Alendronate induces gastric damage by reducing nitric oxide synthase expression and NO/cGMP/K(ATP) signaling pathway.
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.
Post-Graduation Program in Biotechnology, Biotechnology and Biodiversity Center Research (BIOTEC), Federal University of Piauí, Parnaíba, PI, Brazil.
Renan O
RO
Silva
Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil.
Larisse T
LT
Lucetti
Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil.
Deysi V T
DV
Wong
Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil.
Karoline S
KS
Aragão
Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil.
Eudmar M A
EM
Junior
Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil.
Pedro M G
PM
Soares
Post-Graduation Program in Biotechnology, Biotechnology and Biodiversity Center Research (BIOTEC), Federal University of Piauí, Parnaíba, PI, Brazil; Post-Graduation Program in Pharmacology, Federal University of Piauí, Teresina, PI, Brazil.
André Luiz R
AL
Barbosa
Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil.
Ronaldo A
RA
Ribeiro
Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil.
Marcellus H L P
MH
Souza
Post-Graduation Program in Biotechnology, Biotechnology and Biodiversity Center Research (BIOTEC), Federal University of Piauí, Parnaíba, PI, Brazil; Post-Graduation Program in Pharmacology, Federal University of Piauí, Teresina, PI, Brazil. Electronic address: jandvenes@ufpi.edu.br.
Jand-Venes R
JV
Medeiros
D000284:Administration, Oral; D019386:Alendronate / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D054086:KATP Channels / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D013329:Structure-Activity Relationship
D054086:KATP Channels; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D019386:Alendronate
Alendronate; Gastric damage; Nitric oxide; Nitric oxide synthase