title: Integrated pharmacological preconditioning in combination with adenosine, a mitochondrial KATP channel opener and a nitric oxide donor.
abstract: BACKGROUND
  Mitochondrial K(ATP) 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.
  
  
  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 K(ATP) 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 K(ATP) 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 K(ATP) channel activation, but is presumably mediated through amplified protein kinase C signaling promoted by coordinated interaction of adenosine, mitochondrial K(ATP) channel activation, and nitric oxide.
authors.affiliation: Department of Anesthesiology, Kansai Medical University, Moriguchi City, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Hajime
authors.initials: H
authors.lastname: Otani
authors.forename: Takayuki
authors.initials: T
authors.lastname: Okada
authors.forename: Takamichi
authors.initials: T
authors.lastname: Uchiyama
authors.forename: Hideki
authors.initials: H
authors.lastname: Ninomiya
authors.forename: Masakuni
authors.initials: M
authors.lastname: Kido
authors.forename: Hiroji
authors.initials: H
authors.lastname: Imamura
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nakao
authors.forename: Koh
authors.initials: K
authors.lastname: Shingu
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D003131:Combined Modality Therapy; D003326:Coronary Circulation / Q000187:drug effects; D003402:Creatine Kinase / Q000187:drug effects / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D005420:Flavoproteins / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D015640:Ion Channel Gating / Q000502:physiology; D019194:Ischemic Preconditioning; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology*; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009336:Necrosis; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D015221:Potassium Channels; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D005420:Flavoproteins; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D015221:Potassium Channels; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D011493:Protein Kinase C; D003402:Creatine Kinase; D000241:Adenosine; D003981:Diazoxide