Pharmacokinetics and pharmacodynamics of 7-nitroindazole, a selective nitric oxide synthase inhibitor, in the rat hippocampus.
OBJECTIVE
This study was conducted to assess the pharmacokinetics and pharmacodynamics of 7-nitroindazole (7-NI), a selective inhibitor of neuronal nitric oxide synthase (NOS).


METHODS
Male Sprague-Dawley rats were equipped with peritoneal/ venous cannulae and a microdialysis probe in the hippocampal cortex. Rats received 7-NI 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 microdialysate for determination of extracellular 7-NI and NO was obtained every 20 min. A pharmacokinetic-pharmacodynamic model was constructed to evaluate the effects of 7-NI on NOS activity.


RESULTS
Consistent with previous reports. NOS activity in controls evidenced circadian variation. These cyclic changes in NO production were incorporated 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 approximately 50% decrease in hippocampal NO, which was sustained during 7-NI administration. The decrease in NOS activity by 7-NI was concentration-dependent with an apparent IC50 of approximately 17 microg/ml.


CONCLUSIONS
Multiple ip injections of 7-NI result in a predictable, sustained decrease in NO production in the hippocampus. The pharmacokinetic-pharmacodynamic model developed allows design of dosing regimens that can produce designated changes in brain NO content, facilitating use of 7-NI to probe the pharmacological implications of NO in the central nervous system.
Bush
M A
MA
Division of Drug Delivery and Disposition, School of Pharmacy, The University of North Carolina at Chapel Hill, 27599-7360, USA.
Pollack
G M
GM
D000465:Algorithms; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D007191:Indazoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D007191:Indazoles; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; C080122:7-nitroindazole