Khan Mahmood, Mohan Iyyapu K, Kutala Vijay Kumar, Kumbala Damodar, Kuppusamy Periannan
Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, Ohio State University, Columbus, OH 43210, USA.
J Pharmacol Exp Ther. 2007 Dec;323(3):813-21. doi: 10.1124/jpet.107.129486. Epub 2007 Sep 14.
Cytochrome P450 (P450) enzymes play a significant role in promoting myocardial ischemia-reperfusion (I/R) injury. CYP2C9, an isoform of P450, is known to generate superoxide radicals in the reperfused heart. Sulfaphenazole (SPZ), a CYP2C9 inhibitor, has been shown to decrease I/R injury; however, the mechanism of cardioprotection by SPZ is not well elucidated. The objective of this study was to test whether SPZ mitigates myocardial I/R injury by scavenging reactive oxygen species (ROS). Isolated rat hearts were subjected to 30 min of global ischemia followed by 45 min of reperfusion. Hearts were perfused with SPZ and/or N(omega)-nitro-L-arginine methylester (L-NAME). Coronary flow (CF), left-ventricular developed pressure (LVDP), and rate-pressure product (RPP) were monitored. Superoxide and nitric oxide (NO) generation in the reperfused tissue was determined using fluorescence methods. Myocardial infarct size was measured using triphenyltetrazolium chloride staining. The SPZ-treated group showed a significant recovery of cardiac function compared with the untreated I/R group (CF, 53 versus 45%; LVDP, 48 versus 22%; RPP, 51 versus 20%). The infarct size was significantly reduced in the SPZ-treated group (15%) compared with the I/R control (42%). Coadministration of L-NAME with SPZ significantly attenuated the beneficial effects of SPZ. In addition, SPZ treatment showed significantly decreased superoxide levels and enhanced NO bioavailability in the reperfused heart. In conclusion, the protective effect of SPZ against I/R-mediated myocardial damage appears to be due to a reduction in the superoxide level caused by its inhibition of CYP2C9, as well as scavenging of oxygen free radicals generated in the reperfused heart.
细胞色素P450（P450）酶在促进心肌缺血再灌注（I/R）损伤中起重要作用。CYP2C9是P450的一种同工酶，已知其在再灌注心脏中产生超氧阴离子自由基。磺胺苯吡唑（SPZ）是一种CYP2C9抑制剂，已被证明可减少I/R损伤；然而，SPZ的心脏保护机制尚未完全阐明。本研究的目的是测试SPZ是否通过清除活性氧（ROS）减轻心肌I/R损伤。将离体大鼠心脏进行30分钟的全心缺血，随后再灌注45分钟。心脏用SPZ和/或N（ω）-硝基-L-精氨酸甲酯（L-NAME）灌注。监测冠状动脉流量（CF）、左心室舒张末压（LVDP）和心率-压力乘积（RPP）。使用荧光方法测定再灌注组织中超氧阴离子和一氧化氮（NO）的生成。使用氯化三苯基四氮唑染色测量心肌梗死面积。与未处理的I/R组相比，SPZ处理组的心脏功能有显著恢复（CF，53%对45%；LVDP，48%对22%；RPP，51%对20%）。与I/R对照组（42%）相比，SPZ处理组的梗死面积显著减小（15%）。L-NAME与SPZ联合给药显著减弱了SPZ的有益作用。此外，SPZ处理显示再灌注心脏中的超氧阴离子水平显著降低，NO生物利用度增强。总之，SPZ对I/R介导的心肌损伤的保护作用似乎是由于其抑制CYP2C9导致超氧阴离子水平降低，以及清除再灌注心脏中产生的氧自由基。
