PROLONGED INHIBITION OF BRAIN NITRIC-OXIDE SYNTHASE BY SHORT-TERM SYSTEMIC ADMINISTRATION OF NITRO-L-ARGININE METHYL-ESTER

We studied the dose-response characteristics and the temporal profile of inhibition of brain nitric oxide (NO) synthase (NOS) elicited by i. v. administration of the NOS inhibitor nitro-L-arginine methyl ester ( L-NAME). L-NAME was administered i.v. in awake rats equipped with a ve nous cannula. L-NAME was injected in cumulative doses of 5, 10, 20 and 40 mg/kg and rats were sacrificed 30 min after the last dose. NOS cat alytic activity was assayed in forebrain cytosol as the conversion of [H-3]L-arginine into [H-3]L-citrulline. L-NAME attenuated brain NOS ac tivity in a dose-dependent manner but enzyme activity could not be inh ibited by more than approximate to 50%. After a single 20 mg/kg inject ion of L-NAME the inhibition of brain NOS activity was time dependent and reached a stable level at 2 hrs (52% of vehicle). Inhibition after a single injection was still present at 96 hrs, albeit to a lower mag nitude. We conclude that intravenous administration of L-NAME in rats at concentrations commonly used in physiological experiments leads to a dose and time-dependent but partial inhibition of brain NOS catalyti c activity. The finding that the inhibition persists for several days after a single administration is consistent with the hypothesis that n itro-L-arginine, the active principle of L-NAME, binds to NOS irrevers ibly.