Affiliation:
1. Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
2. Faculty of Medicine and Health Sciences, University of Aden, Yemen
Abstract
Abstract
Objectives
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 ε (PKCε) 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.
Key findings
Isoproterenol produced compromised left ventricular systolic pressure, left ventricular pressure rise (dp/dtmax) and fall (dp/dtmin), and left ventricular end-diastolic pressure, associated with oxidative stress, abnormal FKBP12.6, NADPH oxidase p67phox and PKCε 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 PKCε 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 PKCε hyperphosphorylation in vivo and in vitro.
Publisher
Oxford University Press (OUP)
Subject
Pharmaceutical Science,Pharmacology
Cited by
2 articles.
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