s-nitro-n-acetylpenicillamine and Edema

Carrageenan produces both inflammation and pain when injected in rat paws via enhancement of the formation of reactive oxygen species. We have tested the effect of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL), a membrane-permeable superoxide dismutase (SOD) mimetic in carrageenan-induced rat paw edema. Treatment of rats with TEMPOL (15, 30, and 60 mg/kg, 15 min prior to carrageenan) inhibited the paw edema. Furthermore, treatment of rats with the SOD inhibitor diethylthiocarbamate (DETCA, 100 mg/kg, 1 h before carrageenan) enhanced the carrageenan-induced paw edema. Co-administration of peroxynitrite with carrageenan produced a similar fortification of the carrageenan-induced edema. Prior treatment of rats with TEMPOL (30 mg/kg) inhibited the enhancement produced by DETCA treatment (endogenous superoxide anion stress) as well as that produced by the peroxynitrite stress. The effect of TEMPOL as well as the influence of superoxide anion and peroxynitrite stresses was also tested in carrageenan-induced hyperalgesia model. Carrageenan (500 mug/paw) produced significant hyperalgesia presented as shortening of withdrawal latency times using hot plate (52 degrees C) starting 30 min after carrageenan and lasting for 3 h. TEMPOL (60 mg/kg, injected 15 min before carrageenan) ameliorated this hyperalgesia during the first 2 h. Concurrent administration of peroxynitrite promptly intensified the carrageenan hyperalgesia. TEMPOL (60 mg/kg, 15 min before peroxynitrite-carrageenan) inhibited the peroxynitrite enhancement of carrageenan hyperalgesia when tested at 60 min after injection of the cocktail. The present investigation gives the proof for the effectiveness of TEMPOL as anti-inflammation and analgesic agents in carrageenan-induced model of inflammation and hyperalgesia. It further indicated the importance of superoxide anion and peroxynitrite in acute inflammation and inflammatory pain. This raises the chances for considering pharmacologic interventions that interrupt superoxide anion and peroxynitrite stress for putative alternative agents as anti-inflammatory analgesic new medical strategies.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cyclic N-Oxides; Edema; Enzyme Inhibitors; Foot; Free Radical Scavengers; Hot Temperature; Hyperalgesia; Male; Nitric Oxide Donors; Penicillamine; Peroxynitrous Acid; Pyrogallol; Rats; Rats, Wistar; Spin Labels; Superoxide Dismutase; Superoxides; Thiocarbamates

To investigate the effect of nitric oxide (NO) donors on inflammatory mouse paw edema (MPE).. Mice previously treated with sodium nitroprusside (SNP; 1.5, 5 and 10 micromol/kg) or S-nitroso-N-acetyl-DL-penicillamine (SNAP; 7, 14 and 28 micromol/kg) were injected with inflammatory mediators in the paw. Paw edema, myeloperoxidase activity and vascular dye leakage were measured.. Pre-treatment with SNP and SNAP (4 h or 12 h) reduced (approximately 50%) MPE induced by carrageenan, dextran sulfate, bradykinin and histamine but not by serotonin. Pre-treatment with SNP also inhibited carrageenan-induced increases in myeloperoxidase activity and vascular dye leakage. Methylene blue blocked the SNP-induced reduction in MPE when injected 30 min before or 2 h after SNP, but not 4 or 6 h after the NO donor. Tetraethylammonium blocked the SNP-induced reduction in MPE if injected 30 min before or 2, 4 or 6 h after SNP.. NO donors have a long-lasting anti-inflammatory effect in MPE, which involves guanylate cyclase and tetraethylammonium-sensitive potassium channels.

