nocloprost and aluminum-hydroxide--magnesium-hydroxide--drug-combination

Cytoprotective drugs, including sucralfate, colloidal bismuth (De-Nol), aluminium-containing antacids (Maalox), carbenoxolone-like agents (sofalcone), and stable PGE2 analogues (nocloprost), are known to prevent acute gastric mucosal damage induced by topical irritants. This effect is usually accompanied by an elevation in mucosal blood flow. Recently, nitric oxide (NO), a potent vasorelaxant, has been implicated in gastroprotection by carbenoxolone, the prototype of cytoprotective drugs. In this study we assessed the involvement of NO in acute gastric damage induced by ethanol and in the prevention of this damage by sucralfate, Maalox, De-Nol, sofalcone, and nocloprost. Each of these drugs dose-dependently reduced the formation of ethanol-induced gastric lesions. The optimal gastroprotective dose was used in further studies to check the possible contribution of NO in this protection. Pretreatment with NG-nitro-L-arginine (L-NNA) (12.5-50 mg/kg i.v.), an inhibitor of NO synthase, dose-dependently enhanced the mucosal damage by ethanol itself and reduced the protective effects of sucralfate and Maalox but not those of sofalcone, De-Nol or nocloprost against the ethanol injury. Reduction by L-NNA of the mucosa-protective action of sucralfate or Maalox was accompanied by a decrease in gastric blood flow, which was antagonized by L-arginine (a substrate of NO synthase) but not by D-arginine. This study suggest that gastroprotective agents such sucralfate and Maalox, but not sofalcone or De-Nol, activate the NO system that may contribute to mucosal integrity and preservation of mucosal microcirculation.

Topics: Aluminum Hydroxide; Animals; Anti-Ulcer Agents; Arginine; Chalcone; Chalcones; Dose-Response Relationship, Drug; Drug Combinations; Ethanol; Gastric Mucosa; Magnesium Hydroxide; Male; Nitric Oxide; Nitroarginine; Organometallic Compounds; Prostaglandins F, Synthetic; Rats; Rats, Wistar; Regional Blood Flow; Sucralfate; Vasodilator Agents

Pretreatment with aluminium-containing antacids at their original pH or after acidification is known to protect the gastric mucosa against the damaging action of strong irritants and this protection is accompanied by an increase in gastric blood flow (GBF) but the mechanisms underlying these effects have not been elucidated. We investigated the role of endogenous nitric oxide (NO) and prostaglandins (PS) in the prevention of ethanol-induced gastric damage and the alteration of GBF by Maalox and its active component Al(OH)3. Maalox and Al(OH)3 at their original and acidic pH induced dose-dependent gastroprotection accompanied by attenuation of the reduction in GBF caused by 100% ethanol; similar protective and hyperemic effects were recorded after treatment with nocloprost, a locally active PGE2 analog, and nitroglycerin, a donor of NO. Pretreatment with indomethacin that suppressed mucosal PGE2 by about 90%, failed to affect the protective influence of Maalox or Al(OH)3 at their original or acidic pH. On the contrary, pretreatment with NG-nitro-L-arginine (L-NNA), a potent selective inhibitor of NO synthase, reversed the gastroprotective and hyperemic effects of Maalox or Al(OH)3 at original and acidic pH and this reversal was significantly antagonized by L-arginine but not D-arginine. The gastroprotective and hyperemic effects of nocloprost were not influenced by the pretreatment with L-NNA. We conclude that aluminium-containing antacids activate the NO system, which may contribute to the gastroprotective activity of these drugs through an increase in mucosal microcirculation.

Topics: Aluminum Hydroxide; Animals; Antacids; Arginine; Dinoprostone; Drug Combinations; Ethanol; Gastric Mucosa; Hydrogen-Ion Concentration; Magnesium Hydroxide; Male; Nitric Oxide; Nitroarginine; Nitroglycerin; Prostaglandins F, Synthetic; Rats; Rats, Wistar; Regional Blood Flow