Lipid free radical generation and brain cell membrane alteration following nitric oxide synthase inhibition during cerebral hypoxia in the newborn piglet.
Nitric oxide (NO) is reported to cause neuronal damage through various mechanisms. The present study tests the hypothesis that NO synthase inhibition by N(omega)-nitro-L-arginine (NNLA) will result in decreased oxygen-derived free radical production leading to the preservation of cell membrane structure and function during cerebral hypoxia. Ten newborn piglets were pretreated with NNLA (40 mg/kg); five were subjected to hypoxia, whereas the other five were maintained with normoxia. An additional 10 piglets without NNLA treatment underwent the same conditions. Hypoxia was induced with a lowered FiO2 and documented biochemically by decreased cerebral ATP and phosphocreatine levels. Free radicals were detected by using electron spin resonance spectroscopy with a spin trapping technique. Results demonstrated that free radicals, corresponding to alkoxyl radicals, were induced by hypoxia but were inhibited by pretreatment with NNLA before inducing hypoxia. NNLA also inhibited hypoxia-induced generation of conjugated dienes, products of lipid peroxidation. Na+,K+-ATPase activity, an index of cellular membrane function, decreased following hypoxia but was preserved by pretreatment with NNLA. These data demonstrate that during hypoxia NO generates free radicals via peroxynitrite production, presumably causing lipid peroxidation and membrane dysfunction. These results suggest that NO is a potentially limiting factor in the peroxynitrite-mediated lipid peroxidation resulting in membrane injury.
Numagami
Y
Y
Department of Physiology, University of Pennsylvania, Philadelphia, U.S.A.
Zubrow
A B
AB
Mishra
O P
OP
Delivoria-Papadopoulos
M
M
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D001927:Brain Diseases / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000648:ultrastructure; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D008055:Lipids / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology; D010710:Phosphates / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013552:Swine
D004791:Enzyme Inhibitors; D005609:Free Radicals; D008055:Lipids; D010710:Phosphates; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D000254:Sodium-Potassium-Exchanging ATPase