Published Online
on December 22, 2003

A more recent version of this article appeared on January 20, 2004

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Submitted on January 27, 2003
Revised on August 11, 2003
Accepted on September 22, 2003

Adrenomedullin Infusion Attenuates Myocardial Ischemia/Reperfusion Injury Through the Phosphatidylinositol 3-Kinase/Akt-Dependent Pathway

Hiroyuki Okumura MD, Noritoshi Nagaya MD^*, Takefumi Itoh MD, Ichiro Okano PhD, Jun Hino PhD, Kenji Mori PhD, Yoshitane Tsukamoto MD, Hatsue Ishibashi-Ueda MD, Senri Miwa MD, Keiichi Tambara MD, Shinya Toyokuni MD, Chikao Yutani MD, and Kenji Kangawa PhD

From the Department of Biochemistry (H.O., I.O., J.H., K.M., K.K.), National Cardiovascular Center Research Institute, Osaka, Japan; Department of Internal Medicine (N.N., T.I.) and Department of Pathology (Y.T., H.I.-U., C.Y.), National Cardiovascular Center, Osaka, Japan; and Department of Cardiovascular Surgery (S.M., K.T.) and Department of Pathology and Biology of Diseases (S.T.), Graduate School of Medicine, Kyoto University, Kyoto, Japan.

^* To whom correspondence should be addressed. E-mail: nagayann{at}hsp.ncvc.go.jp.

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.

Methods and 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.

Key words: peptides • reperfusion • apoptosis • myocardial infarction • hemodynamics

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