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Effect of ATP-Sensitive Potassium Channel Agonists on Ventricular Remodeling in Healed Rat Infarcts

Tsung-Ming Lee, MD, FESC^_*, Mei-Shu Lin, PhD and Nen-Chung Chang, MD, PhD, FACC^,_*

^_* Cardiology Section, Department of Medicine, Taipei Medical University and Chi-Mei Medical Center, Tainan, Taiwan
Department of Pharmacy, National Taiwan University and Hospital, Taipei, Taiwan
Cardiology Section, Department of Medicine, Taipei Medical University and Hospital, Taipei, Taiwan.

Manuscript received June 7, 2007; revised manuscript received October 29, 2007, accepted November 19, 2007.

^_* Reprint requests and correspondence: Prof. Nen-Chung Chang, Cardiology Section, Department of Medicine, Taipei Medical University and Hospital, 252, Wu-Hsing Street, Taipei, 110, Taiwan. (Email: ncchang{at}tmu.edu.tw).

Objectives: The purpose of this study was to determine whether ATP-sensitive potassium (K_ATP) channel agonists exert a beneficial effect on the structural, functional, and molecular features of the remodeling heart in infarcted rats.

Background: Myocardial K_ATP channels have been implicated in the ventricular remodeling after myocardial infarction by inhibition of 70-kDa S6 (p70S6) kinase.

Methods: Male Wistar rats after induction of myocardial infarction were randomized to either vehicle, agonists of K_ATP channels nicorandil and pinacidil, an antagonist of K_ATP channels glibenclamide, or a combination of nicorandil and glibenclamide or pinacidil and glibenclamide for 4 weeks. To verify the role of p70S6 kinase in ventricular remodeling, rapamycin was also assessed.

Results: Significant ventricular hypertrophy was detected by increased myocyte size at the border zone isolated by enzymatic dissociation after infarction. Increased synthesis of p70S6 kinase messenger ribonucleic acid after infarction in vehicle-treated rats was confirmed by reverse transcription-polymerase chain reaction, consistent with the results of immunohistochemistry and Western blot for phosphorylated p70S6 kinase. Rats in the nicorandil- and pinacidil-treated groups significantly attenuated cardiomyocyte hypertrophy and phosphorylated p70S6 kinase expression with similar potency, as compared with vehicle. The beneficial effects of nicorandil and pinacidil were abolished by administering either glibenclamide or 5-hydroxydecanoate. Addition of rapamycin attenuated ventricular remodeling and did not have additional beneficial effects compared with those seen in rats treated with either nicorandil or pinacidil alone.

Conclusions: Activation of K_ATP channels by either nicorandil or pinacidil can attenuate ventricular remodeling, probably through a p70S6 kinase-dependent pathway after infarction.

Abbreviations and Acronyms   GAPDH = glyceraldehyde3-phosphate-dehydrogenase   HD = hydroxydecanoate   KATP = ATP-sensitive potassium   LV = left ventricle/ventricular   LVEDD = left ventricular end-diastolic diameter dimension   LVESD = left ventricular end-systolic diameter dimension   MI = myocardial infarction   p70S6 = 70-kDa S6   RT-PCR = reverse transcription-polymerase chain reaction