INHIBITION OF NITRIC-OXIDE SYNTHASE ACTIVITY IN CEREBRAL CORTICAL SYNAPTOSOMES BY NITRIC-OXIDE DONORS - EVIDENCE FOR FEEDBACK AUTOREGULATION

Despite evidence which supports a neurotransmitter-like role for nitri c oxide (NO) in the CNS, relatively little is known regarding mechanis ms which control NO formation within CNS neurons. In this study, isola ted nerve endings (synaptosomes) from rat cerebral cortex were used to ascertain whether NO can autoregulate its own formation within neuron s through feedback inhibition of the NO biosynthetic enzyme nitric oxi de synthase (NOS). Under the conditions described here, N-omega-nitro- L-arginine methyl ester-sensitive conversion of L-[H-3]arginine into L -[H-3]citrulline (i.e., NOS activity) was found to be highly calcium-d ependent and strongly inhibited (up to 60 percent) by NO donors, inclu ding sodium nitroprusside, hydroxylamine and nitroglycerin. The inhibi tory effect of sodium nitroprusside was concentration-dependent (IC(50 )approximate to 100 mu M) and prevented by the NO scavenger oxyhemoglo bin. L-Citrulline,the other major end-product from NOS, had no apparen t effect on synaptosomal NOS activity. Taken together, these results i ndicate that neuronal NOS can be inhibited by NO released from exogeno us donors and, therefore, may be subject to end-product feedback inhib ition by NO that is formed locally within neurons or released from pro ximal cells.