Abstract
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 E2 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 H2 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.
Highlights
Angiotensin II, the central product of the renin–angiotensin system, induces oxidative stress and inflammation[8], and constricts the gastric vasculature[9] by activating the angiotensin II type 1 (AT1) receptor[10]
More than 90% of Asymmetric dimethylarginine (ADMA) in rats is degraded via hydrolysis by dimethylarginine dimethylaminohydrolase-1 (DDAH-1), which plays a vital role in maintaining nitric oxide (NO) bioavailability[32]
The present study depicted for the first time a significant gastroprotective potential of irbesartan in indomethacin-induced gastric injury in rats
Summary
Angiotensin II, the central product of the renin–angiotensin system, induces oxidative stress and inflammation[8], and constricts the gastric vasculature[9] by activating the angiotensin II type 1 (AT1) receptor[10]. Angiotensin II type 1 receptor blockers, have emerged as intriguing candidates for gastroprotection showing anti-secretory, antioxidant and anti-inflammatory effects[10,11] They have shown beneficial effects on healing of pre-existing gastric ulcers via enhancing gastric macro- and microcirculations as well as gastric tissue oxygenation[12]. There is indisputable evidence that other prostaglandin-independent mechanisms are involved These include generation of reactive oxygen species (ROS), initiation of lipid peroxidation and infiltration of neutrophils secondary to the production of inflammatory mediators such as tumor necrosis factor alpha (TNF-α) and leukotrienes[20,21,22]. The present study was, undertaken to investigate the possible gastroprotective role of irbesartan in indomethacin-induced gastric injury model in rats, in an attempt to introduce a single drug that can concomitantly control hypertension and gastric injury. Targeting gastric mucosal DDAH/ADMA and EGFR/ERK1/2 signaling, MMP-9 activation, inflammatory and apoptotic cascades by AT1 receptor blockade has been addressed
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