Characterization of the novel nitric oxide synthase inhibitor 7-nitro indazole and related indazoles: antinociceptive and cardiovascular effects.
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.
Moore
P K
PK
Biomedical Sciences Division, King's College, University of London.
Wallace
P
P
Gaffen
Z
Z
Hart
S L
SL
Babbedge
R C
RC
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005557:Formaldehyde; D066298:In Vitro Techniques; D007191:Indazoles / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019001:Nitric Oxide Synthase; D010147:Pain Measurement / Q000187:drug effects; D011817:Rabbits; D051381:Rats
D000700:Analgesics; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D007191:Indazoles; D005557:Formaldehyde; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; C080122:7-nitroindazole