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Am J Physiol Heart Circ Physiol 296: H1949-H1959, 2009. First published April 3, 2009; doi:10.1152/ajpheart.00903.2008
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Effect of ATP-sensitive potassium channel agonists on sympathetic hyperinnervation in postinfarcted rat hearts

Chih-Sen Kang,1 Chien-Chang Chen,2 Chih-Chan Lin,3 Nen-Chung Chang,4 and Tsung-Ming Lee5

1Department of Cardiovascular Medicine, Min-Sheng General Hospital, Taoyuan, and 2Cardiology Section, Department of Surgery; 3Department of Medical Research, Chi-Mei Medical Center, 4Cardiology Section, Department of Medicine, Taipei Medical University and Hospital; and 5Cardiology Section, Department of Medicine, Taipei Medical University and Chi-Mei Medical Center, Tainan, Taiwan

Submitted 18 August 2008 ; accepted in final form 18 March 2009

Although the acute administration of ATP-sensitive potassium (KATP) channel agonists provides a neuroprotection, it is unclear whether similar benefits are found by modulating sympathetic innervation in chronic settings after myocardial infarction. We assessed whether KATP channel agonists can attenuate the sprouting of cardiac sympathetic nerves after infarction. Male Wistar rats after ligating coronary artery were randomized to either saline, nicorandil, pinacidil, glibenclamide, or a combination of 1) nicorandil and glibenclamide or 2) pinacidil and glibenclamide for 4 wk. To elucidate the role of mitochondrial KATP channels in modulating nerve growth factor, 5-hydroxydecanoate was assessed in an in vitro model. The measurement of myocardial norepinephrine levels revealed a significant elevation in saline-treated infarcted rats compared with sham-operated rats, consistent with excessive sympathetic innervation. Excessive sympathetic innervation was blunted after giving the rats either nicorandil or pinacidil, compared with saline, as assessed by the immunohistochemical analysis of tyrosine hydroxylase, growth associated protein-43, and neurofilament and Western blot analysis and real-time quantitative RT-PCR of nerve growth factor. The arrhythmic scores during programmed stimulation in the saline- or glibenclamide-treated infarcted rats were significantly higher than those of rats treated with KATP channel agonists. In contrast, the beneficial effects of nicorandil and pinacidil were abolished by administering either glibenclamide or 5-hydroxydecanoate. The sympathetic hyperinnervation after infarction is attenuated by the activation of mitochondrial KATP channels. The chronic use of mitochondrial KATP channel agonists after infarction may attenuate the arrhythmogenic response to programmed electrical stimulation.

adenosine 5'-triphosphate-sensitive potassium channel; myocardial infarction; norpinephrine; sympathetic innervation


Address for reprint requests and other correspondence: T.-M. Lee, Cardiology Section, Dept. of Medicine, Chi-Mei Medical Ctr., 901, Chung-Hwa Rd., Yang-Kan City, Tainan, 710, Taiwan (e-mail: tsungm.lee{at}msa.hinet.net)






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