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Abstract
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.
Highlights
Proton pump inhibitors (PPIs) are frequently used to prevent or treat peptic ulcers, especially in patients with acute coronary syndrome who need dual antiplatelet treatment
Given that a negative correlation has been reported between magnesium levels and plasma superoxide anions [7], it is important to determine whether the use of PPIs is associated with hypomagnesemia
The values of +dP/dt and -dP/dt were significantly decreased in the infarcted group treated with omeprazole, which could be improved after the coadministration of magnesium sulfate
Summary
Proton pump inhibitors (PPIs) are frequently used to prevent or treat peptic ulcers, especially in patients with acute coronary syndrome who need dual antiplatelet treatment. Their safety has not been approved by regulatory authorities after myocardial infarction (MI). A few epidemiological studies have reported inconsistent results regarding the association between the use of PPIs and cardiovascular events. Given that a negative correlation has been reported between magnesium levels and plasma superoxide anions [7], it is important to determine whether the use of PPIs is associated with hypomagnesemia
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