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(Circulation Research. 1997;81:415-422.)
© 1997 American Heart Association, Inc.

Articles

Ischemic Preconditioning Prevents the Impairment of Hypoxic Coronary Vasodilatation Caused by Ischemia/Reperfusion

Role of Adenosine A₁/A₃ and Bradykinin B₂ Receptor Activation

Eliana Giannella, Hans-Christian Mochmann, , Roberto Levi

From the Department of Pharmacology, Cornell University Medical College, New York, NY.

Correspondence to Roberto Levi, MD, Department of Pharmacology, Cornell University Medical College, 1300 York Ave, New York, NY 10021. E-mail rlevi{at}mail.med.cornell.edu

Abstract We previously reported that hypoxic coronary vasodilatation (HCVD) is initiated by endothelial NO and sustained by adenosine. Prolonged ischemia/reperfusion impairs endothelium-dependent coronary vasodilatation, whereas transient ischemia (ie, preconditioning) protects the myocardium from subsequent ischemic events. Accordingly, we assessed whether prolonged ischemia/reperfusion impairs HCVD and whether preconditioning prevents this dysfunction. HCVD, elicited in isolated guinea pig hearts by a 1-minute exposure to 100% N₂, consisted of an 70% increase in coronary flow associated with enhanced nitrite/nitrate and adenosine overflow (+40% and 5-fold, respectively). After 30-minute global ischemia and 20-minute reperfusion, HCVD was decreased by 60%, and the increases in nitrite/nitrate and adenosine overflow were abolished. Preconditioning (ie, three cycles of 5-minute global ischemia+5-minute reperfusion) prevented the impairment of HCVD and fully restored the increase in nitrite/nitrate overflow, but not that of adenosine. The protective effect of preconditioning was mimicked by perfusion with the adenosine A₁ receptor agonist N⁶-cyclopentyladenosine and prevented by the A₁ receptor antagonist N-0861. In addition, the A₃ receptor agonist N⁶-(3-iodobenzyl)adenosine-5'-N-methyl-carboxamide had a similar protective effect. The bradykinin B₂ receptor antagonist HOE 140 abolished the protective effect of preconditioning, whereas the NO synthase inhibitor N-methyl-L-arginine and the cycloxygenase inhibitor indomethacin did not. Our data indicate that preconditioning restores HCVD by a process that is triggered by activation of adenosine A₁/A₃ and bradykinin B₂ receptors. The action of bradykinin is independent of NO and prostacyclin production. Once restored by preconditioning, HCVD is mediated by NO but no longer sustained by adenosine.

Key Words: adenosine • bradykinin • hypoxic coronary vasodilation • ischemic preconditioning • nitric oxide

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