Divison of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
PLoS One. 2012;7(7):e42038. doi: 10.1371/journal.pone.0042038. Epub 2012 Jul 31.
Consumption of L-arginine contributes to reduced bioavailability of nitric oxide (NO) that is critical for the development of ischemia-reperfusion injury. The aim of the study was to determine myocardial arginase expression and activity in ischemic-reperfusion myocardium and whether local inhibition of arginase within the ischemic myocardium results in increased NO production and protection against myocardial ischemia-reperfusion. Anesthetized pigs were subjected to coronary artery occlusion for 40 min followed by 4 h reperfusion. The pigs were randomized to intracoronary infusion of vehicle (n = 7), the arginase inhibitor N-hydroxy-nor-L-arginine (nor-NOHA, 2 mg/min, n = 7), the combination of nor-NOHA and the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 0.35 mg/min, n = 6) into the jeopardized myocardial area or systemic intravenous infusion of nor-NOHA (2 mg/min, n = 5) at the end of ischemia and start of reperfusion. The infarct size of the vehicle group was 80 ± 4% of the area at risk. Intracoronary nor-NOHA reduced infarct size to 46 ± 5% (P<0.01). Co-administration of L-NMMA abrogated the cardioprotective effect mediated by nor-NOHA (infarct size 72 ± 6%). Intravenous nor-NOHA did not reduce infarct size. Arginase I and II were expressed in cardiomyocytes, endothelial, smooth muscle and poylmorphonuclear cells. There was no difference in cytosolic arginase I or mitochondrial arginase II expression between ischemic-reperfused and non-ischemic myocardium. Arginase activity increased 2-fold in the ischemic-reperfused myocardium in comparison with non-ischemic myocardium. In conclusion, ischemia-reperfusion increases arginase activity without affecting cytosolic arginase I or mitochondrial arginase II expression. Local arginase inhibition during early reperfusion reduces infarct size via a mechanism that is dependent on increased bioavailability of NO.
精氨酸的消耗会导致对缺血再灌注损伤发展至关重要的一氧化氮（NO）生物利用度降低。本研究的目的是确定缺血再灌注心肌中的精氨酸酶表达和活性，以及局部抑制缺血心肌中的精氨酸酶是否会导致 NO 产生增加和对心肌缺血再灌注的保护作用。麻醉猪的冠状动脉被阻塞 40 分钟，然后再灌注 4 小时。将猪随机分为冠状动脉内输注载体（n = 7）、精氨酸酶抑制剂 N-羟基-N-硝基-L-精氨酸（nor-NOHA，2mg/min，n = 7）、nor-NOHA 和一氧化氮合酶抑制剂 N(G)-单甲基-L-精氨酸（L-NMMA，0.35mg/min，n = 6）进入危险区域或在缺血结束和再灌注开始时静脉内输注 nor-NOHA（2mg/min，n = 5）。载体组的梗死面积为危险区面积的 80±4%。冠状动脉内 nor-NOHA 将梗死面积缩小至 46±5%（P<0.01）。L-NMMA 的共同给药消除了 nor-NOHA 介导的心脏保护作用（梗死面积为 72±6%）。静脉内 nor-NOHA 并未减少梗死面积。精氨酸酶 I 和 II 在心肌细胞、内皮细胞、平滑肌细胞和多形核细胞中表达。缺血再灌注和非缺血心肌之间的细胞质精氨酸酶 I 或线粒体精氨酸酶 II 表达没有差异。与非缺血心肌相比，缺血再灌注心肌中的精氨酸酶活性增加了 2 倍。总之，缺血再灌注会增加精氨酸酶活性，而不影响细胞质精氨酸酶 I 或线粒体精氨酸酶 II 的表达。早期再灌注时局部抑制精氨酸酶可通过增加 NO 生物利用度来减少梗死面积。
