ABSTRACT
Bacterial endotoxin produces sepsis associated with alterations in body temperature (fever or hypothermia). The intraperitoneal administration of bacterial endotoxin, lipopolysaccharide (LPS; 50 microg/mouse) led to a decrease in colonic temperature starting 1 hr after the injection. The hypothermic effect was accompanied by a significant increase in hypothalamic leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) levels. 5-lipoxygenase inhibitor, zileuton (200 and 400 mg/kg, po) administered 30 min before LPS challenge significantly prevented hypothermia. However, non-selective cyclooxygenase inhibitor, indomethacin (10, 20 mg/kg, po) did not reverse the hypothermic response. Further, pretreatment of mice with zileuton prevented LPS-stimulated increase in hypothalamic LTB4 levels and caused a relatively small increase in PGE2 levels. Indomethacin had no effect on LTB4 levels but it reduced PGE2 levels. These results suggest a possible involvement of leukotrienes in LPS-induced hypothermia and the potential protective role of 5-lipoxygenase inhibitors in endotoxemia.
Subject(s)
Animals , Arachidonate 5-Lipoxygenase/antagonists & inhibitors , Colon/drug effects , Dinoprostone/metabolism , Female , Hydroxyurea/analogs & derivatives , Hypothalamus/drug effects , Hypothermia/drug therapy , Hypothermia, Induced , Indomethacin/pharmacology , Leukotriene B4/metabolism , Leukotrienes/physiology , Lipopolysaccharides/pharmacology , Lipoxygenase Inhibitors/pharmacology , Male , MiceABSTRACT
The present study was aimed to evaluate the effect of licofelone, a dual inhibitor of cycloxygenase1/2-5-lipoxygenase against indomethacin-induced gastric damage in rats and mice in order to assess the role of leukotrienes if any, in non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastrointestinal inflammation. Acute pretreatment with licofelone reversed the indomethacin-induced gastric ulceration, neutrophil adhesion in mesentery venules, neutrophil count in blood, lipid peroxides and vascularity in the stomachs of mice and rats. Further, chronic pretreatment of licofelone also prevented indomethacin-induced gastric morphological changes and cellular infiltration in mesentery venules. Moreover, acute administration of indomethacin elevated leukotriene B4 levels in gastric mucosa, which was reversed by pretreatment with licofelone The results suggest that licofelone offered gastroprotection against NSAIDs-induced gastropathy through its effect on leukotrienes and by inhibiting extravasation of neutrophils.
Subject(s)
Acetates/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Ulcer Agents/pharmacology , Female , Humans , Indomethacin/adverse effects , Inflammation/drug therapy , Leukotriene B4/metabolism , Lipid Peroxidation , Male , Mesentery/metabolism , Mice , Neutrophils/drug effects , Pyrroles/pharmacology , Rats , Stomach Ulcer/chemically induced , Time FactorsABSTRACT
Nitric oxide (NO) is an important neurotransmitter in the gut and has been demonstrated to be a key physiological mediator of non-adrenergic non-cholinergic (NANC) relaxation of gastrointestinal smooth muscle. In the present study the effect of PDE 5 inhibitor sildenafil on the gastrointestinal function (gastric emptying and intestinal transit) has been demonstrated in mice. Sildenafil (0.5-2 mg/kg, po) did not alter the percent gastric emptying however, in higher doses (5, 10 and 30 mg/kg, po) it inhibited the gastric emptying. On acute administration (0.5-5 mg/kg, po) it did not alter the intestinal transit but in higher doses (10 and 30 mg/kg, p.o.) delayed the intestinal transit. Further, the inhibitory effect of sildenafil was significantly blocked by L-NAME (10 mg/kg, ip), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor. These findings suggest the participation of NO-cGMP transduction pathway in the inhibitory effect of sildenafil (higher doses) on the gastrointestinal smooth muscles and its potential application in patients with nutcracker oesophagus, hypertensive lower oesophageal sphincter (LOS), achalsia and diabetic gastroparesis or colitis where there is a loss of nNOS.
Subject(s)
Administration, Oral , Animals , Cyclic GMP/metabolism , Dose-Response Relationship, Drug , Female , Gastric Emptying/drug effects , Gastrointestinal Motility/drug effects , Gastrointestinal Tract/drug effects , Male , Mice , Muscle, Smooth/drug effects , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/metabolism , Nitric Oxide Synthase/antagonists & inhibitors , Piperazines/pharmacology , Purines , Signal Transduction/drug effects , SulfonesABSTRACT
Leukotrienes play a part in inflammatory response. The unique role of the enzyme 5-lipoxygenase (5-LOX) in the production of leukotrienes makes it a likely therapeutic target for inflammatory conditions like asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD). The aim of the present study was to evaluate the effect of zileuton, an orally active selective 5-LOX inhibitor against the events associated with dextran sodium sulphate-induced colitis in a rat model of IBD. The animals were administered simultaneously zileuton (100mg/kg) or sulphasalazine (100mg/kg) orally for 7 days. On day eight, rats were sacrificed, and distal colon isolated to determine myeloperoxidase activity, in vivo superoxide dismutase activity, prostaglandin E2 levels and histological examination. Both zileuton and sulphasalazine significantly prevented the development of inflammatory events associated with colitis. The effect of zileuton was more pronounced towards reducing myeloperoxidase activity and increasing PGE2 levels in distal colon. The results show that chemotactic leukotrienes are responsible for inflammatory surge in damaged colon and, zileuton, significantly improved healing by inhibition of neutrophil recruitment and indirectly through increase in prostaglandins at the site of inflammation. It is suggested that inhibitors of 5-LOX enzyme may have useful therapeutic role in the treatment of chronic intestinal inflammation.
Subject(s)
Animals , Arachidonate 5-Lipoxygenase/antagonists & inhibitors , Dinoprostone/metabolism , Female , Inflammatory Bowel Diseases/drug therapy , Lipoxygenase Inhibitors/pharmacology , Male , Oxidative Stress , Peroxidase/antagonists & inhibitors , Rats , Rats, WistarABSTRACT
Acetylcholine and cholinomimetic agents with predominant muscarinic action are known to increase the concentration of cGMP by activation of nitric oxide signaling pathway in the nociceptive conditions. The present study was aimed to investigate the NO-cGMP-PDE5 pathway in nociceptive conditions in the experimental animals. Nociceptive threshold was assessed by acetic acid-induced writhing assay (chemonociception) or carrageenan-induced hyperalgesia. Sildenafil [1-5 mg/kg, ip, 50-200 microg/paw, intraplantar (ipl)] produced dose dependent antinociception in both the tested models. Coadministration of acetylcholine (50 mcg/paw, ipl) or cholinomimetic agent, neostigmine (0.1 mcg/kg, ip and 25 ng/paw, ipl) augmented the peripheral antinociceptive effect of sildenafil. This effect was sensitive to blockade by L-NAME (20 mg/kg, ip, 100 microg/paw, ipl), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor, which per se had little or no effect in both the models of nociception. Further, the per se analgesic effect of acetylcholine and neostigmine was blocked by both L-NAME and methylene blue in the models of nociception, suggesting the activation of NO-cGMP pathway. Also, both L-NAME and methylene blue blocked the per se analgesic effect of sildenafil. These results indicate the peripheral accumulation of cGMP may be responsible for antinociceptive effect, and a possible interaction between cholinergic agents and PDE5 system in models of nociception.