51 EFFECT OF NORDIHYDROGUAIARETIC ACID(NDGA) ON CEREBRAL RESPONSE TO HYPOXIA IN NEWBORN PIGLETS

Abstract

Cerebral hypoxia reduces brain cell membrane Na+, K+-ATPase activity (ATPase) and increases membrane lipid peroxidation (conjugated dienes, CD, and fluorescent compounds, FC). To test the hypothesis that NDGA, an inhibitor of Lipoxygenase, modifies hypoxia-induced membrane changes, we measured ATPase, CD, and FC in 8 ventilated newborn piglets. Five received 3 mg/kg NDGA IV 15 min before reducing FiO2 (HX). Cerebral hypoxia was confirmed with 31P-NMR spectroscopy as a decrease in PCr/Pi and maintained for 45 min. Three piglets were kept normoxic for 45 min after NDGA (NX). Direct effects were assessed in vitro by exposing normoxic brain cell membranes to 0.1 mM NDGA. ATPase (μmole Pi/mg protein/hr) in vivo was 44.1 ±7, 39-9±4.9, and 45.5±5 in HX, NX, and untreated controls (C), respectively (p=NS). FC (μg quinine sulfate/g brain) increased to 0-26±0.05 in HX (p<0.05 vs C of 0.18) but were not elevated in NX. CD were not significantly higher than C in HX or NX. In vitro, NDGA reduced ATPase 95% vs activity before exposure. Thus in vivo, NDGA reduces hypoxia-induced brain cell membrane changes. However, our in vitro data, as well as reports by others that NDGA reduces cellular O2 consumption (VO2), suggest that NDGA has a direct action on cellular metabolism. Therefore the mechanism of its effect during hypoxia may be reduction of Na+, K+-ATPase activity and total cell metabolism rather than inhibition of lipoxygenase. By decreasing cellular ATP utilization and VO2, NDGA would eluninate the mismatch between O2 supply and demand during hypoxia, preserving membrane function.