title: Adrenomedullin infusion attenuates myocardial ischemia/reperfusion injury through the phosphatidylinositol 3-kinase/Akt-dependent pathway.
abstract: BACKGROUND
  Infusion of adrenomedullin (AM) has beneficial hemodynamic effects in patients with heart failure. However, the effect of AM on myocardial ischemia/reperfusion remains unknown.
  
  
  RESULTS
  Male Sprague-Dawley rats were exposed to a 30-minute period of ischemia induced by ligation of the left coronary artery. They were randomized to receive AM, AM plus wortmannin (a phosphatidylinositol 3-kinase [PI3K] inhibitor), or saline for 60 minutes after coronary ligation. Hemodynamics and infarct size were examined 24 hours after reperfusion. Myocardial apoptosis was also examined 6 hours after reperfusion. The effect of AM on Akt phosphorylation in cardiac tissues was examined by Western blotting. Intravenous administration of AM significantly reduced myocardial infarct size (28+/-4% to 16+/-1%, P<0.01), left ventricular end-diastolic pressure (19+/-2 to 8+/-2 mm Hg, P<0.05), and myocardial apoptotic death (19+/-2% to 9+/-4%, P<0.05). Western blot analysis showed that AM infusion accelerated Akt phosphorylation in cardiac tissues and that pretreatment with wortmannin significantly attenuated AM-induced Akt phosphorylation. Moreover, pretreatment with wortmannin abolished the beneficial effects of AM: a reduction of infarct size, a decrease in left ventricular end-diastolic pressure, and inhibition of myocardial apoptosis after ischemia/reperfusion.
  
  
  CONCLUSIONS
  Short-term infusion of AM significantly attenuated myocardial ischemia/reperfusion injury. These cardioprotective effects are attributed mainly to antiapoptotic effects of AM via a PI3K/Akt-dependent pathway.
authors.affiliation: Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okumura
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Nagaya
authors.forename: Takefumi
authors.initials: T
authors.lastname: Itoh
authors.forename: Ichiro
authors.initials: I
authors.lastname: Okano
authors.forename: Jun
authors.initials: J
authors.lastname: Hino
authors.forename: Kenji
authors.initials: K
authors.lastname: Mori
authors.forename: Yoshitane
authors.initials: Y
authors.lastname: Tsukamoto
authors.forename: Hatsue
authors.initials: H
authors.lastname: Ishibashi-Ueda
authors.forename: Senri
authors.initials: S
authors.lastname: Miwa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tambara
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.forename: Chikao
authors.initials: C
authors.lastname: Yutani
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
mesh_terms: D053607:Adrenomedullin; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D053607:Adrenomedullin; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494920:Akt1 protein, rat