Spermine dependent activation of the N-methyl- d-aspartate receptor and the effect of nitric oxide synthase inhibition during hypoxia in the cerebral cortex of newborn piglets

• Published in: Brain research Vol. 854; no. 1; pp. 11 - 18
• Main Authors: Zubrow, Alan B, Numagami, Yoshihiro, Fritz, Karen I, Mishra, Om P, Delivoria-Papadopoulos, Maria
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 31.01.2000; Amsterdam Elsevier; New York, NY
• Subjects: Adenosine Triphosphate - metabolism; Animals; Animals, Newborn - physiology; Biochemistry and metabolism; Biological and medical sciences; Central nervous system; Cerebral Cortex - enzymology; Cerebral Cortex - metabolism; Dizocilpine Maleate - metabolism; Enzyme Inhibitors - pharmacology; Excitatory Amino Acid Antagonists - metabolism; Fundamental and applied biological sciences. Psychology; Hypoxia; Hypoxia - enzymology; Hypoxia - metabolism; MK-801 receptor ion-channel complex; Newborn; Nitric oxide synthase; Nitric Oxide Synthase - antagonists & inhibitors; Nitroarginine - pharmacology; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - metabolism; Reference Values; Spermine; Spermine - physiology; Swine; Vertebrates: nervous system and sense organs; Hypoxia; Nitric oxide synthase; Newborn; Spermine; MK-801 receptor ion-channel complex; Oxygen; Cerebral cortex; Enzyme; Central nervous system; Enzyme inhibitor; Environmental factor; Glutamate receptor; Nitric-oxide synthase; Pig; Vertebrata; Mammalia; Newborn animal; Artiodactyla; Oxidoreductases; NMDA receptor; Ungulata; Brain (vertebrata)
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(99)02252-0

This study tests the hypothesis that brain tissue hypoxia results in modification of spermine-dependent activation of the cerebral N-methyl- d-aspartate (NMDA) receptor ion-channel in newborn piglet brains and that pretreatment with N ω-nitro- l-arginine (NNLA), an inhibitor of nitric oxide synthase, will reduce the hypoxia-induced modification of the spermine-dependent activation of the receptor. Piglets were assigned to one of four groups; normoxia or hypoxia with or without NNLA. The infusion of NNLA or vehicle lasted for 60 min while the animals were ventilated under either hypoxic or normoxic conditions. Cerebral tissue hypoxia was confirmed by measuring ATP and phosphocreatine (PCr) levels. P 2 membranes were isolated and 3 H -MK-801 binding was measured in the presence of spermine. Steady state 3 H -MK-801 binding in the presence of spermine, showed an increase in receptor affinity in both normoxic (47% of control) and hypoxic (42% of control) animals without change in receptor density. During hypoxia, the spermine-dependent increase in the maximal response of the 3 H -MK-801 binding correlated inversely with the ATP concentrations. NNLA pretreatment prior to hypoxia, resulted in a decrease in the slope of the regression line describing the relationship between cellular energy state (ATP) and percent change in maximal response to spermine compared with vehicle treated animals indicating attenuation of the response to hypoxia. We conclude that the spermine-dependent modification of the affinity of the NMDA receptor ion-channel as assessed by 3 H -MK-801 binding is similar in hypoxic and normoxic cortical tissue. NNLA administration reduces the hypoxia-induced spermine-dependent activation of the receptor indicating that nitric oxide mediates modification of the spermine site activation of the NMDA receptor ion-channel complex.