Mechanism of endothelin-1-induced pulmonary vasoconstriction.
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 greater than or equal to 10(-10) M, ET-1 produced dose-dependent increases in mean pulmonary artery pressure (EC50, approximately 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Horgan
M J
MJ
Department of Pediatrics, Albany Medical College of Union University, NY 12208.
Pinheiro
J M
JM
Malik
A B
AB
D000818:Animals; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D008168:Lung / Q000033:anatomy & histology; D008297:Male; D009929:Organ Size; D011652:Pulmonary Circulation / Q000187:drug effects*; D013929:Thromboxane B2 / Q000097:blood; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014666:Vasomotor System / Q000187:drug effects; D014680:Veins
D016232:Endothelins; D013929:Thromboxane B2