Endothelium-derived relaxing factor inhibits hypoxic pulmonary vasoconstriction in rats.
The hypothesis that endothelium-derived relaxing factor (EDRF) modulates hypoxic pulmonary vasoconstriction (HPV) was tested in isolated, blood-perfused rat lungs ventilated with gas mixtures of 21% O2-5% CO2-74% N2 (normoxia) or of 3% O2-5% CO2-92% N2 (hypoxia); 30 microM NG-monomethyl-L-arginine (L-NMMA), an inhibitor of EDRF production, caused a reduction in the endothelium-dependent relaxant response to acetylcholine (ACh) from 62 +/- 7, 88 +/- 4, and 100 +/- 4% to 26 +/- 8, 49 +/- 12, and 75 +/- 7% at ACh concentrations of 1, 10, and 100 microM, respectively (p less than 0.05 at all concentrations), indicating that L-NMMA acts via the inhibition of EDRF production. L-NMMA induced a concentration-related augmentation in HPV of 20 +/- 5, 32 +/- 8, and 34 +/- 8% at concentrations of 30, 300, and 1,000 microM (p less than 0.05, compared with a vehicle control group at all concentrations). The pressor response to a dose of angiotensin II (A-II), which produced the same increase in pulmonary artery pressure as that induced by hypoxia, was also significantly augmented (2 +/- 0.6%), but to a lesser extent. The augmentation of HPV by 30 microM L-NMMA was completely reversed by 1 mM L-arginine (a precursor of EDRF), but not by D-arginine (an isomer of L-arginine). One and 6 mM L-arginine, but not 6 mM D-arginine caused a significant inhibition of HPV by 20 +/- 2 and 47 +/- 12% (p less than 0.05, compared with the vehicle control group) and a small but not significant reduction in A-II-mediated contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
Liu
S F
SF
Department of Thoracic Medicine, National Heart and Lung Institute, London, United Kingdom.
Crawley
D E
DE
Barnes
P J
PJ
Evans
T W
TW
D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D014661:Vasoconstriction / Q000187:drug effects*; D019323:omega-N-Methylarginine
D000804:Angiotensin II; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D000109:Acetylcholine