期刊
CARDIOVASCULAR RESEARCH
卷 58, 期 3, 页码 589-601出版社
OXFORD UNIV PRESS
DOI: 10.1016/S0008-6363(03)00259-1
关键词
experimental; heart; organ; pathophysiology
Objectives: Signaling in adenosine-mediated preconditioning is controversial. We examined roles of mitochondrial (mito) K-ATP channels, protein kinase C (PKC) and nitric oxide (NO). Methods: Langendorff perfused C57/B16 mouse hearts were subjected to 20 min ischemia and 45 min reperfusion. Effects of adenosine-mediated preconditioning were assessed in the absence and presence of signaling inhibitors. Results: Control hearts recovered 70+/-2 mmHg ventricular pressure, and released 18.1+/-2.0 IU/g lactate dehydrogenase (LDH). Preconditioning with 10 muM adenosine limited necrosis (10.6+/-1.4 IU/g) without modifying contractility (72 +/-2 mmHg) whereas 50 muM adenosine reduced necrosis (10.3+/-1.6 IU/g) and contractile dysfunction (91+/-2 mmHg). All protective effects of 10 and 50 muM adenosine were abrogated by mito, K-ATP channel blockade with 100 muM 5-hydroxydecanoate (5-HD) during the 'trigger' phase, but unaltered by PKC or NO synthase inhibition with 3 muM chelerythrine or 100 muM N-G-nitro-L-arginine methyl ester (L-NAME), respectively. Protection against necrosis was eliminated by 5-HD but unaltered by chelerythrine or L-NAME during the 'mediation' phase (ischemia-reperfusion). Reduced contractile dysfunction with 50 muM adenosine was partially sensitive to 5-HD and chelerythrine, and only eliminated by co-infusion of the inhibitors. Conclusions: Adenosine-mediated preconditioning is dose-dependent with high level stimulation reducing contractile dysfunction in addition to necrosis. Preconditioning is triggered by a mito K-ATP channel dependent process independently of PKC and NO. Subsequent protection against necrosis is also mediated by a mito, K-ATP channel dependent process independent of PKC and NO. In contrast, functional protection may be mediated by parallel mito K-ATP and PKC dependent paths. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.
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