Effects of KR-31378, a novel ATP-sensitive potassium channel activator, on hypertrophy of H9c2 cells and on cardiac dysfunction in rats with congestive heart failure.
The present study was performed to evaluate the effects of (2S, 3S, 4R)-N"-cyano-N-(6-amino-3, 4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-1-benzopyran-4yl)-N'-benzylguanidine (KR-31378), a novel mitochondrial ATP-sensitive potassium channel activator, on hypertrophy of H9c2 cells and on cardiac dysfunction in rats with congestive heart failure. In rat heart-derived H9c2 cells treated with hypertrophic agonists, such as angiotensin II, phenylephrine, isoproterenol, and urotensin II, cell size was significantly increased by 27-47%. The increases in cell size induced by the hypertrophic agonists were inhibited by treatment of KR-31378 in a concentration-dependent manner. This was confirmed by the results showing that KR-31378 inhibited the angiotensin II-induced increase in cell protein content. The effect of KR-31378 on the angiotensin II-induced increase in cell size was reversed by mitochondrial ATP-sensitive potassium channel blockers, 5-hydroxydecanoate or glibenclamide. In rats with congestive heart failure, induced by permanent coronary artery occlusion for 8 weeks, KR-31378 significantly reversed the cardiac dysfunction (increase in ratios of stroke volume or cardiac output to body weight) induced by myocardial infarction without reducing infarct size. In addition, KR-31378 significantly inhibited atrial hypertrophy (decrease in ratio of right atrium to body weight) and decreased the serum pro-atrial natriuretic peptide level, a biochemical marker of heart failure. These results suggest that KR-31378 suppresses hypertrophy induced by hypertrophic agonists in H9c2 cells and improves cardiac dysfunction in rats with congestive heart failure induced by myocardial infarction, and that the effects may be mediated by the activation of mitochondrial ATP-sensitive potassium channels.
Hwang
Geum Shil
GS
Medicinal Science Division, Korea Research Institute of Chemical Technology, #100, Jangdong, Yuseong, Daejon, 305-343, South Korea.
Oh
Kwang-Seok
KS
Koo
Hyun-Na
HN
Seo
Ho Won
HW
You
Kwan-Hee
KH
Lee
Byung Ho
BH
D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D015153:Blotting, Western; D049108:Cell Enlargement / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006333:Heart Failure / Q000097:blood / Q000209:etiology / Q000503:physiopathology*; D006984:Hypertrophy / Q000209:etiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032446:Myoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists / Q000502:physiology; D011498:Protein Precursors / Q000097:blood; D011714:Pyrans / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006146:Guanidines; C438686:N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine; D024661:Potassium Channels, Inwardly Rectifying; D011498:Protein Precursors; D011714:Pyrans; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; D020928:Mitogen-Activated Protein Kinases