Role of pentose phosphate pathway-derived NADPH in hypoxic pulmonary vasoconstriction.
We have previously shown that pentose phosphate pathway (PPP) inhibitors, 6-aminonicotinamide (6-AN) and epiandrosterone (EPI), markedly reduce hypoxic pulmonary vasoconstriction (HPV). Although it has been suggested that changes in the NADPH/NADP+ ratio and redox status are involved in the mechanism of HPV, the role of PPP-derived NADPH in this phenomenon is not known. The aim of this study, therefore, was to investigate the role of PPP-derived NADPH in HPV using isolated rat pulmonary arteries (PA) and perfused rat lungs. The NADPH/NADP+ ratio and NADPH levels in PA and lungs exposed to hypoxia increased 2-fold and 7-fold, respectively, compared to time-matched normoxic controls. Both hypoxia-induced increases in lung NADPH levels and lung perfusion pressure were inhibited by 6-AN (500 microM) or EPI (300 microM). The chemical inhibitors of PPP and hypoxia similarly decreased lung tissue NOx levels by approximately 50%. In contrast, hypoxia increased the lung soluble guanylate cyclase (sGC) activity (from 22.9+/-6.3 to 57.1+/-7.6 pmol/min/g), which was prevented by PPP inhibitors. ODQ, a sGC inhibitor, potentiated HPV. These results suggest that while PPP-derived NADPH may play a significant role in HPV, it may also moderate the magnitude of HPV through activation of the NO-sGC-cGMP vasodilation pathway.
Gupte
Sachin A
SA
Departments of Physiology and Respiratory Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Tokyo 113, Japan. sachin_gupte@yahoo.com
Okada
Takao
T
McMurtry
Ivan F
IF
Oka
Masahiko
M
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D015120:6-Aminonicotinamide / Q000494:pharmacology; D000738:Androsterone / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019298:Glucose-6-Phosphate / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009249:NADP / Q000378:metabolism*; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010427:Pentose Phosphate Pathway / Q000187:drug effects / Q000502:physiology*; D010477:Perfusion; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D010069:Oxadiazoles; D011810:Quinoxalines; D015120:6-Aminonicotinamide; D009249:NADP; D019298:Glucose-6-Phosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000738:Androsterone; D005954:Glucosephosphate Dehydrogenase; D006162:Guanylate Cyclase