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

Abstract

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 10mg/kg), or the NO synthase (NOS) substrate, l-arginine (l-Arg; 50, 100, and 200mg/kg). Some rats were pretreated with either ODQ (a guanylate cyclase inhibitor; 10mg/kg) or glibenclamide (KATP channels blocker; 10mg/kg). In other experiments, rats were pretreated with l-NAME (non-selective NOS inhibitor; 10mg/kg), 1400W (selective inducible NOS [iNOS] inhibitor; 10mg/kg), or l-NIO (a selective endothelial NOS [eNOS] inhibitor; 30mg/kg). After 1h, the rats were treated with alendronate (30mg/kg) by gavage for 4days. 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.