Blockade of Cardiac Proton Pump Impairs Ventricular Remodeling Through a Superoxide-DDAH-Dependent Pathway in Infarcted Rats.

backgroundProton pump inhibitors (PPIs) are frequently used to prevent or treat peptic ulcers. Recently, PPIs have been shown to increase the risk of myocardial infarction. The purpose of this study was to determine whether PPIs adversely affect ventricular remodeling in infarcted rats.

methodsMale Wistar rats were randomly assigned to receive either vehicle, omeprazole, omeprazole + vitamin C, omeprazole + olmesartan, or famotidine treatment for 4 weeks starting 24 hours after inducing myocardial infarction by ligating coronary arteries.

resultsCompared with vehicle-treated infarcted rats, omeprazole-treated infarcted rats had significant changes with reduced myocardial vitamin C levels, increased oxidant production, and decreased dimethylarginine dimethylaminohydrolase 2 (DDAH2) activity, which in turn increased asymmetric dimethylarginine (ADMA) levels and impaired ventricular remodeling. With gastric protection similar to omeprazole, the H2 blocker famotidine had no effect on ventricular remodeling. In contrast to the in vivo results, the ex vivo study showed similar superoxide and DDAH2 protein levels between vehicle- and omeprazole-treated infarcted rats, suggesting involvement of gastric vitamin C uptake rather than myocardial vitamin C in mediating the impaired axis of vitamin C-superoxide-DDAH2 in the in vivo measurements. The administration of PPIs was associated with impaired DDAH2 expression and increased myocardial ADMA, which impaired ventricular remodeling after infarction. These effects were prevented by the coadministration of vitamin C or olmesartan.

conclusionsOur results indicate that the administration of PPIs was associated with impaired DDAH2 expression and increased myocardial ADMA by reducing gastric vitamin C uptake, which impaired ventricular remodeling after infarction.