Nicorandil, a Nitric Oxide Donor and ATP-Sensitive Potassium Channel Opener, Protects Against Dystrophin-Deficient Cardiomyopathy. J Cardiovasc Pharmacol Ther 2016 Nov;21(6):549-562
Date
03/05/2016Pubmed ID
26940570Pubmed Central ID
PMC5010518DOI
10.1177/1074248416636477Scopus ID
2-s2.0-84990055894 (requires institutional sign-in at Scopus site) 44 CitationsAbstract
BACKGROUND: Dystrophin-deficient cardiomyopathy is a growing clinical problem without targeted treatments. We investigated whether nicorandil promotes cardioprotection in human dystrophin-deficient induced pluripotent stem cell (iPSC)-derived cardiomyocytes and the muscular dystrophy mdx mouse heart.
METHODS AND RESULTS: Dystrophin-deficient iPSC-derived cardiomyocytes had decreased levels of endothelial nitric oxide synthase and neuronal nitric oxide synthase. The dystrophin-deficient cardiomyocytes had increased cell injury and death after 2 hours of stress and recovery. This was associated with increased levels of reactive oxygen species and dissipation of the mitochondrial membrane potential. Nicorandil pretreatment was able to abolish these stress-induced changes through a mechanism that involved the nitric oxide-cyclic guanosine monophosphate pathway and mitochondrial adenosine triphosphate-sensitive potassium channels. The increased reactive oxygen species levels in the dystrophin-deficient cardiomyocytes were associated with diminished expression of select antioxidant genes and increased activity of xanthine oxidase. Furthermore, nicorandil was found to improve the restoration of cardiac function after ischemia and reperfusion in the isolated mdx mouse heart.
CONCLUSION: Nicorandil protects against stress-induced cell death in dystrophin-deficient cardiomyocytes and preserves cardiac function in the mdx mouse heart subjected to ischemia and reperfusion injury. This suggests a potential therapeutic role for nicorandil in dystrophin-deficient cardiomyopathy.
Author List
Afzal MZ, Reiter M, Gastonguay C, McGivern JV, Guan X, Ge ZD, Mack DL, Childers MK, Ebert AD, Strande JLAuthor
Allison D. Ebert PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCardiomyopathies
Cell Line
Disease Models, Animal
Dose-Response Relationship, Drug
Humans
Induced Pluripotent Stem Cells
KATP Channels
Male
Mice, Inbred mdx
Mitochondria, Heart
Muscular Dystrophy, Animal
Myocardial Reperfusion Injury
Myocytes, Cardiac
Nicorandil
Nitric Oxide
Nitric Oxide Donors
Oxidative Stress
Reactive Oxygen Species
Recovery of Function
Signal Transduction
Ventricular Function, Left
Xanthine Oxidase
