Pharmacokinetics and pharmacodynamics of 7-nitroindazole, a selective nitric oxide synthase inhibitor, in the rat hippocampus.
Pharm Res
; 18(11): 1607-12, 2001 Nov.
Article
em En
| MEDLINE
| ID: mdl-11758770
ABSTRACT
PURPOSE:
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.
Buscar no Google
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Óxido Nítrico Sintase
/
Inibidores Enzimáticos
/
Hipocampo
/
Indazóis
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Pharm Res
Ano de publicação:
2001
Tipo de documento:
Article