Ischemic preconditioning prevents the impairment of hypoxic coronary vasodilatation caused by ischemia/reperfusion - Role of adenosine A(1)/A(3) and bradykinin B-2 receptor activation

被引:47
作者
Giannella, E [1 ]
Mochmann, HC [1 ]
Levi, R [1 ]
机构
[1] CORNELL UNIV, COLL MED, DEPT PHARMACOL, NEW YORK, NY 10021 USA
关键词
adenosine; bradykinin; hypoxic coronary vasodilation; ischemic preconditioning; nitric oxide;
D O I
10.1161/01.RES.81.3.415
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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% N-2, consisted of an approximate to 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 approximate to 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 A(1) receptor agonist N-6-cyclopentyladenosine and prevented by the A(1) receptor antagonist N-0861. In addition, the A(1) receptor agonist N-6-(3-iodobenzyl)adenosine-5'-N-methyl-carboxamide had a similar protective effect. The bradykinin B-2 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 A(1)/A(3) and bradykinin B-2 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.
引用
收藏
页码:415 / 422
页数:8
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