European journal of pharmacology
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We investigated the effect of two inhibitors of nitric oxide (NO) synthesis, N(w)-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine, on lung inflammation caused by intestinal ischemia/reperfusion in rats. Relative to the sham-operated rats, intestinal ischemia/reperfusion (ischemia: 45 min; reperfusion: 30 min, 2 and 4 h) induced neutrophil recruitment (increased myeloperoxidase activity) and increased microvascular permeability (Evans blue dye extravasation) in the lungs and increased tumor necrosis factor (TNF) levels in the serum (L-929 cytotoxicity assay). L-NAME given before the ischemia exacerbated neutrophil accumulation, plasma extravasation, serum TNF and caused death of the animals, which was prevented by concomitant injection of L-arginine. ⋯ Treatment with aminoguanidine inhibited plasma extravasation without affecting the other parameters evaluated. Dexamethasone reduced all the parameters. Our results indicate that during intestinal ischemia/reperfusion both constitutive and inducible NO synthases are called to exert a differential modulatory effect on lung inflammation and that maintenance of adequate levels of NO during ischemia is essential for the animals survival.
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The involvement of the nitric oxide (NO)/cyclic GMP pathway in the molecular mechanisms of antinociceptive drugs like morphine has been previously shown by our group. Additionally, it is known that the desensitisation of nociceptors by K(+) channel opening should be the final target for several analgesic drugs including nitric oxide donors and exogenous micro-opioid receptor agonists. In our previous study, we demonstrated that bremazocine, a kappa-opioid receptor agonist, induces peripheral antinociception by activating nitric oxide/cyclic GMP pathway. ⋯ The supposed participation of other types of K(+) channels was tested using the Ca(2+)-activated K(+) channel blockers dequalinium (12.5, 25 and 50 microg) and charybdotoxin (0.5, 1 and 2 microg) and different types of the non-selective K(+) channel blockers tetraethylammonium (25, 50 and 100 microg) and 4-aminopyridine (10, 25 and 50 microg). None of the K(+) channel blockers reversed the antinociceptive effect of bremazocine. On the basis of these results, we suggest that K(+) channels are not involved in the peripheral antinociceptive effect of bremazocine, although this opioid receptor agonist induces nitric oxide/cGMP pathway activation.