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(Circulation. 2008;118:S32-S37.)
© 2008 American Heart Association, Inc.

Myocardial Protection, Perioperative Management, and Vascular Biology

Loss of Myocardial Ischemic Postconditioning in Adenosine A₁ and Bradykinin B₂ Receptors Gene Knockout Mice

Lei Xi, MD; Anindita Das, PhD; Zhi-Qing Zhao, MD, PhD; Vanessa F. Merino, PhD; Michael Bader, PhD; Rakesh C. Kukreja, PhD

From the Division of Cardiology, Department of Internal Medicine (L.X., A.D., R.C.K.), Virginia Commonwealth University, Richmond; Division of Cardiothoracic Surgery, Department of Surgery (Z.-Q.Z.), Emory University, Atlanta, Ga; Max-Delbrück-Center for Molecular Medicine (V.F.M., M.B.), Berlin-Buch, Germany.

Correspondence to Lei Xi, MD, Assistant Professor, Division of Cardiology, Box 980204, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-042, Richmond, VA 23298-0204. E-mail lxi{at}vcu.edu

Background— Ischemic postconditioning (PostC) is a recently described cardioprotective modality against reperfusion injury, through series of brief reflow interruptions applied at the very onset of reperfusion. It is proposed that PostC can activate a complex cellular signaling cascade, in which cell membrane receptors could serve as the upstream triggers of PostC. However, the exact subtypes of such receptors remain controversial or uninvestigated. To this context, the purpose of present study was to determine the definitive role of adenosine A₁ and bradykinin B₁ and B₂ receptors in PostC.

Methods and Results— The hearts isolated from adult male C57BL/6J wild-type mice or the mice lacking adenosine A₁, or bradykinin B₁ or B₂ receptors subjected to zero-flow global ischemia and reperfusion in a Langendorff model. PostC, consisting of 6 cycles of 10 seconds of reperfusion and 10 seconds of ischemia, demonstrated significantly reduced myocardial infarct size (22.8±3.1%, mean±SEM) as compared with the non-PostC wild-type controls (35.1±2.8%, P<0.05). The infarct-limiting protection of PostC was absent in adenosine A₁ receptor knockout mice (34.9±2.7%) or bradykinin B₂ receptor knockout mice (33.3±1.7%) and was partially attenuated in bradykinin B₁ receptor-deficient mice (25.6±2.9%; P>0.05). On the other hand, PostC did not significantly alter postischemic cardiac contractile function and coronary flow.

Conclusions— With the use of three distinctive strains of gene knockout mice, the current study has provided the first conclusive evidence showing PostC-induced infarct-limiting cardioprotection could be triggered by activation of multiple types of cell membrane receptors, which include adenosine A₁ and bradykinin B₂ receptors.

Key Words: adenosine • bradykinin • infarction • receptors • reperfusion

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