Mechanism of endothelin-1-induced pulmonary vasoconstriction

Abstract

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 ≥10-10 M, ET-1 produced dose-dependent increases in mean pulmonary artery pressure (EC50, ~10-9.5 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 (10-5 M), the thromboxane A2 receptor antagonist SQ-29,548 (4 x 10-6 M), or papaverine (10-5 M). Nifedipine (10-5 or 10-7 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 125I-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.