Leptin in gastroprotection induced by cholecystokinin or by a meal. Role of vagal and sensory nerves and nitric oxide

Leptin, detected recently in the stomach, is a product of the ob gene relea sed by cholecystokinin (CCK) and plays an important role in the control of food intake but its influence on gastroprotection against the damage caused by noxious agents has not been studied. This study was designed no compare the effects of leptin and cholecystokinin-8 (CCK-8) on gastric mucosal les ions induced by topical application of 75% ethanol or acidified aspirin. Fo ur series of Wistar rats (A, B, C and D) were used to determine the effects of: (A) suppression of prostaglandin biosynthesis by indomethacin (5 mg/kg i.p.); (B) inhibition of nitric oxide (NO)-synthase by nitro-L-arginine me thyl ester (L-NAME) (5 mg/kg i.v.); (C) blockade of sensory nerves by capsa icin (125 mg/kg s.c.) and (D) bilateral vagotomy, on the gastric lesions in duced by intragastric (i.g.) application of ethanol with or without pretrea tment with CCK-8, a known gastroprotective substance or leptin. CCK-8 (1-10 0 mu g/kg i.p.) and leptin (0.1-50 mu g/kg i.p.) dose dependently attenuate d gastric lesions induced by 75% ethanol; the dose reducing these lesions b y 50% being about 10 mu g/kg and 8 mu g/kg, respectively. The protective ef fects of CCK-8 and leptin were accompanied by a significant rise in gastric blood flow (GBF) and luminal NO concentration. Leptin was also effective t o attenuate aspirin-induced damage and the accompanying fall in the GBF, wh ereas CCK-8 dose dependently worsened aspirin damage and failed to influenc e GBF. CCK (1-100 mu g/kg i.p.), given in graded doses, produced a dose-dep endent increase in the plasma leptin level and a rise of the expression of ob messenger RNA (mRNA) in gastric mucosa, the maximum being reached at a d ose of 100 mu g/kg. Pretreatment with CCK-8 (10 mu g/kg i.p.) or with 8% pe ptone. that is known to stimulate CCK release. also produced a significant rise in plasma leptin levels and up-regulation of oil mRNA while reducing s ignificantly the gastric lesions induced by 75% ethanol to the same extent as that induced by exogenous leptin (10 mu g/kg i.p.). Indomethacin, which suppressed prostaglandin generation by similar to 90%, failed to influence leptin- or CCK-8-induced protection against ethanol, whereas L-NAME attenua ted significantly CCK-8- and leptin-induced protection and hyperemia but ad dition to L-NAME of L-arginine, but not D-arginine, restored the protective and hyperemic effects of both hormones. The ob mRNA was detected as a weak signal in the intact gastric mucosa and in that exposed to ethanol alone b ut this was further enhanced after treatment with graded doses of CCK-8 or peptone meal applied prior to ethanol. We conclude that: (I) exogenous lept in or that released endogenously by CCK or meal exerts a potent gastroprote ctive action depending upon vagal activity, and involving hyperemia probabl y mediated by NO and sensory nerves but unrelated to endogenous prostagland ins; (2) leptin mimics the gastroprotective effect of CCK and probably medi ates the protective and hyperemic actions of CCK in the rat stomach. (C) 19 99 Elsevier Science B.V. All rights reserved.