INACTIVATION OF CEREBELLAR NITRIC-OXIDE SYNTHASE BY ETHANOL IN-VITRO

The N-methyl-D-aspartate receptor/nitric oxide synthase (NOS)/guanylat e cyclase pathway, which plays a crucial role in synaptic plasticity i n the brain, is modulated by ethanol. We studied the effect of ethanol in vitro on NOS in rat cerebellum and showed that ethanol (25-200 mM) inactivated NOS in a dose-dependent manner. This inactivation was pre vented by the biopterin cofactor tetrahydrobiopterin (BH4) as well as by L-arginine, a NOS substrate, but not by NADPH. These results sugges t that ethanol reduces NOS activity by modulating the conformation of the enzyme and thereby its stability, probably by interacting with the binding sites of BH4 and/or of L-arginine. Our data also suggest that inactivation of NOS may contribute to the decrease in the cGMP level, and thus may play a role in the pharmacological actions of ethanol in vivo.