Topics: Animals; Blood Pressure; Bradykinin; Carrageenan; Dextran Sulfate; Edema; Female; Guanylate Cyclase; Histamine; Injections, Subcutaneous; Mice; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Penicillamine; Peroxidase; Potassium Channels; Rats; Serotonin; Time Factors

This study characterizes the receptor subtypes and investigates some of the mechanisms by which glutamate, injected intraplantarly (i.pl.) into the mouse paw, produces nociception and paw oedema. I.pl. injection of glutamate induced a rapid-onset, dose-related pain response associated with oedema formation, with mean ED(50) values of 2.6 (1.6-4.3) and 0.5 (0.4-0.7) micromol/kg, respectively. Pretreatment with Chicago sky blue 6B (100 microg/kg), an inhibitor of glutamate uptake, caused a significant (about sixfold) reduction of the mean ED(50) value for glutamate-induced nociception, but not paw oedema. NMDA receptor antagonist MK 801, given by systemic (i.p.), intracerebroventricular (i.c.v.), i.pl. or intrathecal (i.t.) routes, produced graded inhibition of glutamate-induced nociception. Non-NMDA receptor antagonists NBQX or GAMS, metabotropic antagonist E4CPG, and also the antagonist that acts at the NMDA receptor-associated glycine binding site felbamate, significantly inhibited the nociception induced by glutamate. L(omega)-N-nitro-arginine (given i.p., i.t., i.pl. or i.c.v.) prevented the nociception and paw oedema caused by glutamate, an effect that was reversed by L-arginine but not by D-arginine. S-nitroso-N-acetyl-D,L-penicillamine (SNAP), given i.pl., greatly potentiated glutamate-induced nociception and oedema formation. Finally, the i.pl. injection of glutamate was accompanied by a graded increase in the nitrite levels of the hindpaw exudate. It is concluded that the nociception caused by i.pl. injection of glutamate probably involves the activation of NMDA and non-NMDA receptors by a mechanism which largely depends on the activation of L-arginine-nitric oxide pathway. Glutamate-induced paw oedema seems to be primarily mediated by non-NMDA ionotropic glutamate receptors and release of nitric oxide.

Topics: Animals; Azo Compounds; Coloring Agents; Dizocilpine Maleate; Dose-Response Relationship, Drug; Edema; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Extremities; Glutamic Acid; Glutamine; Male; Mice; Nitric Oxide; Nitric Oxide Donors; Nitrites; Nitroarginine; Nociceptors; Penicillamine; Quinoxalines; Trypan Blue

To clarify the role of nitric oxide (NO) in the development and progression of acute pancreatitis, we investigated the effect of different NO synthase inhibitors and NO donors on experimental pancreatitis in rats. Closed duodenal loop (CDL)-induced pancreatitis was produced in male Wistar rats, and the animals were treated with normal saline, the NO-synthase substrate L-arginine, the NO donor S-nitroso-N-acetylpenicillamine, aminoguanidine, which is a more powerful inhibitor of inducible NO synthase (iNOS) than is endothelial NO synthase (eNOS), and N-nitro-L-arginine methyl ester (L-NAME), a more powerful inhibitor of eNOS than of iNOS. All drugs were infused intravenously during a period of 6 or 12 h in each group. Pancreatic tissue was removed at 6 and 12 h after creating the CDL. L-Arginine, S-nitroso-N-acetyl-penicillamine, and aminoguanidine treatment had no effect on the elevation of serum pancreatic enzymes, whereas L-NAME administration significantly exacerbated their elevation. Pathologically, L-NAME treatment resulted in a significantly worse histologic score at 6 and 12 h, especially in terms of the degree of hemorrhage, acinar cell necrosis, and microvascular thrombosis. Addition of L-arginine clearly reversed the effect of L-NAME. Neither the NO substrate nor NO donor could inhibit the progression of hemorrhagic pancreatitis in CDL-induced pancreatitis. Aminoguanidine had no effect on the severity of the pancreatitis. We therefore concluded that NO production by eNOS may play a significant role in preventing the development and progression of acute pancreatitis.

Topics: Acute Disease; Animals; Arginine; Ascitic Fluid; Duodenum; Edema; Enzyme Inhibitors; Guanidines; Ligation; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Pancreatitis; Penicillamine; Rats; Rats, Sprague-Dawley