillary hypertension. However, the pulmonary capillary filtration coefficient was unchanged, indicating that pulmonary vascular permeability did not increase. ET-1 also had no effect on transendothelial I-albumin flux. The results indicate that ET-1 is a potent thromboxane-dependent venoconstrictor in the guinea pig lung. ET-1 induces pulmonary edema because of its ability to increase pulmonary capillary hydrostatic pressure. The mechanism of the sustained pulmonary venoconstriction may involve calcium mobilization via dihydropyridine-sensitive calcium channels. (Circulation Research 1991;69:157-164)