Wall T M, Sheehy R, Hartman J C
Cardiovascular Diseases Research Unit, Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan.
J Pharmacol Exp Ther. 1994 Aug;270(2):681-9.
The role of bradykinin in the cardioprotective action of ischemic preconditioning was investigated in an anesthetized, open-chest rabbit model of acute coronary occlusion. A branch of the left main coronary artery was reversibly ligated to produce ischemia followed by reperfusion, after which the degree of myocardial necrosis (infarct size as a percent of area at risk) was assessed by tetrazolium staining. Before 30 min of coronary occlusion, rabbits received either ischemic preconditioning (5 min occlusion followed by 10 min reperfusion), no preconditioning, H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140) i.v. (bradykinin receptor antagonist, 1 micrograms/kg) plus preconditioning, HOE 140 alone, a 5-min intra-atrial bradykinin infusion (250 micrograms/kg/min) followed by a 10-min recovery period or HOE 140 plus bradykinin infusion with 10 min recovery. Systemic hemodynamic responses were similar between treatment groups except that both bradykinin infusion groups had a significantly depressed rate of left ventricular pressure development (LV+dP/dtmax) after the 10-min recovery period. Preconditioning reduced infarct size significantly (12 +/- 2%, compared to non-preconditioned controls at 41 +/- 6%), whereas pretreatment with HOE 140 abolished the cardioprotective effect (41 +/- 4%). In addition, bradykinin infusion reduced infarct size significantly (16 +/- 1%), an effect which was also prevented by HOE 140 (41 +/- 5%). HOE 140 alone did not exacerbate the degree of myocardial necrosis (43 +/- 4%). Myocardial area at risk as a percentage of total left ventricular mass was not different between the six treatment groups. The results indicate that endogenously generated bradykinin may mediate the cardioprotective events associated with ischemic preconditioning.
在麻醉开胸的急性冠状动脉闭塞兔模型中，研究了缓激肽在缺血预处理心脏保护作用中的角色。可逆性结扎左冠状动脉主干的一个分支以产生缺血，随后再灌注，之后通过四氮唑染色评估心肌坏死程度（梗死面积占危险区域面积的百分比）。在冠状动脉闭塞30分钟前，兔子接受以下处理：缺血预处理（闭塞5分钟后再灌注10分钟）、无预处理、静脉注射H-D-精氨酸-精氨酸-脯氨酸-羟脯氨酸-甘氨酸-硫代丝氨酸-D-噻唑烷二酮-异亮氨酸-精氨酸-OH（HOE 140）（缓激肽受体拮抗剂，1微克/千克）加预处理、单独使用HOE 140、心房内缓激肽输注5分钟（250微克/千克/分钟），随后恢复10分钟，或HOE 140加缓激肽输注并恢复10分钟。各治疗组之间的全身血流动力学反应相似，只是两个缓激肽输注组在恢复10分钟后左心室压力上升速率（LV + dP/dtmax）显著降低。预处理显著减小了梗死面积（12±2%，与未预处理对照组的41±6%相比），而用HOE 140预处理则消除了心脏保护作用（41±4%）。此外，缓激肽输注显著减小了梗死面积（16±1%），这一作用也被HOE 140阻止（41±5%）。单独使用HOE 140并未加重心肌坏死程度（43±4%）。六个治疗组之间，危险心肌面积占左心室总质量的百分比无差异。结果表明，内源性产生的缓激肽可能介导与缺血预处理相关的心脏保护事件。
