Yada Toyotaka, Shimokawa Hiroaki, Hiramatsu Osamu, Haruna Yoshisuke, Morita Yoshitaka, Kashihara Naoki, Shinozaki Yoshiro, Mori Hidezo, Goto Masami, Ogasawara Yasuo, Kajiya Fumihiko
Department of Medical Engineering and Systems Cardiology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan.
Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1138-46. doi: 10.1152/ajpheart.00187.2006. Epub 2006 Apr 28.
We have recently demonstrated that endogenous H2O2 plays an important role in coronary autoregulation in vivo. However, the role of H2O2 during coronary ischemia-reperfusion (I/R) injury remains to be examined. In this study, we examined whether endogenous H2O2 also plays a protective role in coronary I/R injury in dogs in vivo. Canine subepicardial small coronary arteries (>or=100 microm) and arterioles (<100 microm) were continuously observed by an intravital microscope during coronary I/R (90/60 min) under cyclooxygenase blockade (n=50). Coronary vascular responses to endothelium-dependent vasodilators (ACh) were examined before and after I/R under the following seven conditions: control, nitric oxide (NO) synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA), catalase (a decomposer of H2O2), 8-sulfophenyltheophylline (8-SPT, an adenosine receptor blocker), L-NMMA+catalase, L-NMMA+tetraethylammonium (TEA, an inhibitor of large-conductance Ca2+-sensitive potassium channels), and L-NMMA+catalase+8-SPT. Coronary I/R significantly impaired the coronary vasodilatation to ACh in both sized arteries (both P<0.01); L-NMMA reduced the small arterial vasodilatation (both P<0.01), whereas it increased (P<0.05) the ACh-induced coronary arteriolar vasodilatation associated with fluorescent H2O2 production after I/R. Catalase increased the small arterial vasodilatation (P<0.01) associated with fluorescent NO production and increased endothelial NOS expression, whereas it decreased the arteriolar response after I/R (P<0.01). L-NMMA+catalase, L-NMMA+TEA, or L-NMMA+catalase+8-SPT further decreased the coronary vasodilatation in both sized arteries (both, P<0.01). L-NMMA+catalase, L-NMMA+TEA, and L-NMMA+catalase+8-SPT significantly increased myocardial infarct area compared with the other four groups (control, L-NMMA, catalase, and 8-SPT; all, P<0.01). These results indicate that endogenous H2O2, in cooperation with NO, plays an important cardioprotective role in coronary I/R injury in vivo.
我们最近证明，内源性过氧化氢在体内冠状动脉自身调节中起重要作用。然而，过氧化氢在冠状动脉缺血再灌注（I/R）损伤中的作用仍有待研究。在本研究中，我们检测了内源性过氧化氢在犬体内冠状动脉I/R损伤中是否也发挥保护作用。在环氧化酶阻断情况下（n=50），利用活体显微镜在冠状动脉I/R（90/60分钟）期间持续观察犬的心外膜下小冠状动脉（≥100微米）和小动脉（<100微米）。在以下七种条件下，检测I/R前后冠状动脉对内皮依赖性血管舒张剂（乙酰胆碱）的反应：对照、一氧化氮（NO）合酶（NOS）抑制剂N G-单甲基-L-精氨酸（L-NMMA）、过氧化氢酶（过氧化氢的分解剂）、8-磺基苯基茶碱（8-SPT，一种腺苷受体阻滞剂）、L-NMMA+过氧化氢酶、L-NMMA+四乙铵（TEA，一种大电导钙敏感钾通道抑制剂）以及L-NMMA+过氧化氢酶+8-SPT。冠状动脉I/R显著损害了两种大小动脉对乙酰胆碱的冠状动脉舒张功能（均P<0.01）；L-NMMA降低了小动脉的舒张功能（均P<0.01），而在I/R后，它增加了（P<0.05）乙酰胆碱诱导的与荧光过氧化氢产生相关的冠状动脉小动脉舒张功能。过氧化氢酶增加了与荧光NO产生相关的小动脉舒张功能（P<0.01），并增加了内皮型NOS的表达，而它降低了I/R后的小动脉反应（P<0.01）。L-NMMA+过氧化氢酶、L-NMMA+TEA或L-NMMA+过氧化氢酶+8-SPT进一步降低了两种大小动脉的冠状动脉舒张功能（均P<0.01）。与其他四组（对照、L-NMMA、过氧化氢酶和8-SPT）相比，L-NMMA+过氧化氢酶、L-NMMA+TEA和L-NMMA+过氧化氢酶+8-SPT显著增加了心肌梗死面积（均P<0.01）。这些结果表明，内源性过氧化氢与NO协同作用，在体内冠状动脉I/R损伤中发挥重要的心脏保护作用。
