7‐Nitro indazole, an inhibitor of nitric oxide synthase, exhibits anti‐nociceptive activity in the mouse without increasing blood pressure

Moore, Peter K.; Babbedge, R.C.; Wallace, P; Gaffen, Z.; Hart, Stephen L.

doi:10.1111/j.1476-5381.1993.tb12798.x

Cited by 398 publications

(170 citation statements)

References 6 publications

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“…Consistent with the findings of Moore et al (1993), we did not observe any increase in MABP following 7-NI. Moreover, 7-NI did not affect the CBF response to OXO, a muscarinic agonist that, like acetylcholine, dilates cerebral vessels through eNOS (Pelligrino et aI., 1992).…”

Section: Discussionsupporting

confidence: 92%

The Role of Neuronal Nitric Oxide Synthase in Regulation of Cerebral Blood Flow in Normocapnia and Hypercapnia in Rats

Wang

Pelligrino

Baughman

et al. 1995

J Cereb Blood Flow Metab

157

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Summary:The nitric oxide synthase (NOS) inhibitors, ni tro-L-arginine, its methyl ester, and N-monomethyl-L arginine, have been shown to attenuate resting CBP and hypercapnia-induced cerebrovasodilation. Those agents nonspecific ally inhibit the endothelial and neuronal NOS (eNOS and nNOS). In the present study, we used a novel nNOS inhibitor, 7-nitroindazole (7-NI) to examine the role of nNOS in CBP during normocapnia and hypercap nia in fentanyUN20-anesthetized rats. CBP was moni tored using laser-Doppler flowmetry. Administration of 7-NI (80 mg kg-I i.p.) reduced cortical brain NOS activ ity by 57%, the resting CBP by 19-27%, and the CBP response to hypercapnia by 60%. The 60% reduction was similar in magnitude to the CBP reductions observed in previous studies in which nonspecific NOS inhibitors Nitric oxide (NO) has emerged as an important endogenous modulator of brain function, and has been shown to play a role in the cerebral vasodila tory responses (CVDRs) to a wide variety of stim uli, including, muscarinic agonists, neuronal activa tion, volatile anesthetics, hypoxia, and hypercapnia (Iadecola et aI., 1994). NO is produced by the action of NO synthase (NOS) (Luscher and Vanhoutte, 1990). In the brain, NOS is not only located in the Received June 2, 1994; final revision received December 16, 1994; accepted December 20, 1994. Address correspondence and reprint requests to Dr. Q. Wang at Department of Anesthesiology, Michael Reese Hospital, 2929 S. Ellis Ave., Chicago, IL 60616, U. S.A.Abbreviations used: AMB, atropine methyl bromide; CVDRs, cerebral vasodilatory responses; EDT A, ethylenediamine tetraacetic acid; HEPES, N-2-hydroxyethylpiperazine-N' -2-ethanesulfonic acid; L-NA, nitro-L-arginine; L-NAME, methyl ester of L-NA; L-NMMA, N-monomethyl-L-arginine; 7-NI, 7-nitroindazole; NO, nitric oxide; NOS, NO synthase; eNOS, constitutive NOS; eNOS, endothelial NOS; iNOS, inducible NOS; nNOS, neuronal NOS; OXO, oxotremorine. 774were used. In the pre�ent study, 7-NI did not increase the MABP. ,Furthermore, the CBP response to oxotremo rine, a blood-brain barrier permeant muscarinic agonist that induces cerebrovasodilation via endothelium-derived NO, was unaffected by 7-NI. These results confirmed that 7-NI does not influence eNOS; they also indicated that the effects of 7-NI on the resting CBP and on the CBP response to hypercapnia in this study were solely related to its inhibitory action on nNOS. The results fur ther suggest that the NO synthesized by the action of nNOS participates in regulation of basal CBP and is the major, if not the only, category of NO contributing to the hypercapnic CBP response. Key Words: Hypercapnia-7 -NI-N itric oxide-eN OS-nN OS-Oxotremorine.endothelium, but also in neurons, perivascular nerves, and astrocytes (Bredt et aI., 1990; Murphy et aI., 1993). There are at least two constitutive NOS (cNOS) isoforms in the brain (i.e., the endo thelial [eNOS] and neuronal [nNOS] forms) that generate NO phasically (Moncada et aI., 1991). Ow ing to the rapidity of the CVDRs to the abo...

