title: High-dose fasudil preserves postconditioning against myocardial infarction under hyperglycemia in rats: role of mitochondrial KATP channels.
abstract: BACKGROUND
  The current study was carried out to determine whether fasudil hydrochloride (fasudil), a Rho-kinase inhibitor, has myocardial postconditioning (PostC) activity under hyperglycemia as well as normoglycemia, and if so, whether the effects could be mediated by mitochondrial ATP-sensitive potassium (m-KATP) channels.
  
  
  METHODS
  Male Sprague-Dawley rats were anesthetized with sodium pentobarbital. After opening the chest, all rats underwent 30-min coronary artery occlusion followed by 2-h reperfusion. The rats received low-dose (0.15 mg/kg) or high-dose (0.5 mg/kg) fasudil or diazoxide, an m-KATP channel opener, at 10 mg/kg, just before reperfusion under normoglycemic or hyperglycemic conditions. In another group, rats received 5-hydroxydecanoic acid (5HD), an m-KATP channel blocker, at 10 mg/kg, before high-dose fasudil. Myocardial infarct size was expressed as a percentage of area at risk (AAR).
  
  
  RESULTS
  Under normoglycemia, low-dose and high-dose fasudil and diazoxide reduced myocardial infarct size (23 ± 8%, 21 ± 9% and 21 ± 10% of AAR, respectively) compared with that in the control (42 ± 7%). Under hyperglycemia, low-dose fasudil (40 ± 11%) and diazoxide (44 ± 14%) could not exert this beneficial effect, but high-dose fasudil reduced myocardial infarct size in the same manner as under normoglycemia (21 ± 13%). 5HD prevented fasudil-induced reduction of myocardial infarct size (42 ± 13%).
  
  
  CONCLUSIONS
  Fasudil induces PostC against myocardial infarction via activation of m-KATP channels in the rat. Although hyperglycemia attenuates the PostC, high-dose fasudil can restore cardioprotection.
authors.affiliation: Department of Anesthesiology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Taiga
authors.initials: T
authors.lastname: Ichinomiya
authors.forename: Sungsam
authors.initials: S
authors.lastname: Cho
authors.forename: Ushio
authors.initials: U
authors.lastname: Higashijima
authors.forename: Shuhei
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Takuji
authors.initials: T
authors.lastname: Maekawa
authors.forename: Koji
authors.initials: K
authors.lastname: Sumikawa
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006880:Hydroxy Acids / Q000494:pharmacology; D006943:Hyperglycemia / Q000150:complications* / Q000503:physiopathology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D023421:Models, Animal; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000503:physiopathology; D015221:Potassium Channels / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D003652:Decanoic Acids; D006880:Hydroxy Acids; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; C117780:mitochondrial K(ATP) channel; C052853:5-hydroxydecanoic acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D003981:Diazoxide; C049347:fasudil