Role of pentose phosphate pathway-derived NADPH in hypoxic pulmonary vasoconstriction

• Published in: Pulmonary pharmacology & therapeutics Vol. 19; no. 4; pp. 303 - 309
• Main Authors: Gupte, Sachin A., Okada, Takao, McMurtry, Ivan F., Oka, Masahiko
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2006
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; 6-Aminonicotinamide; 6-Aminonicotinamide - pharmacology; Androsterone - pharmacology; Animals; Enzyme Inhibitors - pharmacology; Epiandrosterone; Glucose-6-Phosphate - metabolism; Glucosephosphate Dehydrogenase - antagonists & inhibitors; Guanylate Cyclase; Guanylate Cyclase - antagonists & inhibitors; Guanylate Cyclase - metabolism; Hypoxia - metabolism; Hypoxia - physiopathology; In Vitro Techniques; Lung - blood supply; Lung - drug effects; Lung - metabolism; Male; NADP - metabolism; Nitrates - metabolism; Nitric Oxide; Nitrites - metabolism; Oxadiazoles - pharmacology; Pentose Phosphate Pathway - drug effects; Pentose Phosphate Pathway - physiology; Perfusion; Pulmonary Artery - drug effects; Pulmonary Artery - metabolism; Pulmonary Artery - physiopathology; Quinoxalines - pharmacology; Rats; Rats, Sprague-Dawley; Vascular Resistance - drug effects; Vasoconstriction - drug effects; Vasoconstriction - physiology; 6-Aminonicotinamide; Nitric Oxide; Guanylate Cyclase; Epiandrosterone
• ISSN: 1094-5539; 1522-9629
• DOI: 10.1016/j.pupt.2005.08.002

We have previously shown that pentose phosphate pathway (PPP) inhibitors, 6-aminonicotimade (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 μM) or EPI (300 μM). 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.