Document Detail


Characterization of the novel nitric oxide synthase inhibitor 7-nitro indazole and related indazoles: antinociceptive and cardiovascular effects.
MedLine Citation:
PMID:  7693278     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
1. 7-Nitro indazole (7-NI, 10-50 mg kg-1), 6-nitro indazole and indazole (25-100 mg kg-1) administered i.p. in the mouse produce dose-related antinociception in the late phase of the formalin-induced hindpaw licking and acetic acid-induced abdominal constriction assays. The ED50 values (mg kg-1) were as follows: 7-NI (27.5 and 22.5), 6-nitro indazole (62.5 and 44.0) and indazole (41.0 and 48.5) in the two assays respectively. 3-Indazolinone, 6 amino indazole and 6-sulphanilimido indazole (all 50 mg kg-1) were without effect. With the exception of 5-nitro indazole (50 mg kg-1) which produced sedation, none of the other indazole derivates examined caused overt behavioural changes. 2. The antinociceptive effect of 7-NI (25 mg kg-1, i.p.) in the late phase of the formalin-induced hindpaw licking assay was partially (46.7 +/- 16.2%, n = 18) reversed by pretreatment with L- but not D-arginine (both 50 mg kg-1, i.p.). 3. The time course of 7-NI induced antinociception in the mouse was correlated with inhibition of brain (cerebellum) nitric oxide synthase (NOS) activity. Maximum antinociceptive activity and NOS inhibition was detected 18-30 min following i.p. administration. In contrast, no antinociceptive effect or inhibition of cerebellar NOS was detected 75 min post-injection. 4. 7-NI, 6-nitro indazole, indazole, 3-indazolinone and 6-amino indazole (all 50 mg kg-1) failed to influence mean arterial pressure (MAP) over the 45 min after i.p. administration in the anaesthetized mouse. Similarly, 7-NI (25 mg kg-1) administered i.v. in the anaesthetized rat did not increase MAP or influence the vasodepressor effect of i.v. injected acetylcholine (ACh) over the same period.5. 7-NI (100 microM) did not influence the vasorelaxant effect of ACh (IC50, 0.2 +/- 0.04 microM, cf. 0.16+/-0.06 microM, n = 6) in phenylephrine-precontracted rabbit aortic rings.6. These data provide further evidence that antinociception following administration of 7-NI in the mouse results from inhibition of central NOS activity and is not associated with inhibition of in vivo vascular endothelial cells NOS. Accordingly, 7-NI (or a derivative thereof) may provide an alternative approach to the development of novel antinociceptive drugs.
Authors:
P K Moore; P Wallace; Z Gaffen; S L Hart; R C Babbedge
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  110     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  1993 Sep 
Date Detail:
Created Date:  1993-12-14     Completed Date:  1993-12-14     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  219-24     Citation Subset:  IM    
Affiliation:
Biomedical Sciences Division, King's College, University of London.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Oxidoreductases / antagonists & inhibitors*
Analgesics / pharmacology*
Animals
Arginine / pharmacology
Blood Pressure / drug effects
Cardiovascular Agents / pharmacology*
Cerebellum / drug effects,  enzymology
Enzyme Inhibitors / pharmacology*
Formaldehyde
Indazoles / antagonists & inhibitors,  pharmacokinetics,  pharmacology*
Male
Mice
Muscle Contraction / drug effects
Muscle, Smooth, Vascular / drug effects
Nitric Oxide Synthase
Pain Measurement / drug effects
Rabbits
Rats
Chemical
Reg. No./Substance:
0/Analgesics; 0/Cardiovascular Agents; 0/Enzyme Inhibitors; 0/Indazoles; 2942-42-9/7-nitroindazole; 50-00-0/Formaldehyde; 74-79-3/Arginine; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.4.-/Amino Acid Oxidoreductases
Comments/Corrections

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