A Novel Role of Irbesartan in Gastroprotection against Indomethacin-Induced Gastric Injury in Rats: Targeting DDAH/ADMA and EGFR/ERK Signaling

• Published in: Scientific reports 2018-03, Vol.8 (1), p.4280-12, Article 4280
• Main Authors: Shahin, Nancy N., Abdelkader, Noha F., Safar, Marwa M.
• Format: Article
• Language: English
• Subjects: 13/51; 14/63; 38/77; 692/308/2778; 692/4020/1503/583/1722; Acidity; Angiotensin; Angiotensin II; Apoptosis; Caspase; Caspase-3; Cyclooxygenase-2; Epidermal growth factor; Epidermal growth factor receptors; Extracellular matrix; Extracellular signal-regulated kinase; Gastric juice; Gene expression; Humanities and Social Sciences; Indomethacin; Inflammation; Kinases; Matrix metalloproteinase; Metalloproteinase; Mucosa; multidisciplinary; Oral administration; Pharmacodynamics; Pharmacokinetics; Prostaglandin E2; Ranitidine; Rodents; Science; Science (multidisciplinary); Tumor necrosis factor-α
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-22727-6

The advent of angiotensin II type 1 receptor blockers (ARBs) as intriguing gastroprotective candidates and the superior pharmacokinetics and pharmacodynamics displayed by irbesartan compared to many other ARBs raised the interest to investigate its gastroprotective potential in a rat model of gastric injury. Irbesartan (50 mg/Kg) was orally administered to male Wistar rats once daily for 14 days; thereafter gastric injury was induced by indomethacin (60 mg/Kg, p.o). Irbesartan reduced gastric ulcer index, gastric acidity, and ameliorated indomethacin-induced gastric mucosal apoptotic and inflammatory aberrations, as demonstrated by hampering caspase-3, prostaglandin E 2 and tumor necrosis factor-alpha levels and cyclooxygenase-2 mRNA expression. This ARB increased mucosal dimethylarginine dimethylaminohydrolase-1 (DDAH-1) gene expression and decreased elevated levels of matrix metalloproteinase-9, asymmetric dimethylarginine (ADMA), epidermal growth factor receptor (EGFR) mRNA and phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Histopathological evaluation corroborated biochemical findings. Overall efficacy of irbesartan was comparable to ranitidine, the widely used H 2 receptor blocker. In conclusion, irbesartan exerts significant gastroprotection against indomethacin-induced mucosal damage via acid-inhibitory, anti-inflammatory, anti-apoptotic and extracellular matrix remodeling mechanisms that are probably mediated, at least partly, by down-regulating DDAH/ADMA and EGFR/ERK1/2 signaling.