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

Tsung Ming Lee, Nen Chung Chang, Shinn Zong Lin

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere0202979
JournalPLoS One
Volume13
Issue number8
DOIs
Publication statusPublished - Aug 1 2018

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Proton Pump Inhibitors
nerve growth factor
Omeprazole
Superoxides
superoxide anion
Magnesium
Nerve Growth Factor
Rats
magnesium
infarction
arrhythmia
magnesium sulfate
Magnesium Sulfate
Infarction
Cardiac Arrhythmias
rats
1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
innervation
in vivo studies
Famotidine

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Effect of proton pump inhibitors on sympathetic hyperinnervation in infarcted rats : Role of magnesium. / Lee, Tsung Ming; Chang, Nen Chung; Lin, Shinn Zong.

In: PLoS One, Vol. 13, No. 8, e0202979, 01.08.2018.

Research output: Contribution to journalArticle

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