NF-KAPPA-B INDUCTION DURING IN-VIVO HYPOXIA IN DORSOCAUDAL BRAIN-STEMOF RAT - EFFECT OF MK-801 AND L-NAME

In the nucleus of the solitary tract, NMDA receptors are critical for the hypoxic ventilatory response while neuronal nitric oxide synthase (NOS) modulates the late component of this response. Nuclear factor (N F)-kappa B is a ubiquitous transcription factor that increases the exp ression of multiple stress-activated genes. We sought to examine tempo ral changes in expression of NF-kappa B within the dorsocaudal brain s tem of conscious rats after exposures to 10% O-2. Time-dependent incre ases in NF-kappa B occurred with hypoxia and peaked at 60 min. Pretrea tment with the N-methyl-D-aspartate (NMDA)-receptor channel antagonist dizocilpine maleate (MK-801) markedly attenuated NF-kappa B complexes during hypoxia. In contrast, after NOS inhibition with N-G-nitro-L-ar ginine methyl ester (L-NAME), although NF-kappa B was diminished in no rmoxia, increased NF-kappa B expression still occurred with hypoxia. I ncreased phosphorylation of the NF-kappa B regulatory unit [inhibitory (I)kappa B] was detected by immunoblotting and also peaked at 60 min. Phosphorylation of I kappa-B during hypoxia was attenuated by MK-801 but not by L-NAME. Thus NMDA-receptor activation in the dorsocaudal br ain stem during hypoxia elicits in NF-kappa B activity marked enhancem ents that are unaffected after NOS blockade.