Alendronate induces gastric damage by reducing nitric oxide synthase expression and NO/cGMP/KATP signaling pathway

•We evaluate the role of the NO/cGMP/KATP signaling pathway.•We study the nitric oxide synthase (NOS) expression in alendronate-induced gastric damage.•Sodium nitroprusside and l-arginine protects the gastric mucosa.•Alendronate reduced NO generation by modulating NOS expression.

Chronic use of alendronate has been linked to gastrointestinal tract problems. Our objective was to evaluate the role of the NO/cGMP/KATP signaling pathway and nitric oxide synthase expression in alendronate-induced gastric damage. Rats were either treated with the NO donor, sodium nitroprusside (SNP; 1, 3, and 10 mg/kg), or the NO synthase (NOS) substrate, l-arginine (l-Arg; 50, 100, and 200 mg/kg). Some rats were pretreated with either ODQ (a guanylate cyclase inhibitor; 10 mg/kg) or glibenclamide (KATP channels blocker; 10 mg/kg). In other experiments, rats were pretreated with l-NAME (non-selective NOS inhibitor; 10 mg/kg), 1400W (selective inducible NOS [iNOS] inhibitor; 10 mg/kg), or l-NIO (a selective endothelial NOS [eNOS] inhibitor; 30 mg/kg). After 1 h, the rats were treated with alendronate (30 mg/kg) by gavage for 4 days. SNP and l-Arg prevented alendronate-induced gastric damage in a dose-dependent manner. Alendronate reduced nitrite/nitrate levels, an effect that was reversed with SNP or l-Arg treatment. Pretreatment with ODQ or glibenclamide reversed the protective effects of SNP and l-Arg. l-NAME, 1400W, or l-NIO aggravated the severity of alendronate-induced lesions. In addition, alendronate reduced the expression of iNOS and eNOS in the gastric mucosa. Gastric ulcerogenic responses induced by alendronate were mediated by a decrease in NO derived from both eNOS and iNOS. In addition, our findings support the hypothesis that activation of the NO/cGMP/KATP pathway is of primary importance for protection against alendronate-induced gastric damage.