Low gastric toxicity of nitric oxide-releasing aspirin, NCX-4016, in rats with cirrhosis and arthritis

The gastric toxic effects of aspirin (ASA) and NCX-4016, a nitric oxide (NO )-releasing ASA, were compared in normal, cirrhotic, and arthritic rats. Or al administration of ASA (100 mg/kg) produced hemorrhagic lesions on the ga stric mucosa in normal rats. The gastric ulcerogenic response to ASA was si gnificantly worsened in both cirrhotic rats induced by N-nitrosodiethylamin e and in arthritic rats induced by Freund's complete adjuvant. By contrast, NCX-4016 at 190 mg/kg (a dose equimolar to 100 mg/kg of ASA) did not induc e damage in normal rat stomachs but caused slight lesions in the gastric mu cosa of both cirrhotic and arthritic rats. Plasma salicylate levels followi ng administration of ASA or NCX-4016 were not different between normal, cir rhotic, and arthritic rats, although the latter drug gave significantly low er values in any group of rats as compared to the former. Acid secretion wa s significantly increased in both cirrhotic and arthritic rats. ASA with 15 0 mM HCl caused severe gastric lesions in normal rats, the degree of damage being significantly greater than that induced by ASA alone. Coadministrati on of NOR-3, a NO donor, significantly prevented the development of gastric lesions induced by ASA, irrespective of whether or not ASA was given toget her with HCL Gastric mucosal application of ASA (100 mg/kg) for 30 min caus ed a marked reduction of transmucosal potential difference (PD) with a mini mal effect on gastric mucosal blood flow in both normal and cirrhotic rats, while that of NCX-4016 did not cause a PD reduction and produced a marked increase in the mucosal blood flow in both groups of rats. These results su ggest that gastric mucosal susceptibility to ASA-induced damage is increase d in both cirrhotic and arthritic rats (the process being partly accounted for by acid hypersecretion in these animals), NCX-4016 has even less gastri c toxicity in both cirrhotic and arthritic rats, and the gastric-sparing ef fect of NCX-4016 is due, at least partly, to an increase of gastric mucosal blood flow, mediated by NO released from this drug.