83 IN VIVO EFFECT OF 3-(2-CARBOXYPIPERAZIN-4-YL)PROPYL-l-PHOSPHONIC ACID (CPP), AN ANTAGONIST OF THE NMDA RECEPTOR, ON PORCINE BRAIN CELL MEMBRANE Na⁺,K⁺-ATPase

Abstract

Hypoxia has been reported to decrease Na⁺, K⁺-ATPase activity and modify the NMDA receptor in cell membranes of the cerebral cortex of newborn piglets. CPP, a glutamate antagonist of the NMDA receptor, has been shown to reduce cerebral injury in animal stroke models. The present study tested the hypothesis that in vivo administration of CPP could preserve brain cell membrane Na⁺, K⁺-ATPase acitvity during hypoxia. Studies were performed in 18 anesthetized, ventilated newborn piglets (9 normoxic control--Nx, 4 CPP-treated normoxic--CPP-Nx and 5 CPP-treated hypoxic--CPP-Hx animals). Hypoxia was induced by lowering the FiO₂ to 0.05-0.07 in the CPP-Hx group, and was maintained for one hour. CPP-Hx animals received CPP 30 min prior to the decrease in FiO₂. Both CPP-Nx and CPP-Hx groups received CPP 2 mg/kg IV. Brain cell membrane Na⁺, K⁺-ATPase activity (μmol Pi/mg protein/hr) was decreased in CPP-Hx (37.0±3.6) and CPP-Nx (35.0±1.6) groups compared to the Nx (46.9±4.6) group (P<0.05), indicating that 2 mg/kg CPP did not prevent the decrease of brain cell membrane Na⁺, K⁺-ATPase activity following hypoxia. These results could be due to either a too low dose of CPP, or an overwhelming release of free radicals during one hour of severe hypoxia. Alternatively, given that in vitro CPP does not alter the enzyme activity, the unexpected decrease of Na⁺, K⁺-ATPase activity in the CPP-Nx group might be due to metabolites of CPP. Funded by NIH WD-20337.USA and Ter Meulen Fund, the Netherlands.

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