Protective effect of pranlukast, a cysteinyl-leukotriene receptor 1 antagonist, on indomethacin-induced small intestinal damage in rats.
We examined the effect of pranlukast, the receptor antagonist of the cysteinyl leukotrienes (CysLTs; LTC(4), LTD4 and LTE4), on indomethacin-induced small intestinal lesions in rats. Animals non-fasted were given indomethacin (10 mg/kg) s.c., and killed 24 hr later. Pranlukast (1-10 mg/kg) was given p.o. twice, 30 min before and 6 hr after the administration of indomethacin. A single s.c. administration of indomethacin provoked multiple haemorrhagic lesions in the small intestine, mainly in the jejunum and ileum. This treatment also caused an increase in MPO activity, microvascular permeability, and enterobacterial counts in the mucosa. Pretreatment of the animals with pranlukast (1-10 mg/kg) dose-dependently reduced the severity of these lesions and improved the patho-physiological alterations occurred after indomethacin treatment. Although indomethacin increased intestinal motility and decreased mucus secretion, the events being responsible for bacterial invasion, these changes were not significantly affected by pranlukast. These results showed that pranlukast prevents indomethacin-induced small intestinal lesions, probably through its inhibitory action, primarily on bacterial invasion and secondly on neutrophil migration as well as vascular permeability, and suggest the importance of CysLTs in the pathogenic mechanism of this lesion model.
Nishio
H
H
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, 607-8414, Japan.
Hayashi
Y
Y
Terashima
S
S
Takeuchi
K
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018988:Bacterial Translocation / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002867:Chromones / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D004755:Enterobacteriaceae / Q000502:physiology; D005769:Gastrointestinal Motility / Q000187:drug effects; D007213:Indomethacin; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007421:Intestine, Small / Q000473:pathology*; D020024:Leukotriene Antagonists / Q000627:therapeutic use*; D015289:Leukotrienes / Q000378:metabolism; D008297:Male; D009093:Mucus / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014456:Ulcer / Q000139:chemically induced / Q000517:prevention & control
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002867:Chromones; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D009195:Peroxidase; D015232:Dinoprostone; C047681:pranlukast; D007213:Indomethacin