Differential effect of phosphodiesterase-3 inhibitors on sympathetic hyperinnervation in healed rat infarcts

Tsung-Ming Lee, Shinn Zong Lin, Nen Chung Chang

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


Background: The effect of phosphodiesterase-3 (PDE-3) inhibitors on arrhythmia remains controversial, so the purpose of this study was to determine their differential effects on sympathetic hyperinnervation and the involved mechanisms in a rat model of myocardial infarction. Methods and Results: After ligating the coronary artery, male Wistar rats were randomized to cilostazol or milrinone, chemically unrelated inhibitors of PDE-3, or vehicle for 4 weeks. The postinfarction period was associated with increased myocardial norepinephrine levels and oxidant release, as measured by myocardial superoxide level and dihydroethidine fluorescence staining. Infarcted rats in the milrinone- and cilostazol-treated groups had favorable ventricular remodeling with similar potency. Compared with milrinone, cilostazol significantly increased interstitial adenosine levels and reduced the production of myocardial cAMP and superoxide. Cilostazol significantly blunted sympathetic hyperinnervation, as assessed by immunofluorescent analysis of sympathetic innervation, and western blotting and real-time quantitative RT-PCR of nerve growth factor. Furthermore, the inhibitory effect of cilostazol on nerve growth factor was reversed by 8-cyclopentyl-1,3-dipropylxanthine, a selective A1 receptor antagonist, and enhanced by tempol administration. In spite of similar arrhythmic vulnerability during programmed stimulation in both the vehicle- and cilostazol-treated groups, cilostazol did not have proarrhythmic effects compared with milrinone. Conclusions: Unlike milrinone, cilostazol has therapeutic neutrality in arrhythmias because of adenosine uptake inhibition, which antagonizes the PDE-3-induced increase of sympathetic reinnervation via mediation of an adenosine A1 receptor-mediated antioxidation.

Original languageEnglish
Pages (from-to)366-376
Number of pages11
JournalCirculation Journal
Issue number2
Publication statusPublished - 2014


  • Arrhythmia
  • Myocardial infarction
  • Phosphodiesterase-3 inhibitors
  • Remodeling
  • Sympathetic innervation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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