1. Alendronate induces gastric damage by reducing nitric oxide synthase expression and NO/cGMP/K(ATP) signaling pathway.
- Author
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Silva RO, Lucetti LT, Wong DV, Aragão KS, Junior EM, Soares PM, Barbosa AL, Ribeiro RA, Souza MH, and Medeiros JV
- Subjects
- Administration, Oral, Alendronate administration & dosage, Animals, Dose-Response Relationship, Drug, Female, Nitric Oxide Synthase biosynthesis, Nitric Oxide Synthase metabolism, Rats, Rats, Wistar, Signal Transduction, Stomach Ulcer enzymology, Stomach Ulcer metabolism, Structure-Activity Relationship, Alendronate pharmacology, Cyclic GMP metabolism, KATP Channels metabolism, Nitric Oxide metabolism, Nitric Oxide Synthase antagonists & inhibitors, Stomach Ulcer chemically induced
- 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 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), 1400 W (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, 1400 W, 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., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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