Effect of proton pump inhibitors on sympathetic hyperinnervation in infarcted rats: Role of magnesium

The long-term use of proton pump inhibitors (PPIs) has been shown to increase the risk of cardiovascular mortality, however the molecular mechanisms are unknown. Superoxide has been implicated in the regulation of nerve growth factor (NGF), a mediator of sympathetic innervation. The purpose of this study was to determine whether PPIs increase ventricular arrhythmias through magnesium-mediated superoxide production in infarcted rats. Male Wistar rats were randomly assigned to receive vehicle, omeprazole, omeprazole + magnesium sulfate, or famotidine treatment for 4 weeks starting 24 hours after the induction of myocardial infarction by ligating the coronary artery. Increased myocardial superoxide and nitrotyrosine levels were noted post-infarction, in addition to a significant upregulation of NGF expression on mRNA and protein levels. Sympathetic hyperinnervation after infarction was confirmed by measuring myocardial norepinephrine and immunofluorescent analysis. Compared with the vehicle, omeprazole-treated infarcted rats had significantly reduced myocardial magnesium content, increased oxidant production, and increased sympathetic innervation, which in turn increased ventricular arrhythmias. These effects were prevented by the coadministration of magnesium sulfate. In an in vivo study, an omeprazole-induced increase in NGF was associated with a superoxide pathway, which was further confirmed by an ex vivo study showing the attenuation of NGF levels after coadministration of the superoxide scavenger Tiron. Magnesium sulfate did not further attenuate NGF levels compared with omeprazole + Tiron. Our results indicate that the long-term administration of PPIs was associated with reduced tissue magnesium content and increased myocardial superoxide production, which exacerbated ventricular arrhythmias after infarction. Magnesium may be a potential target for PPI-related arrhythmias after infarction.