Effects of sucralfate on gastric prostaglandin and ...

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Effects of sucralfate on gastric prostaglandin and leukotriene synthesis: relationship to protective actions JOHNL. WALL ACE,^ GERALD P. MORRIS,PAUL L. BECK,TODDE. WILLIAMSON, AND GUYR. GINGRAS Gas~rodntestinalDis~asesResearch Unit, Departments sf Physiology and Biology, Queen's University, Kingston, Ont., Canada K7L 3N6

Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by 199.201.121.12 on 06/04/13 For personal use only.

Received October 29, 1987

WALLACE, J. L., MORRIS,G. P., BECK,PoE., WILLIAMSON, T. E.. and GHNGRAS, 6 . R. 1988. Effects of sucralfate on gastric prostaglandin and Beukotriene synthesis: relationship to protective actions. Can. J. Physiol. Phamacol. 66: 666-670. The mechanism of the protective actions of sucralfate against ethanol-induced gastric mucosal damage in the rat has been investigated. In particular, the role of prostaglandins as mediators of such protection was assessed. Oral administration of sucralfate at a dose causing a significant reduction of ethanol-induced gastric damage (500 mg/kg) did not significantly alter gastric 6-ketoprostaglandin F~l;.l,synthesis. Pretreatment with indomethacin at a dose that inhibited gastric cyclooxygenase activity by an average of 88% did not affect the protective actions of sucralfate. To further investigate the mechanism of action of sucmlfate, an e-x vVio gastric chamber model was used in which sucralfate could be applied to only one side of the mucosa. Sucralfate did not affect gastric prostaglandin synthesis, but did cause a significant increase in leukotriene C4synthesis, a fall in transmaacosal potential difference, and a significant decrease in gastric myeloperoxidase activity on the side exposed to sucralfate. These observations suggest that sucralfate has an irritant action on the mucosa. The release of mediators in response to such initation may play an important role in the protective action of sucralfate. The present study supports the hypothesis that prostaglandins do not mediate the protection afforded by exposure to sucralfate. WALLACE, J. E., MORRIS,G . P.,BECK,P. E., WILLIAMSON, T. E., et GINGWAS, G. R. 1988. Effects of sucralfate on gastric prostaglandin and leukotriene synthesis: relationship to protective actions. Can. J . Physiol. P h m a c o l . 66 : 666-670. Le mCcanisme des actions protectrices du sucralfate contre la lCsion de la muqueuse gastrique induite par B'tthanol a Ct6 examink chez le rat. Plus prCcisCment, on a CvaluC le r81e des prostaglandines en tant que mddiatrices d'une telle protection. L'administration orale de sucralfate a une dose provoquant une rkduction significative de Ba lCsion gastrique induite par l'kthanol (500 mg/kg) n'a pas altCrC signifisativement la synthkse de la 6-~CtoprostaglandineF1, gastrique. Un pretraitement avec lqindomCthacinea une dose qui a inhibt I'activitC de cyclo-oxygtnase gastrique de 88% en moyenne n'a pas affect6 les actions protectrices du sucralfate. Pour Ctudier davantage le mecanisme d'action du sucralfate, on a utilisC un msdkle de chambre gastrique ex vivo dans laquelle le sucralfate we pouvait &re appliquC que d'un seul c6tC de la muqueuse. Le sucralfate n9apas modifid la synthkse des prostaglandines gastriques, mais il a provoqud une augmentation significative de Ba symthkse des leucotriknes C4, une chute de la diffkrence du potentiel transmuqueux et une diminution significative de 19activitCde myClopmxydase gastrique sur le c6tC expos6 au sucralfate. Ces observations suggkrent que le sucralfate a eu un effet irritant sur la muqueuse. La liberation des mediateurs em r6ponse 2i une telle irritation pourrait jouer un r61e important dans l'action prokctrice du sucralfate. La prCsente Ctude supporte 19hypoth&seque les prostaglandines ne mtdiemt pas la protection procurke par l'exposition au sucralfate. [Traduit par la revue]

Introduction Sueralfate is an aluminium salt of sucrose octasulfate, which has been shown to be an effective agent in the treatment of duodenal ulcer (Hollander 1981). Furthemore, sucralfate can significantly reduce ethanol- or aspirin-induced gastric damage in rats (Hollander et al. 1984; Konturek et al. 1987) and aspirin-induced gastric damage in man (Tesler and Lim 1981; Konturek et al. 1986). The mechanism for this protective action of sucrdfate is not known, but several groups have suggested that stimulation of gastric prostaglandin synthesis may be an important contributing factor (Hollander et a1. B 984; Konturek et al. 1986, 1987; Ligumsky et al. 1984). A similar mechanism of action has been proposed for the reduction of gastric mucosd damage observed after oral administration of a "mild il~itant," such as 4% NaCl, 20% ethanol, or 8.25 M HCl (Konturek et al. 1982; Robert et al. 1983). Since sucralfate has also been shown to have an irritant action on the rat gastric mucosa (Tmawski et 1986)9 we investigated the possibility that this compound reduces ethanol-induced gastric damage via the same mechanism as do "mild irritants." This may be of particular relevance in light of recent evidence that the protection observed after administration of "mild irritants" is not mediated via prsstaglandin synthesis (Hawkey et al. L 985; Wallace 19881, and the ' ~ u t h o rfor correspondence.

report of Shea-Donahue et aB. (1986) that sueralfate administration to rhesus monkeys did not result in significant increases in gastric prostaglandin synthesis, but did provide significant protection against aspirin-induced damage. Thus, in the present study the effects sf sucralfate on gastric 6-ketoprostaglandin F1, (6WGF)synthesis were assessed, as was the effect of inhibition of endogenous prostaglandin bicasynthesis on the protective properties of suemlfate. Since an irritant might be expected to stimulate the release of other mediators, we have also examined the effects of sucralfate on gastric leukstriene C4 (LTC4) synthesis. An ex viva gastric chamber preparation was used in some of these studies, as it facilitated the local application of sucralfate to only one side (dorsal or ventral) of the mucosa, allowing for comparisons in a paired manner to the untreated side of the mucosa.

Methods

Male Wistar rats weighing 175-200 g were obtained from Canadian Breeding Farms (Montreal) and were housed in rack-mounteda wire-mes cages (