The present study investigated the gastroprotective effects of the proton pump inhibitor pantoprazole on gastric mucosal damage induced by ethanol-HCl in rats. Omeprazole was used as reference drug. The morphometric analysis of gastric histological sections revealed that pantoprazole and omeprazole dose-dependently prevented the necrotic mucosal injury evoked by ethanol-HCl (ED50 = 14.1 and 21.6 micromol/kg, respectively). These effects were associated with a marked increment of Alcian blue recovery from gastric bound mucus (ED50 = 18.8 and 29.3 micromol/kg, respectively). In addition, both pantoprazole and omeprazole inhibited gastric acid secretion in pylorus-ligated rats (ED50 = 1.5 and 3.3 micromol/kg, respectively). Further experiments indicated that the protective effects of pantoprazole were not modified by L-365,260 (a gastrin receptor antagonist), suramin (a drug able to interfere with endogenous growth factors), N(G)-nitro-L-arginine (an inhibitor of nitric oxide synthase) or systemic ablation of capsaicin-sensitive sensory nerves, whereas they were partly blocked by indomethacin (an inhibitor of prostaglandin synthesis) and fully prevented by N-ethylmaleimide (a potent blocker of sulfhydryl compounds). The present data provide histomorphometric evidence that: 1) pantoprazole is endowed with gastroprotective properties and is more active than omeprazole in preventing the necrotic mucosal damage induced by ethanol-HCl; 2) according to the rank order of ED50 values, the protective effects of both drugs appear to depend mainly on the enhancement of the gastric mucosal barrier rather than on the inhibition of acid secretion; 3) an increased production of prostaglandins, as well as an increased availability of sulfhydryl radicals at the level of the gastric mucosa may account for the gastroprotective effects of pantoprazole.

The present study investigates the possibility that imidazoline receptors mediate modulation of cholinergic motor functions of the guinea-pig ileum. For this purpose, the effects of a series of compounds with known affinity for alpha2-adrenoceptors and/or imidazoline recognition sites were examined on the cholinergic twitch contractions evoked by electrical field stimulation (0.1 Hz) of longitudinal muscle-myenteric plexus preparations. Additional experiments were carried out on ileal strips preincubated with [3H]choline, superfused with physiological salt solution containing hemicholinium-3, and subjected to electrical field stimulation (1 Hz). The stimulation-induced outflow of radioactivity was taken as an index of endogenous acetylcholine release. Alpha-methyl-noradrenaline, noradrenaline, clonidine, medetomidine, oxymetazoline and xylazine caused a concentration-dependent inhibition of twitch responses (IC50 from 0.13 to 1.05 microM; Emax from 85.9 to 92.5%). Rilmenidine and agmatine were less potent in reducing the twitch activity, and the latter compound acted also with low intrinsic activity (IC50=44.9 microM; Emax=35.5%). In interaction experiments, the inhibitory action of clonidine on twitch responses was competitively antagonized by RX 821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline), idazoxan, rauwolscine, yohimbine and BRL 44408 (2-[2H-(1-methyl-1,3-dihydroisoindole)-methyl] -4,5-dihydroimidazoline), whereas prazosin (10 microM), ARC 239 (2-(2,4-(O-methoxy-phenyl)-piperazin-1-yl)-ethyl-4,4-dimethyl- 1,3-(2H,4H)-isoquinolindione; 10 microM) and BRL 41992 (1,2-dimethyl-2,3,9,13b-tetrahydro-1H-dibenzo[c,f]imidazol[1,5-a]a zepine; 10 microM) were without effect. Rauwolscine antagonized the inhibitory effects of various agonists on ileal twitch activity in a competitive manner and with similar potency. Agmatine and idazoxan did not significantly modify the twitch contractions when tested in the presence of alpha2-adrenoceptor blockade by rauwolscine (3 microM) or RX 821002 (1 microM). Linear regression analysis showed that the affinity values of antagonists correlated with their affinity at the alpha2A and alpha2D binding sites as well as at previously classified alpha2A/D adrenoceptor subtypes, whereas no significant correlation was obtained when comparing the potency estimates of agonists and antagonists with the affinity at I1 or I2 binding sites. When tested on the electrically induced outflow of tritium, alpha-methyl-noradrenaline, noradrenaline, clonidine, medetomidine, oxymetazoline, xylazine and rilmenidine yielded inhibitory concentration-response curves which were shifted rightward to a similar extent in the presence of rauwolscine (3 microM). In the absence of further drugs, agmatine significantly reduced the evoked tritium outflow at the highest concentrations tested (10 and 100 microM), whereas idazoxan (up to 100 microM) was without effect. When RX 821002 (1 microM) was added to the superfusion medium, neither agmatine nor idazoxan modified the evoked outflow of radioactivity. The ...

In the present study, the protective effect of omeprazole on gastric mucosa injury induced by ethanol •HCl in rats and the putative mechanisms involved in this action were investigated. Misoprostol and ranitidine were used as reference drugs. The morphometric analysis of histological sections showed that omeprazole caused a significant reduction of mucosal necrotic damage, this effect being associated with a marked increase in Alcian blue recovery from gastric bound mucus. In addition, omeprazole elicited a significant inhibition of gastric acid secretion from pylorus-ligated rats. Misoprostol exerted similar effects to those obtained with omeprazole, even if the Alcian blue recovery and the acid output were affected to a lesser extent. By contrast, ranitidine failed to influence both the mucosal damage and the Alcian blue recovery, while it exerted a marked inhibition on acid secretion. The present results indicate that omeprazole is effective in protecting gastric mucosa from necrotic damage induced by ethanol •HCl and suggest that an enhancement of gastric mucus barrier may account for this protective action.

No abstract

No abstract