Prolonged inhibition of brain nitric oxide synthase by short-term systemic administration of nitro-l-arginine methyl ester

• DOI: 10.1007/bf00967330
• Publication Date: 2005-01-12T06:11:48Z
• Authors: Costantino Iadecola; Xiaohong Xu; Fangyi Zhang; Jingru Hu; Esam E. El-Fakahany
• Keywords: Male; 0301 basic medicine; Time Factors; Dose-Response Relationship, Drug; Brain; Arginine; Rats; Rats, Sprague-Dawley; Kinetics; 03 medical and health sciences; Cytosol; NG-Nitroarginine Methyl Ester; Prosencephalon; Injections, Intravenous; Animals; Citrulline; Amino Acid Oxidoreductases; Nitric Oxide Synthase

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 venous 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 catalytic activity was assayed in forebrain cytosol as the conversion of [3H]L-arginine into [3H]L-citrulline. L-NAME attenuated brain NOS activity in a dose-dependent manner but enzyme activity could not be inhibited by more than approximately 50%. After a single 20 mg/kg injection 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 magnitude. 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 catalytic activity. The finding that the inhibition persists for several days after a single administration is consistent with the hypothesis that nitro-L-arginine, the active principle of L-NAME, binds to NOS irreversibly.