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J Thorac Cardiovasc Surg 2003;126:148-159
© 2003 The American Association for Thoracic Surgery

Cardiopulmonary support and physiology

Integrated pharmacological preconditioning in combination with adenosine, a mitochondrial KATP channel opener and a nitric oxide donor

Yuka Uchiyama, MDa, Hajime Otani, MDb,*, Takayuki Okada, MDb, Takamichi Uchiyama, MDb, Hideki Ninomiya, MDb, Masakuni Kido, MDb, Hiroji Imamura, MDb, Shinichi Nakao, MDa, Koh Shingu, MDa

a Department of Anesthesiology, Kansai Medical University, Moriguchi City, Japan
b Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Moriguchi City, Japan

Received for publication June 21, 2002; revisions received August 28, 2002; accepted for publication September 16, 2002.

* Address for reprints: Hajime Otani, MD, The Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, 570-8507 Japan
otanih{at}takii.kmu.ac.jp

BACKGROUND: Mitochondrial KATP channel activation is an essential component of ischemic preconditioning. These channels are selectively opened by diazoxide and may be up-regulated by adenosine and nitric oxide. Therefore, pharmacological preconditioning with diazoxide in combination with adenosine and a nitric oxide donor (triple-combination pharmacological preconditioning) may enhance cardioprotection.

METHODS AND RESULTS: Isolated and perfused rat hearts underwent ischemic preconditioning with 3 cycles of 5 minutes of ischemia and 5 minutes of reperfusion before 5 minutes of oxygenated potassium cardioplegia and 35 minutes of ischemia. Pharmacological preconditioning was performed by adding adenosine, diazoxide, and a nitric oxide donor S-nitroso-N-acetyl-penicillamine each alone or in combinations for 25 minutes followed by 10 minutes washout before cardioplegic arrest. Only triple-combination pharmacological preconditioning conferred significant cardioprotection as documented by highly improved left ventricular function and limited creatine kinase release during reperfusion that was comparable to that afforded by ischemic preconditioning. Mitochondrial KATP channel activity assessed by flavoprotein oxidation was increased by diazoxide, but no further increase in flavoprotein oxidation was obtained by ischemic preconditioning and triple-combination pharmacological preconditioning. Significant activation of protein kinase C-{epsilon} was observed in only ischemic preconditioning and triple-combination pharmacological preconditioning. Pretreatment with the mitochondrial KATP channel inhibitor 5-hydroxydecanoate or the protein kinase C inhibitor chelerythrine abrogated activation of protein kinase C-{epsilon} and cardioprotection afforded by ischemic preconditioning and triple-combination pharmacological preconditioning.

CONCLUSIONS: Integrated pharmacological preconditioning is not simply mediated by enhanced mitochondrial KATP channel activation, but is presumably mediated through amplified protein kinase C signaling promoted by coordinated interaction of adenosine, mitochondrial KATP channel activation, and nitric oxide.




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