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P Pu ur rp po os se e: : To assess the systemic and nociceptive effects of nitric oxide synthase (NOS) inhibitors in the modulation of acute pain in rats subjected to the formalin test.M Me et th ho od ds s: : Formalin 5% was injected in the hind paw in the presence and absence of NOS inhibitors (e.g., 7-nitro indazole, Nnitro-L-arginine and aminoguanidine). Catheters were chronically implanted to continuously record mean arterial blood pressure (MAP) and heart rate (HR). MAP, HR and paw lifting time were recorded at control and every five minutes for 35 min following formalin and NOS inhibitors.R Re es su ul lt ts s: : Formalin injected into the rat hind paw induced a biphasic nociceptive behaviour: an initial acute phase (phase 1: during zero to five minutes after the formalin injection) followed by a prolonged tonic response (phase 2: beginning about ten minutes after the formalin injection). Aminoguanidine, an inhibitor of the inducible NOS and 7-nitro indazole, an inhibitor of the neuronal NOS, did not affect phase 1, whereas N-nitro-L-arginine, a non-selective NOS inhibitor decreased it (49%). All three NOS inhibitors diminished nociceptive behaviours during phase 2. L-arginine reversed antinociceptive effects of N-nitro-L-arginine in phase 1 and in phase 2. Pressor effects induced by formalin in phase 1 were abolished following all three NOS inhibitors. During phase 2, formalininduced pressor effects remained unaffected by N-nitro-L-arginine and aminoguanidine but were inhibited by 7-nitro indazole.C Co on nc cl lu us si io on n: : Our data demonstrate that NO is predominantly generated by vascular endothelial NOS in phase 1 and phase 2, whereas the neuronal NOS and the inducible NOS exhibit antinociceptive effects through a non-NO related pathway in phases 1 and 2 in rats subjected to the formalin test. Objectif : Évaluer les effets généraux et nociceptifs des inhibiteurs de la nitric oxide synthase (NOS) dans la modulation de la douleur aiguë chez des rats soumis au test de formaline. Méthode : De la formaline à 5 % a été injectée dans la patte arrière de rats en présence ou non d'inhibiteurs de NOS (par ex., 7-nitro indazole, N-nitro-L-arginine et aminoguanidine). Des cathéters ont été implantés à demeure pour permettre l'enregistrement continu de la tension artérielle moyenne (TAM) et de la fréquence cardiaque (FC). La TAM, la FC et le temps d'élévation de la patte ont été notés au temps témoin et aux cinq minutes pendant 35 min après l'administration de formaline et d'inhibiteurs de NOS. Résultats : La formaline injectée dans la patte arrière des rats a induit un comportement nociceptif biphasique : une phase aiguë initiale (phase 1 : de zéro à cinq minutes après l'injection de formaline) suivie d'une réponse tonique prolongée (phase 2 : débutant environ dix minutes après l'injection de formaline). L'aminoguanidine, un inhibiteur de la NOS inductible et le 7-nitro indazole, un inhibiteur de la NOS neuronale, n'ont pas modifié la phase 1, tandis que la N-nitro-L-arginine, un inhibiteur de NOS non sél...

Background:Specific factors in Parkinson’s disease have become targets as to their protective and degenerative effects. We have demonstrated that cytokines and PD-CSF detrimentally affect microglia and astrocyte growth. While glial cell-derived neurotrophic factor (GDNF) has been recognized as a possible neuron-rescue agent, nitric oxide synthase (NOS) has been implicated in neurodegenerative processes.Objective:To demonstrate that glial cell activation, cytokine production, and NOS induction, play an intimate role in the loss of dopaminergic signaling, via mechanisms that are a result of inflammation and inflammatory stimuli.Methods:Study animals were sacrificed following endotoxin treatment and tissue sections were harvested and probed for GDNF and NOS isomers by fluorescence deconvolution microscopy. Fluorescence was mapped and quantified for each probeResults:An immune cell influx into ‘vulnerable’ areas of the brain was seen, and three NOS isomers, inducible (iNOS), neuronal (nNOS) and endothelial (eNOS), were synthesized in the brains, a finding which suggests that each isomer has a role in neurodegeneration. eNOS was found associated with blood vessels, while iNOS was associated with glial and matrix cells and nNOS was located with both glia and neurons. Following endotoxin treatment, serum levels of nitric oxide were higher at 6-8 hours, while tissue levels of NOS were elevated for much longer. Thus, induction of NOS occurred earlier than the induction of GDNF.Conclusion:Our findings suggest that the protective abilities of GDNF to combat neural destruction are not available rapidly enough, and do not remain at sufficiently high levels long enough to assert its protective effects. (250).

Sepsis is a major cause of morbidity and mortality. NO, an endogenous vasodilator, has been associated with the hypotension, catecholamine hyporesponsiveness, and myocardial depression of septic shock. Although iNOS is thought to be responsible for the hypotension and loss of vascular tone occurring several hours after endotoxin administration, little is known on the effects of constitutive eNOS on LPS-induced organ dysfunction. This study assessed the distribution of eNOS and iNOS in various vascular beds in conscious pigs challenged with LPS. Cardiac and regional hemodynamic parameters were recorded over 8 h in the presence and absence of aminoguanidine, a rather selective inhibitor of iNOS activity, and N-methyl-L-arginine, a nonspecific NOS inhibitor. Our data show that LPS-induced cardiac depression was associated with coronary, renal, and mesenteric vasoconstrictions and a hepatic vasodilatation. LPS also induced increases in eNOS in the heart and lungs, whereas iNOS was mostly detected in the liver. Nitrotyrosine formation was mainly detected in the lungs, with traces in the kidney, liver, and gut. Accordingly, our results suggest that the early decrease in blood pressure and cardiac depression are likely due to activated eNOS, whereas both isoforms are involved in the hepatic vasodilation. In contrast, carotid, coronary, mesenteric, and renal vasoconstrictions were significant at 5 and/or 6 h after LPS infusion, suggesting that NO is not the primary mediator, facilitating and/or unmasking the release of vasoconstrictor mediators. Consequently, developing newer tissue-or isoform-specific NOS inhibitors can lead to novel therapeutic agents in septic shock.

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