Endothelium-derived relaxing factor activity in rat lung during hypoxic pulmonary vascular remodeling.
We have investigated the role of endothelium-derived relaxing factor in modulating hypoxic pulmonary vasoconstriction by inhibiting its synthesis with the false substrate NG-monomethyl-L-arginine (L-NMMA) in the isolated blood-perfused lungs of Wistar rats after chronic hypoxia (CH, fractional inspiratory O2 concentration 10%) for 15 h, 2 days, and 7 days. Lungs were perfused with blood of normal hematocrit at constant flow (18 ml/min) ventilated with 1) 95% air-5% CO2 (normoxia) and 2) 2% O2-5% CO2-93% N2 (hypoxia) and were studied in the absence and presence of L-NMMA (30 and 300 microM) or L-arginine (L-Arg, 1 and 6 mM) in separate groups. Pulmonary arterial pressure (Ppa) rose incrementally with hypoxic exposure (all P < 0.05 vs. normoxic control group). Hypoxic pulmonary vasoconstriction (HPV) was markedly reduced after 15 h and 2 days of CH: the mean increases in Ppa (delta Ppa) in hypoxia were 15.3, 3.5, 3.8, and 13.6 mmHg in control rats and rats exposed to 15 h (P < 0.05 vs. control and 7 days of CH), 2 days (P < 0.001 vs. control and 7 days of CH), and 7 days of CH, respectively. Ppa in control rats and rats exposed to 15 h, 2 days, and 7 days of CH were 137, 179, 184, and 166% of control, respectively, after 30 microM L-NMMA (all P < 0.05 when expressed as percent change vs. no L-NMMA). Similar augmentation in HPV was seen after 30 microM L-NMMA, with all hypoxic groups having a greater response than control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Zhao
L
L
Department of Medicine (Respiratory Division), Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
Crawley
D E
DE
Hughes
J M
JM
Evans
T W
TW
Winter
R J
RJ
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D010477:Perfusion; D011652:Pulmonary Circulation / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D019323:omega-N-Methylarginine
D000804:Angiotensin II; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine