nitroarginine and nocloprost

Sucralfate is known to protect gastric mucosa against the damaging action of strong irritants and to accelerate healing of chronic ulcers, but the mechanisms underlying these effects have not been elucidated. Similar gastroprotective and healing effects can be obtained with exogenous donors of nitric oxide (NO) and prostaglandins (PG).. The area of gastric lesions was measured by planimetry. Gastric blood flow was determined using laser Doppler flowmetry. The role of NO in the prevention of ethanol-induced gastric damage and in the healing of gastric ulcerations by sucralfate and nocloprost, a stable PGE2 analog, was therefore assessed.. Pretreatment with NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase, enhanced ethanol-induced mucosal damage and reduced dose-dependently the gastroprotective and hyperemic effects of sucralfate. The doses of L-NNA attenuating significantly the protective effects of sucralfate were 25-50 mg/kg. The effects of L-NNA were reversed by the addition of L-arginine but not D-arginine. For comparison, the gastroprotective (but not hyperemic) effects of nocloprost were not affected by the pretreatment with L-NNA and/or arginine. Daily treatment with L-NNA (50 mg/kg per day) prolonged the healing of chronic gastric ulcers and significantly reduced the acceleration of healing by sucralfate.. We conclude that (i) the gastroprotective and hyperemic effects of sucralfate involve, at least in part, the NO-arginine pathway, (ii) the ulcer healing effects of sucralfate may also involve NO, probably through the hyperemia around the ulcer, and (iii) NO is not essential for the mucosal protection of PGE2 analog, but may account for the gastric vasodilatory effect of this PG.

Topics: Animals; Anti-Ulcer Agents; Arginine; Dose-Response Relationship, Drug; Ethanol; Gastric Mucosa; Laser-Doppler Flowmetry; Male; Nitric Oxide; Nitroarginine; Prostaglandins F, Synthetic; Rats; Rats, Wistar; Stomach Ulcer; Sucralfate; Vasodilator Agents

Pretreatment with sucralfate is known to protect gastric mucosa against the damaging effect of strong irritants, and this protection is accompanied by an increase in mucosal blood flow but the mechanisms underlying these effects have not been elucidated. Similar gastroprotective and hyperemic effects can be obtained with exogenous prostaglandins (PG), mild irritants such as dilute ethanol, and by capsaicin. In this study we investigated the role of nitric oxide (NO) in the prevention of ethanol-induced gastric damage and gastric blood flow by sucralfate, mild irritant such as 20% ethanol, capsaicin, and nocloprost, a stable PGE2 analog. Pretreatment with NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase, enhanced ethanol-induced mucosal damage and reduced dose-dependently the gastroprotective and hyperemic effects of sucralfate, dilute ethanol, and capsaicin. The doses of L-NNA attenuating significantly the protective effects of sucralfate or 20% ethanol were 25-50 mg/kg, while those reducing the protection by capsaicin were 6.2-12.5 mg/kg. The attenuating effect of L-NNA on gastroprotection was reversed by L-arginine but not D-arginine. For comparison, the gastroprotective (but not hyperemic) effect of nocloprost was not affected by the pretreatment with L-NNA and/or arginine. We conclude that sucralfate, mild irritant, and capsaicin activate the NO system that may contribute to their gastroprotective effect through enhancing mucosal circulation but that NO is not essential for the mucosal protection by PGE2 analog.

Topics: Animals; Arginine; Capsaicin; Ethanol; Gastric Mucosa; Irritants; Male; Nitric Oxide; Nitroarginine; Prostaglandins F, Synthetic; Rats; Rats, Wistar; Regional Blood Flow; Sucralfate

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

We investigated the role of nitric oxide (NO) and prostaglandins (PG) in the prevention by sucralfate of ethanol-induced gastric damage and the decrease of gastric blood flow and compared them with those obtained with nocloprost, a potent locally acting gastroprotective agent. Sucralfate and nocloprost given intragastrically (i.g.) protected dose dependently the gastric mucosa against the damage by absolute ethanol and prevented the decrease in blood flow induced by ethanol. Pretreatment with NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase decreased dose dependently the protection and the maintenance of blood flow provided by sucralfate but not by nocloprost. This decrease of sucralfate protection was antagonized by L-arginine but not D-arginine. Pretreatment with indomethacin also reversed, in part, the protective and hyperemic effects of sucralfate but the combination of both indomethacin and L-NNA completely abolished these effects. We conclude that sucralfate activates both the NO and PG systems that cooperate in the gastroprotective action of this drug and that NO is not involved in the protection induced by a PGE2 analog.

Topics: Animals; Anti-Ulcer Agents; Arginine; Ethanol; Indomethacin; Male; Nitric Oxide; Nitroarginine; Prostaglandins; Prostaglandins F, Synthetic; Rats; Rats, Inbred Strains; Regional Blood Flow; Stomach; Stomach Ulcer; Sucralfate