Antagonism of ketamine-induced anesthesia by an inhibitor of nitric oxide synthesis: A pharmacokinetic explanation

Because ketamine is an antagonist of NMDA receptors, and because some NMDA receptors activate nitric oxide synthesis in brain, this study examined if nitric oxide synthase (NOS) inhibition by L-NAME altered the course of ketamine-induced behavioral impairment. Rats given progressive doses of L-NAME until NOS activity was inhibited at least 90% displayed reduced depth and duration of behavioral depression after IM ketamine. Blood and brain concentrations of ketamine, norketamine, and its dehydrogenated derivative were isolated from rats previously given saline or L-NAME as above, by ether extraction, HPLC separation, and ultraviolet quantitation. The same doses of L-NAME that altered ketamine behavior reduced blood and brain ketamine concentrations 15 min after administration to about three-fourths and one-third of control, respectively. The content of norketamine and its adventitial extraction product were similarly reduced relative to control but the ratio of metabolites to ketamine was not significantly altered (p > 0.05) in brain. The decreased delivery of ketamine into brain, perhaps due to L-NAME-induced alterations in blood now, may explain the reduced behavioral response to ketamine in these rats. (C) 1998 Elsevier Science Inc.