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.