Ischemic preconditioning prevents the impairment of hypoxic coronary vasodilatation caused by ischemia/reperfusion: role of adenosine A1/A3 and bradykinin B2 receptor activation.
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 approximately 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 approximately 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(omega)-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.
Giannella
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E
Department of Pharmacology, Cornell University Medical College, New York, NY 10021, USA.
Mochmann
H C
HC
Levi
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R
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D003331:Coronary Vessels / Q000503:physiopathology*; D006168:Guinea Pigs; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009636:Norbornanes / Q000494:pharmacology; D043684:Receptor, Adenosine A3; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology*
D065168:Bradykinin Receptor Antagonists; D009636:Norbornanes; D043684:Receptor, Adenosine A3; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D018047:Receptors, Purinergic P1; C073387:N 0861; D009569:Nitric Oxide; C065679:icatibant; D019001:Nitric Oxide Synthase; D000225:Adenine; D000241:Adenosine; D001920:Bradykinin