CPU228, a derivative of dofetilide, relieves cardiac dysfunction by normalizing FKBP12.6, NADPH oxidase and protein kinase C epsilon in the myocardium.
OBJECTIVE
The aim of this study was to determine if CPU228, a derivative of dofetilide, is more effective than dofetilide in attenuating isoproterenol-induced heart failure by recovering downregulated FK506 binding protein (FKBP12.6), and suppressing oxidative stress, upregulated NADPH oxidase and protein kinase C epsilon (PKC epsilon) hyperphosphorylation in the myocardium.


METHODS
Heart failure was induced by isoproterenol (1 mg/kg s.c. for 5 days) in male Sprague-Dawley rats. Intervention with either CPU228 or dofetilide (2 mg/kg on Days 3-5) was then conducted in vivo and in vitro.


RESULTS
Isoproterenol produced compromised left ventricular systolic pressure, left ventricular pressure rise (dp/dt(max)) and fall (dp/dt(min)), and left ventricular end-diastolic pressure, associated with oxidative stress, abnormal FKBP12.6, NADPH oxidase p67phox and PKC epsilon in the myocardium. CPU228 was more effective in attenuating these changes than dofetilide in vivo. Dofetilide produced a prolonged QTc to replace a shortened one. In primary neonatal cardiomyocytes, cultured with isoproterenol and treated with either CPU228 or dofetilide at 10(-8), 10(-7) and 10(-6) mol/l, isoproterenol produced a hyperadrenergic state characterized by downregulated FKBP12.6, upregulated NADPH oxidase p67phox and PKC epsilon in vitro. CPU228 was more effective than dofetilide in recovering these changes in a dose-dependent manner without a prolonged QTc.


CONCLUSIONS
CPU228 was more effective than dofetilide in attenuating heart failure by normalizing isoproterenol-induced changes, including downregulation of FKBP12.6, upregulation of NADPH oxidase and PKC epsilon hyperphosphorylation in vivo and in vitro.
Hamed
Khan Hussien
KH
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
Hu
Chen
C
Dai
De-Zai
DZ
Yu
Feng
F
Dai
Yin
Y
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D007545:Isoproterenol; D008297:Male; D019255:NADPH Oxidases / Q000187:drug effects / Q000235:genetics; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010627:Phenethylamines / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
C521406:1-(methanesulfonamido-1-naphthyloxy)-2-(N-(4-methane sulfonamidophenethyl)-N-acetamido)ethane; D000889:Anti-Arrhythmia Agents; D009281:Naphthalenes; D010627:Phenethylamines; D013449:Sulfonamides; D019255:NADPH Oxidases; D051744:Protein Kinase C-epsilon; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D007545:Isoproterenol; C063533:dofetilide