NITRO-L-ARGININE ANALOGS - DOSE-RELATED AND TIME-RELATED NITRIC-OXIDESYNTHASE INHIBITION IN BRAIN

Background and Purpose The purpose of the present study was to measure cortical nitric oxide synthase (NOS) activity and determine the appro priate doses of N-omega-nitro-L-arginine methyl ester (L-NAIL IE) or N -omega-nitro-L-arginine (L-NNA) for near-complete enzyme inhibition in dogs, cats, and pigs. We anticipated that NOS inhibition was dose- an d time-dependent and questioned if the dose-response relationship was related to the specific drug or animal species. Methods Saline or L-NA ME or L-NNA in escalating doses was administered to pentobarbital-anes thetized pigs, dogs, and cats. Brain temperature and arterial blood ga s, hemoglobin, and blood pressure levels were maintained within the ph ysiological range. Cortical tissue was biopsied at baseline and 30, 12 0, and 360 minutes after agent administration for measurement of NOS a ctivity by isotopic assay of the conversion of [C-14]arginine to [C-14 ]citrulline. Results L-NAME produced >70% enzyme inhibition at a dose of 20 mg/kg across the species tested. Arterial blood pressure was ele vated at 30 minutes after L-NAME treatment. However, consistent decrea ses in brain NOS activity required a longer period of rime. Near-compl ete inhibition was apparent in most animals by 120 minutes ana persist ed for 6 hours after administration. A smaller dose of L-NNA was requi red for >70% enzyme inhibition in the cats and dogs (10 mg/kg). Near-c omplete NOS inhibition was evident in most animals at 30 minutes after L-NNA administration, which also persisted for 6 hours. In pigs, this same level of inhibition required 20 mg/kg. Conclusions These results suggest that administration of L-NAME and L-NNA diminishes brain NOS activity in a dose- and time-dependent manner and that the duration of effect is at least 6 hours.