Nitric oxide synthase inhibitors 7- and 6-nitroindazole relax smooth muscle in vitro

doi:10.1016/0014-2999(94)90626-2

European Journal of Pharmacology

Volume 256, Issue 1, 11 April 1994, Pages R5-R6

https://doi.org/10.1016/0014-2999(94)90626-2 Get rights and content

Abstract

7-Nitroindazole induced concentration-dependent relaxation of precontracted rabbit aorta, dog middle cerebral artery, rat anococcygeus muscle and rat stomach fundus. Relaxations to 7-nitroindazole in rabbit aorta were unaffected by nitric oxide synthase blockade or endothelial removal. 6-Nitroindazole also caused concentration-dependent relaxation in dog middle cerebral artery and rabbit aorta, being equipotent with 7-nitroindazole in both tissues. These data suggest that indazole derivatives can induce an endothelium- and nitric oxide synthase-independent relaxation of smooth muscle in vitro.

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Cited by (32)

Interaction of leptin and nitric oxide pathway on penicillin-induced epileptiform activity in rats
2010, Brain Research
Citation Excerpt :
Therefore the findings of the present study may imply that the neuronal NOS but not endothelial NOS participates in the proconvulsant activity of leptin. If this is not the case, these different effects might be attributed to other pharmacological actions of 7-NI including NO-independent vascular actions (Medhurst et al., 1994; Wolff et al., 1994; Southan and Szabo, 1996). Unquestionably, NO cannot be considered the only mediator of these effects, because there is evidence for existence of a number of neuron excitability modulating systems in epilepsy.
The aim of the present study was to investigate the role of NO as a mediator of leptin action at the penicillin-induced epileptiform activity in rat. Thirty minutes after penicillin injection, leptin, at a dose of 1 µg, significantly increased the mean frequency of epileptiform activity without changing the amplitude. The effects of systemic administration of nitric oxide synthase (NOS) inhibitors, non-selective NG-nitro-l-arginine methyl ester (L-NAME), selective neuronal NOS inhibitor, 7-nitroindazole (7-NI) and NO precursor, l-arginine on the effects of leptin were investigated. The occurrence of anticonvulsant activity of 7-NI (40 mg/kg, i.p.) was significantly delayed in the presence of leptin (1 µg). The administration of L-NAME (60 mg/kg, i.p.), 30 min before leptin (1 µg) application, did not influence proconvulsant activity of leptin. The administration of l-arginine (1000 mg/kg, i.p.) 30 min before the effective dose of leptin (1 µg, i.c.v.) reversed the proconvulsant effects of leptin whereas the same dose of its inactive enantiomer, d-arginine (1000 mg/kg, i.p.) failed to influence the proconvulsant effect of leptin. The electrophysiological evidence of the present study suggests that neuronal NOS/NO pathway is involved in mediating leptin effects on penicillin-induced epileptiform activity.
Fluorinated indazoles as novel selective inhibitors of nitric oxide synthase (NOS): Synthesis and biological evaluation
2009, Bioorganic and Medicinal Chemistry
In order to find new compounds with neuroprotective activity and NOS-I/NOS-II selectivity, we have designed, synthesized, and characterized 14 new NOS inhibitors with an indazole structure. The first group corresponds to 4,5,6,7-tetrahydroindazoles (4–8), the second to the N-methyl derivatives (9–12) of 7-nitro-1H-indazole (1) and 3-bromo-7-nitro-1H-indazole (2), and the latter to 4,5,6,7-tetrafluoroindazoles (13–17). Compound 13 (4,5,6,7-tetrafluoro-3-methyl-1H-indazole) inhibited NOS-I by 63% and NOS-II by 83%. Interestingly, compound 16 (4,5,6,7-tetrafluoro-3-perfluorophenyl-1H-indazole) inhibited NOS-II activity by 80%, but it did not affect to NOS-I activity. Structural comparison between these new indazoles further supports the importance of the aromatic indazole skeleton for NOS inhibition and indicate that bulky groups or N-methylation of 1 and 2 diminish their effect on NOS activity. The fluorination of the aromatic ring increased the inhibitory potency and NOS-II selectivity, suggesting that this is a promising strategy for NOS selective inhibitors.
Antidepressant- and anxiolytic-like effects of selective neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole in mice
2003, Behavioural Brain Research
Various inhibitors of nitric oxide synthase (NOS) have been shown to possess antidepressant- and anxiolytic-like properties in animal models. The aim of this study was to compare the behavioural effects of NOS inhibitor 7-nitroindazole (7-NI) with the more selective neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)imidazole (TRIM) in animal models predictive of antidepressant- and anxiolytic-like activity in order to clarify the role of distinct isoforms of NOS in the regulation of depression and anxiety. Both TRIM (50 mg/kg) and 7-NI (50 mg/kg) decreased the immobility time in the forced swimming test. The magnitude of the effect was comparable to that of the tricyclic antidepressant imipramine (15 mg/kg). The antidepressant-like effect of TRIM was counteracted by pretreatment with l-arginine (250 mg/kg). The systemic administration of TRIM (50 mg/kg), but not 7-NI (up to 50 mg/kg) increased the time spent in the light side of the apparatus in the light–dark compartment test. The anxiolytic-like effect of TRIM was antagonised by pretreatment with l-arginine. Both TRIM and 7-NI decreased the locomotion of animals in the open field and caused motor incoordination on rotarod. These motor side effects were more pronounced in the case of 7-NI and were not diminished by pretreatment with l-arginine. We conclude that neuronal NOS seems to play the key role in the antidepressant- and anxiolytic-like effects of NOS inhibitors.
Evidence for a K<inf>ATP</inf> ion channel link in the inhibition of hypercapnic dilation of pial arterioles by 7-nitroindazole and tetrodotoxin
2001, European Journal of Pharmacology
