Gross Eric R, Hsu Anna K, Gross Garrett J
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
J Pharmacol Exp Ther. 2004 Jul;310(1):185-91. doi: 10.1124/jpet.103.064667. Epub 2004 Mar 1.
Patients suffering an acute myocardial infarction routinely receive morphine and nonsteroidal anti-inflammatory drugs (NSAIDs) alone or in combination. However, the importance of the dose, timing, or the combined administration of both on infarct size reduction has not been assessed. Additionally, it is not known whether morphine or NSAIDs require 12-lipoxygenase (12-LO) to mediate infarct size reduction as found previously for ischemic preconditioning. Male Sprague-Dawley rats were subjected to 30 min of ischemia and 2 h of reperfusion, followed by infarct size assessment (mean +/- S.E.M.%, P < 0.01). Morphine (0.3 mg/kg), ibuprofen (3 mg/kg), but not aspirin (3 mg/kg) reduced infarct size when administered 5 min before reperfusion compared with vehicle (42.3 +/- 1.5, 40.8 +/- 2.8**, 60.7 +/- 2.3 versus 59.1 +/- 1.7%, respectively); however, none of these agents reduced infarct size when administered 10 s after reperfusion. Ibuprofen (3 mg/kg) administered with morphine (0.3 mg/kg) reduced infarct size (43.7 +/- 1.3%), whereas aspirin (1 and 3 mg/kg) abolished morphine-induced infarct size reduction. Morphine (0.2 mg/kg) and ibuprofen (0.6 mg/kg) given at doses not effective individually reduced infarct size when given together (59.0 +/- 1.4, 57.6 +/- 2.8, and 43.9 +/- 1.6%, respectively). Morphine- and ibuprofen-induced infarct size reduction was abolished by the 12-LO inhibitor baicalein (3 mg/kg) and mimicked by the 12-LO metabolite 12-(S)-hydroxyeicosa-5Z,8Z,10Z,14Z-tetraenoic acid (45.2 +/- 2.5%**). These data suggest that morphine and ibuprofen reduce infarct size individually or at subthreshold doses in combination by 12-LO when administered 5 min before reperfusion. Furthermore, acute aspirin administration has a detrimental interaction with morphine that abrogates morphine-induced infarct size reduction.
急性心肌梗死患者通常单独或联合使用吗啡和非甾体抗炎药（NSAIDs）。然而，剂量、给药时间或两者联合给药对减小梗死面积的重要性尚未得到评估。此外，尚不清楚吗啡或NSAIDs是否像先前发现的缺血预处理那样需要12-脂氧合酶（12-LO）来介导梗死面积的减小。将雄性Sprague-Dawley大鼠进行30分钟的缺血和2小时的再灌注，随后评估梗死面积（平均值±标准误，P<0.01）。与溶剂对照相比，在再灌注前5分钟给予吗啡（0.3mg/kg）、布洛芬（3mg/kg），而非阿司匹林（3mg/kg）可减小梗死面积（分别为42.3±1.5、40.8±2.8**、60.7±2.3与59.1±1.7%）；然而，在再灌注后10秒给予这些药物均未减小梗死面积。布洛芬（3mg/kg）与吗啡（0.3mg/kg）联合给药可减小梗死面积（43.7±1.3%），而阿司匹林（1和3mg/kg）消除了吗啡诱导的梗死面积减小。单独给药无效的吗啡（0.2mg/kg）和布洛芬（0.6mg/kg）联合给药时可减小梗死面积（分别为59.0±1.4、57.6±2.8和43.9±1.6%）。吗啡和布洛芬诱导的梗死面积减小被12-LO抑制剂黄芩素（3mg/kg）消除，并被12-LO代谢产物12-(S)-羟基二十碳-5Z,8Z,10Z,14Z-四烯酸模拟（45.2±2.5%**）。这些数据表明，在再灌注前5分钟给药时，吗啡和布洛芬可通过12-LO单独或以亚阈值剂量联合减小梗死面积。此外，急性给予阿司匹林与吗啡存在有害相互作用，可消除吗啡诱导的梗死面积减小。
