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.
Tashima
K
K
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Japan.
Fujita
A
A
Umeda
M
M
Takeuchi
K
K
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D001241:Aspirin / Q000031:analogs & derivatives* / Q000633:toxicity*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced; D008297:Male; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000633:toxicity; D009574:Nitro Compounds / Q000494:pharmacology; D009853:Omeprazole / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D020156:Salicylic Acid / Q000097:blood; D013272:Stomach Diseases / Q000139:chemically induced*; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy
D000897:Anti-Ulcer Agents; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D010975:Platelet Aggregation Inhibitors; C061872:FK 409; C102148:nitroaspirin; D009853:Omeprazole; D020156:Salicylic Acid; D001241:Aspirin