Nitro-L-arginine analogues. Dose- and time-related nitric oxide synthase inhibition in brain

Stroke; a Journal of Cerebral Circulation
R J TraystmanP D Hurn

Abstract

The purpose of the present study was to measure cortical nitric oxide synthase (NOS) activity and determine the appropriate doses of N omega-nitro-L-arginine methyl ester (L-NAME) 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- and time-dependent and questioned if the dose-response relationship was related to the specific drug or animal species. Saline or L-NAME or L-NNA in escalating doses was administered to pentobarbital-anesthetized pigs, dogs, and cats. Brain temperature and arterial blood gas, hemoglobin, and blood pressure levels were maintained within the physiological range. Cortical tissue was biopsied at baseline and 30, 120, and 360 minutes after agent administration for measurement of NOS activity by isotopic assay of the conversion of [14C]arginine to [14C]citrulline. L-NAME produced > 70% enzyme inhibition at a dose of 20 mg/kg across the species tested. Arterial blood pressure was elevated at 30 minutes after L-NAME treatment. However, consistent decreases in brain NOS activity required a longer period of time. Near-complete inhibition was apparent in most animals by 120 minutes and persisted for 6 hours after administr...Continue Reading

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