Interleukin-1 beta- and tumour-necrosis-factor-induced inhibition of rat gastric fundus motility in vitro.
In this study, we compared the effects of interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) on in vitro rat gastric fundus motility. IL-1 beta and TNF produced rapid, concentration-dependent relaxation of the rat gastric fundus strips with maximal effect at 300 pg ml-1 and 10 ng ml-1, and estimated EC50S at 10 and 450 pg ml-1, respectively. The relaxant effects of IL-1 beta and TNF were not influenced by the inhibition of cyclo-oxygenase or NO-synthase activities. IL-1 beta- and TNF-induced gastric relaxations were inhibited by BW 755c, which inhibits both cyclo-oxygenase and lipoxygenase (LO), BW A4c, which selectively inhibits the 5-LO pathway, and SC 41930, a selective leukotriene B4 (LTB4) receptor antagonist, providing pharmacological evidence that LTB4 is involved in the relaxant effects of both cytokines. The IL-1 beta- and TNF-induced activation of 5-LO pathway did not appear to be triggered by phospholipase A2. An alternative pathway could involve the activation of a phospholipase C, specific for phosphatidylcholine, from which, in sequence: the formation of diacylglycerol (DAG), DAG-induced activation of protein kinase C and the formation of free arachidonic acid from DAG would ensue. This mechanism is suggested by the finding that LTB4 is able to mimic cytokine-induced strip relaxation only in the presence of phorbol 12-myristate 13-acetate, which selectively activates protein kinase C.
Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy.
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Montuschi
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Preziosi
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Navarra
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005748:Gastric Fundus / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D015289:Leukotrienes / Q000502:physiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000502:physiology
D007375:Interleukin-1; D015289:Leukotrienes; D014409:Tumor Necrosis Factor-alpha; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D010738:Type C Phospholipases