Role of ADMA/DDAH-1 and iNOS/eNOS signaling in the gastroprotective effect of tadalafil against indomethacin-induced gastric injury

Non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric ulcers represent a significant clinical concern and adversely affect the quality of life. Inducible nitric oxide synthase/endothelial nitric oxide synthase (iNOS/ eNOS) and asymmetric dimethylarginine/ dimethylarginine dimethylaminohydrolase-1 (ADMA/DDAH-1) signaling are key players in gastric ulcer pathogenesis. This work was planned to explore the role of iNOS/eNOS and ADMA/DDAH-1 signaling in rats with indomethacin-induced gastric ulcer, as potential pathways for the gastro-protective effect of tadalafil. Split into 5 separate groups, rats were assigned to control, tadalafil (10 mg/ kg, p.o), indomethacin (single oral dose of 60 mg/kg), indomethacin + pantoprazole (40 mg/kg, p.o), and indomethacin + tadalafil (10 mg/kg, p.o). The results indicated that pretreatment with tadalafil significantly reduced ulcer index (UI), increased preventive index (PI), and counteracted indomethacin-induced histopathological aberrations. Tadalafil significantly reduced the gastric content of NO while it significantly elevated that of GSH and enhanced SOD activity. It significantly reduced the gastric expression of TNF-alpha and ADMA while it significantly elevated that of COX-2, PGE-2, and DDAH-1. Western blot analysis revealed that pretreatment with tadalafil significantly reduced iNOS protein expression while it significantly elevated that of eNOS. Collectively, these data suggest that tadalafil exerts potential protective effect against indomethacin-induced ulcer through suppression of inflammation, attenuation of oxidative stress, and boosting of antioxidants. Moreover, tadalafil protective effects are mediated via upregulation of PGE-2 with modulating the signaling pathways of ADMA/ DDAH-1, and iNOS/eNOS. As a result, the current evidence corroborates the use of tadalafil in controlling gastric ulcers and preventing NSAID gastric side effects.