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Section: Discussionsupporting

confidence: 92%

The Role of Neuronal Nitric Oxide Synthase in Regulation of Cerebral Blood Flow in Normocapnia and Hypercapnia in Rats

Wang

Pelligrino

Baughman

et al. 1995

J Cereb Blood Flow Metab

157

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“…NO may have biphasic influences (ie both excitatory and inhibitory) based on a complex interaction among glutamatergic, GABAergic, and other (eg opioid) neuronal systems, all of which are modulated by NO (Lovick and Key, 1996;Wang et al, 1997;Hall and Behbehani, 1998;Lin et al, 2000). This may account for the contradictory results that NO appears to both enhance and suppress not only anxiety but also other functions such as pain (Moore et al, 1993;McDonald et al, 1994), seizure activity (Buisson et al, 1993;De Sarro et al, 1993), and neurotoxicity (Contestabile et al, 2003). These findings are contributing to a more complete understanding of the role of NO in brain function, which would potentially have many ramifications for more effective treatment of not only anxiety but other brain dysfunctions as well.…”

Section: Discussionmentioning

confidence: 79%

Antagonism by NOS Inhibition of the Behavioral Effects of Benzodiazepine and GABAA Receptor Agonists in the Mouse Elevated Plus-Maze

Elfline

Branda

Babich

et al. 2004

Neuropsychopharmacol

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Earlier we implicated nitric oxide (NO) in mediation of the behavioral effects of benzodiazepines. Since benzodiazepines work through facilitation of GABAergic inhibitory neurotransmission, this study was designed to determine whether the direct-acting g-aminobutyric acid A (GABA A ) receptor agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) evokes behavioral effects similar to those of benzodiazepines and whether behavioral effects of THIP are also NO dependent. When challenged with either chlordiazepoxide or THIP in an elevated plus-maze paradigm, male NIH Swiss mice exhibited a dose-related increase in open-arm activity. The chlordiazepoxide-induced effects were sensitive to antagonism by a benzodiazepine antagonist, and the effects of THIP were blocked by a GABA A receptor antagonist. Pretreatment with the NO synthase (NOS) inhibitor L-N G -nitro arginine antagonized the effects of both chlordiazepoxide and THIP; similar pretreatment with the D-isomer, D-N G -nitro arginine, which is inactive as an NOS inhibitor, was without effect on chlordiazepoxide and THIP. These findings indicate that chlordiazepoxide and THIP evoke similar behavioral effects in mice in the elevated plus-maze through actions on different parts of the GABA A receptor, and that NO appears to play a key role in mediation of the behavioral effects of both chlordiazepoxide and THIP.

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“…This suggests that NO acting through peroxynitrite plays an important pathogenic role in RP. The major source of the NO that contributes to the cone cell damage is nNOS rather than iNOS, because 7-nitroindazole, a relatively specific inhibitor of nNOS [30,31], provided significant protection for cones, but aminoguanidine, a selective inhibitor of iNOS, had no effect.…”

Section: Discussionmentioning

confidence: 99%

“…Aminoguanidine is a relatively specific inhibitor of iNOS [29] and 7-nitroindazole is a relatively specific inhibitor of nNOS [30,31]. Twice a day injections of a relatively high dose of aminoguanidine between P18 and P35 had no significant effect on cone survival in rd1 mice ( Figure 5A), but mice treated with 7-nitroindazole showed significantly more cones in the superior and temporal regions of the retina than vehicle treated mice ( Figure 5B).…”

Section: Blockade Of Nnos But Not Inos Promotes Cone Survival In Rd1mentioning

confidence: 99%

Blockade of neuronal nitric oxide synthase reduces cone cell death in a model of retinitis pigmentosa

Komeima

Usui

Shen

et al. 2008

Free Radical Biology and Medicine

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Retinitis pigmentosa (RP) is a group of diseases in which many different mutations cause rod photoreceptor cells to die and then gradually cone photoreceptors die due to progressive oxidative damage. In this study, we have shown that peroxynitrite-induced nitrosative damage also occurs. In the rd1 mouse model of RP, there was increased staining for S-nitrosocysteine and nitrotyrosine protein adducts that are generated by peroxynitrite. Peroxynitrite is generated from nitric oxide (NO) and superoxide radicals. After degeneration of rods, injection of hydroethidine resulted in strong fluorescence in the retina of rd1 mice indicating high levels of superoxide radicals, and this was reduced, as was nitrotyrosine staining, by apocynin suggesting that over action of NADP(H) oxidase is at least partially responsible. Treatment of rd1 mice with a mixture of nitric oxide synthase (NOS) inhibitors markedly reduced S-nitrosocysteine and nitrotyrosine staining and significantly increased cone survival, indicating that NO-derived peroxynitrite contributes to cone cell death. Treatment with 7-nitroindazole, a relatively specific inhibitor of neuronal NOS, also significantly reduced cone cell death, but aminoguanidine, a relatively specific inhibitor of inducible NOS, did not. These data suggest that NO generated by neuronal NOS exacerbates oxidative damage to cones in RP and that combined therapy to reduce NO and oxidative stress should be considered.

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7‐Nitro indazole, an inhibitor of nitric oxide synthase, exhibits anti‐nociceptive activity in the mouse without increasing blood pressure

Cited by 398 publications

References 6 publications

The Role of Neuronal Nitric Oxide Synthase in Regulation of Cerebral Blood Flow in Normocapnia and Hypercapnia in Rats

The Role of Neuronal Nitric Oxide Synthase in Regulation of Cerebral Blood Flow in Normocapnia and Hypercapnia in Rats

Antagonism by NOS Inhibition of the Behavioral Effects of Benzodiazepine and GABAA Receptor Agonists in the Mouse Elevated Plus-Maze

Blockade of neuronal nitric oxide synthase reduces cone cell death in a model of retinitis pigmentosa

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