Characterization of the Novel Nitric Oxide Synthase Inhibitor 7-nitro Indazole and Related Indazoles: Antinociceptive and Cardiovascular Effects

Br J Pharmacol. 1993 Sep;110(1):219-24. doi: 10.1111/j.1476-5381.1993.tb13795.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Oxidoreductases / antagonists & inhibitors*
  • Analgesics / pharmacology*
  • Animals
  • Arginine / pharmacology
  • Blood Pressure / drug effects
  • Cardiovascular Agents / pharmacology*
  • Cerebellum / drug effects
  • Cerebellum / enzymology
  • Enzyme Inhibitors / pharmacology*
  • Formaldehyde
  • In Vitro Techniques
  • Indazoles / antagonists & inhibitors
  • Indazoles / pharmacokinetics
  • Indazoles / pharmacology*
  • Male
  • Mice
  • Muscle Contraction / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Nitric Oxide Synthase
  • Pain Measurement / drug effects
  • Rabbits
  • Rats

Substances

  • Analgesics
  • Cardiovascular Agents
  • Enzyme Inhibitors
  • Indazoles
  • Formaldehyde
  • Arginine
  • Nitric Oxide Synthase
  • Amino Acid Oxidoreductases
  • 7-nitroindazole