7-Nitroindazole, an inhibitor of neuronal nitric oxide synthase, reportedly inhibits hypercapnic dilation, but tetrodotoxin, an inhibitor of neuronal transmission, reportedly does not. Thus, evidence does not uniformly support the hypothesis of a neurogenic link to the hypercapnic response. Others suggest the hypercapnic response is mediated by a K_ATP ion channel. In the following studies, we observed that topically administered tetrodotoxin inhibited dilations produced by hypercapnia. In addition, topical tetrodotoxin and either topical or intraperitoneal 7-nitroindazole, inhibited dilations produced by the K_ATP channel openers, cromakalim and pinacidil. Inhibition of hypercapnic dilation and inhibition of dilation by the openers of the K_ATP channel was immediately reversed by either l-lysine or l-arginine, amino acids previously shown to facilitate opening of the channel. The data strongly supports the previous conclusion that there is a K_ATP ion channel link in the response of pial arterioles to hypercapnia. The location of the channel is not established by these data, nor is it known whether the action of tetrodotoxin on the channel was direct or indirect.
The significance of nitric oxide for parasympathetic vasodilation in the eye and other orbital tissues in the cat
2000, Experimental Eye Research
The role of nitric oxide formation in the vasodilation in the eye and other orbital tissues caused by pre-ganglionic stimulation of the facial nerve was studied in cats under α-chloralose anaesthesia. Regional blood flows were determined with radioactive microspheres during unilateral stimulation of the facial nerve before and after inhibition of nitric oxide synthase (NOS), alone or in combination with muscarinic blockade.
N^ω-nitro-L-arginine (L-NA), a non-selective NOS-inhibitor, caused a significant increase in mean arterial blood pressure (MABP) and a decrease in cardiac output (CO). Concomitantly, local blood flows on the non-stimulated control side were reduced in most of the investigated tissues, indicating marked vasoconstriction. An inhibitor selective for neuronal NOS, 7-nitro-indazole (7-NI), had no significant effect on MABP, CO or local blood flows. During facial nerve stimulation at 5 Hz (n =6), choroidal blood flow on the stimulated side was 108±41% (P⩽0.05) higher than on the non-stimulated side during control conditions, an effect that was completely abolished by L-NA. During stimulation at 10 Hz (n =8), the choroidal blood flow was 171±38% (P⩽0.01) higher on the stimulated side during control conditions. The corresponding values after L-NA and subsequent administration of atropine were 97±21% (P⩽0.05, compared to control conditions) and 50±14% (P⩽0.05, compared to control conditions), respectively. Atropine alone had no significant effect on the increase in choroidal blood flow caused by stimulation at 10 Hz (n =7), whereas subsequent administration of L-NA caused a statistically significant reduction. Administration of 7-NI had no significant effect on the choroidal vasodilation at 10 Hz (n =7), whereas subsequent administration of L-NA caused significant reduction, at least as compared to control conditions.
These results suggest that nitric oxide is of greater significance for the choroidal vasodilation, caused by facial nerve stimulation, in the cat than it is in the rabbit. However, no definitive conclusions can be made concerning the source of the nitric oxide. Direct release of nitric oxide from the parasympathetic nerve fibres could contribute as well as nitric oxide formed in the vascular endothelium, secondary to the release of acetylcholine and/or VIP. At high frequencies, a part of the choroidal vasodilation seems to be independent of nitric oxide.
Further studies on anti- and proconvulsant effects of inhibitors of nitric oxide synthase in rodents
1998, European Journal of Pharmacology
We confirmed that the effects of inhibitors of nitric oxide (NO) synthase, such as N^ω-nitro-l-arginine methyl ester and N^G-nitro-l-arginine, differ depending on several experimental factors. Both compounds but not their less active enantiomers delayed picrotoxin-induced clonus in mice yet increased the incidence of clonus following low-dose picrotoxin. N^ω-nitro-l-arginine methyl ester significantly reduced the latencies of both myoclonus and clonus in older but not younger Sprague–Dawley rats receiving pentylenetetrazol s.c. By contrast, there was no significant change in the latencies for myoclonus and clonus in Wistar rats (older and younger). However, when pentylenetetrazol was administered i.p. rather than s.c., N^ω-nitro-l-arginine methyl ester dramatically increased latencies of convulsive indicators, including tonus, in both Sprague–Dawley and Wistar rats. N^ω-nitro-l-arginine methyl ester also delayed tonus but not myoclonus or clonus in mice, regardless of the systemic route of administration of pentylenetetrazol. Both N^ω-nitro-l-arginine methyl ester and N^G-nitro-l-arginine increased the tonic CD₅₀ of pentylenetetrazol in mice and N^ω-nitro-l-arginine methyl ester delayed 4-aminopyridine-induced tonus. However, N^ω-nitro-l-arginine methyl ester reduced the tonic CD₅₀ of both picrotoxin and 4-aminopyridine in mice and failed to suppress tonus following maximal electroshock. Evidently, inhibitors of NO synthase are not universally effective antitonic drugs.

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Rapid communicationNitric oxide synthase inhibitors 7- and 6-nitroindazole relax smooth muscle in vitro

Abstract

Inhibition of rat cerebellar nitric oxide synthase by 7-nitroindazole and related substituted indazoles

Br. J. Pharmacol.

Effects of 6-hydroxydopamine on pre- and post-junctional 5-HT1-like receptor-mediated responses in dog saphenous vein

Naunyn-Schmied. Arch. Pharmacol.

Rapid communication
Nitric oxide synthase inhibitors 7- and 6-nitroindazole relax smooth muscle in vitro

Effects of 6-hydroxydopamine on pre- and post-junctional 5-HT₁-like receptor-mediated responses in dog saphenous vein