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Role of the NO/cGMP/K(ATP) pathway in the protective effects of sildenafil against ethanol-induced gastric damage in rats.

Medeiros JV, Gadelha GG, Lima SJ, Garcia JA, Soares PM, Santos AA, Brito GA, Ribeiro RA, Souza MH

1Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Ceara, Brazil.

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/K(ATP) pathway in the protective effects of sildenafil against ethanol-induced gastric damage.Experimental approach:Rats were treated with L-NAME (1 or 3 mg kg(-1), i.p.) or with L-arginine (200 mg kg(-1), i.p.) + L-NAME (3 mg kg(-1), i.p.), the guanylate cyclase inhibitor, ODQ (10 mg kg(-1), i.p.), glibenclamide (0.1, 0.3, 1 or 3 mg kg(-1), i.p.) or with glibenclamide (1 mg kg(-1), i.p.) + diazoxide (3 mg kg(-1), i.p.). After thirty minutes, the rats received sildenafil (1 mg kg(-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/K(ATP) pathway.British Journal of Pharmacology (2008) 153, 721-727; doi:10.1038/sj.bjp.0707605; published online 10 December 2007.

Published 18 February 2008 in Br J Pharmacol, 153(4): 721-7.
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