Pharmacokinetics and pharmacodynamics of 7-nitroindazole, a selective nitric oxide synthase inhibitor, in the rat hippocampus

Purpose. This study was conducted to assess the pharmacokinetics and pharma co dynamics of 7-nitroindazole (7-NI), a selective inhibitor of neuronal ni tric oxide synthase (NOS). Methods. Male Sprague-Dawley rats were equipped with peritoneal/venous cann ulae and a microdialysis probe in the hippocampal cortex. Rats received 7-N I in peanut oil (25 mg/kg) ip every 2 h for 14 h or peanut oil alone. Blood samples were obtained at timed intervals for serum 7-NI; brain tissue micr odialysate for determination of extracellular 7-NI and NO was obtained ever y 20 min. A pharmacokinetic-pharmacodynamic model was constructed to evalua te the effects of 7-NI on NOS activity. Results. Consistent with previous reports, NOS activity in controls evidenc ed circadian variation. These cyclic changes in NO production were incorpor ated into the model of 7-NI effects on NOS. 7-NI produced a rapid (within 2 h) decrease in hippocampal NO. Under the conditions of this experiment, 7- NI produced an similar to 50% decrease in hippocampal NO, which was sustain ed during 7-NI administration. The decrease in NOS activity by 7-NI was con centration-dependent with an apparent IC50 of similar to 17 mug/ml. Conclusions. Multiple ip injections of 7-NI result in a predictable, sustai ned decrease in NO production in the hippocampus. The pharmacokinetic-pharm acodynamic model developed allows design of dosing regimens that can produc e designated changes in brain NO content, facilitating use of 7-NI to probe the pharmacological implications of NO in the central nervous system.