Lack of gastric toxicity of nitric oxide-releasing aspirin, NCX-4016, in the stomach of diabetic rats

We compared the gastric toxic effect of aspirin (ASA) in both normal and diabetic rats, with that of NCX-4016, a derivative of ASA with nitric oxide (NO) releasing moiety. Animals were injected with streptozotocin and used after 5 weeks of diabetes with blood glucose levels of >350 mg/dl in the presence of omeprazole. Oral administration of ASA (with 150 mM HCl) did not produce damage at 30 mg/kg in the conscious rat but caused hemorrhagic gastric lesions in STZ-diabetic rats. By contrast, NCX-4016 even at 190 mg/kg (a dose equimolar to 100 mg/kg of ASA) did not cause damage in both normal and STZ-diabetic rat stomachs. Plasma salicylic acid levels were not different between normal and diabetic rats after administration of ASA or NCX-4016, though the latter gave significantly lower levels as compared to ASA. Intragastric application of ASA (80 mM in 50 mM HCl) for 30 min caused a reduction of transmucosal PD and increase of luminal H+ loss with a minimal effect on mucosal blood flow (GMBF) in both normal and diabetic rats, yet resulting in much severe damage in the stomach of the latter group. Mucosal application of NCX-4016, however, did not cause PD reduction and luminal H+ loss, but produced a marked hyperemia, resulting in no damage in the stomach of both normal and STZ-diabetic rats. The increased gastric toxicity of ASA in STZ-diabetic rats was significantly mitigated by co-application of a NO donor FK-409 together with ASA, with an increase of GMBF despite similar degrees of PD reduction and luminal H+ loss being observed. We conclude that NCX-4016 does not have a toxic effect in either normal or diabetic rat stomachs, although the diabetic rat stomach is more vulnerable to ASA-induced damage. NCX-4016, though absorbed more slowly than ASA, counteracts the injurious effect of aspirin on the gastric mucosa, probably by increasing GMBF mediated by NO. (C) 2000 Elsevier Science Inc. All rights reserved.