Gastroprotective effects of pantoprazole against experimental mucosal damage

Abstract

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.

Lansoprazole Induces Mucosal Protection through Gastrin Receptor-Dependent Up-Regulation of Cyclooxygenase-2 in Rats

“…Lansoprazole is a PPI that is widely used to treat peptic ulcers in humans. A previous study reported that the protective effects of lansoprazole were inhibited by pretreatment with indomethacin in gastric lesion models induced by ethanol or ethanol-hydrochloric acid, suggesting that endogenous prostaglandin (PG) synthesis might account for the gastroprotective effects of lansoprazole (Blandizzi et al, 1999). Another study suggested that lansoprazole protects gastric mucosa from ethanol-and acidified taurocholate-induced damage in a dosedependent manner, with ID 50 values of 8.5 mg/kg p.o.…”

“…Proton pump inhibitors (PPIs) are potent antiulcer agents that have both gastric antisecretory and mucosal protective actions (Ruwart et al, 1984;Okabe et al, 1986;Holm, 1988;Bergmann et al, 1992;Kawano et al, 1992;Fukuda et al, 1995;Murakami et al, 1996;Blandizzi et al, 1999). The antisecretory action is due to their inhibitory effects on the H ϩ ,K ϩ -ATPase (proton pump) in parietal cells (Satoh et al, 1989;Nagaya et al, 1990).…”

Molecular mechanism and functional consequences of lansoprazole-mediated heme oxygenase-1 induction

“…These concentrations approximate the concentrations found to be effective at increasing the level of HO-1 expression in the present study. Furthermore, Blandizzi and co-workers have suggested that the ED50 of lansoprazole needed to provide gastroprotection is 2-4 times higher compared to that needed for inhibition of acid secretion [7] . The anti-inflammatory and antiproliferative actions of the HO-1 product CO, as well as the potent antioxidant effect of bilirubin, are thought to contribute to the overall protective effect of HO-1 [12] .…”

“…The anti-secretory action is mediated by their irreversible inhibition of H + /K + -ATPase, the terminal proton pump of parietal cells [5] . However, emerging evidence suggests that the benefit of PPIs is not only mediated by their potent blockade of the gastric H + /K + -ATPase, but also by their ability to provide anti-inflammatory, antiapoptotic, and antioxidative effects [6,7] . By scavenging ROS and thus protecting the mucosa, these pleiotropic effects of PPIs may be responsible for maintaining the anatomical and functional integrity of the gastric mucosa.…”

“…By scavenging ROS and thus protecting the mucosa, these pleiotropic effects of PPIs may be responsible for maintaining the anatomical and functional integrity of the gastric mucosa. In addition to a variety of endogenous factors such as prostaglandins, nitric oxide, and sulfhydryl compounds, which have been proposed to account for the gastroprotective effects of PPIs [7,8] , we previously have shown that PPIs also induce the antioxidant protein heme oxygenase-1 (HO-1) in gastric epithelial and endothelial cells [9] . The inducible stress protein HO-1 is the rate-limiting enzyme involved in heme breakdown to generate equimolar amounts of biliverdin, free iron, and CO [10] .…”