title: Differential effect of phosphodiesterase-3 inhibitors on sympathetic hyperinnervation in healed rat infarcts.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Medicine, Cardiology Section, Tainan Municipal An-Nan Hospital-China Medical University.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Lee
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
authors.forename: Nen-Chung
authors.initials: NC
authors.lastname: Chang
mesh_terms: D000818:Animals; D000077407:Cilostazol; D006321:Heart / Q000294:innervation*; D008297:Male; D020105:Milrinone / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000201:enzymology / Q000503:physiopathology; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D020105:Milrinone; D000077407:Cilostazol