Role of the NO/cGMP/KATP pathway in the protective effects of sildenafil against ethanol-induced gastric damage in rats

Background and purpose: Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase. Sildenafil, acting via NO-dependent mechanisms, prevents indomethacin- induced gastropathy. Activation of ATP-sensitive potassium channels (K-ATP) is involved in gastric defence. Our objective was to evaluate the role of the NO/cGMP/KATP pathway in the protective effects of sildenafil against ethanol-induced gastric damage. Experimental approach: Rats were treated with L-NAME (1 or 3mg kg(-1), i. p.) or with L-arginine (200mgkg(-1), i. p.) + L-NAME (3mgkg(-1), i. p.), the guanylate cyclase inhibitor, ODQ (10mgkg(-1), i. p.), glibenclamide (0.1, 0.3, 1 or 3mgkg(-1), i. p.) or with glibenclamide (1mgkg(-1), i. p.) + diazoxide (3mgkg(-1), i. p.). After thirty minutes, the rats received sildenafil (1mgkg(-1), by gavage), followed by intragastric instillation of absolute ethanol (4 ml kg(-1)) to induce gastric damage. One hour later, gastric damage (haemorrhagic or ulcerative lesions) was measured with a planimetry programme. Samples of stomach were also taken for histopathological assessment and for assays of tissue glutathione and haemoglobin. Key results: Sildenafil significantly reduced ethanol-induced gastric damage in rats. L-NAME alone, without L-arginine, significantly reversed the protection afforded by sildenafil. Inhibition of guanylate cyclase by ODQ completely abolished the gastric protective effect of sildenafil against ethanol-induced gastric damage. Glibenclamide alone reversed sildenafil's gastric protective effect. However, glibenclamide plus diazoxide did not alter the effects of sildenafil. Conclusions: Sildenafil had a protective effect against ethanol-induced gastric damage through the activation of the NO/cGMP/KATP pathway.