Liu Xiuxin, Lukasova Martina, Zubakova Radka, Lewicka Sabina, Hilgenfeldt Ulrich
Department of Pharmaceutical Pharmacology, Institute of Pharmacology, Medical Faculty, University of Heidelberg, Im Neuenheimer Feld 366, Heidelberg D69120, Germany.
Br J Pharmacol. 2005 Dec;146(7):952-7. doi: 10.1038/sj.bjp.0706402.
Bradykinin is thought to play a major role among the endogenous cardioprotective candidates of ischaemic preconditioning (IPC). Little attention has been paid to the fact that in the tissue kallidin (KAL), rather than bradykinin might be the physiological mediator of the kallikrein-kinin system. In order to evaluate the importance of one or the other peptide the release and effect of both kinins has been investigated in isolated rat hearts following IPC. Bradykinin- and a KAL-like peptide were measured in the effluent of the rat isolated Langendorff heart with two different specific radioimmunoassays. The creatine kinase activity in the effluent was judged as degree of cardiac injury caused by ischaemia. During IPC, which consists of three 5 min no-flow and 5 min reperfusion cycles prior to the 30 min ischaemia, the bradykinin level in the effluent did not change significantly (15.4-19.4 pg ml(-1)). In the control group the bradykinin levels were 15.9-16.6 pg ml(-1). During IPC KAL-like peptide (Arg(1)-, instead of Lys(1)-KAL), which has recently been verified by mass spectrometry, displays 5.8-fold higher levels in the effluent and significantly increases in the same time interval from 90.4 to 189 pg ml(-1). After 30 min ischaemia the bradykinin levels in the IPC group were not significantly different to those of the control group (18.7 vs 14.4 pg ml(-1)). The KAL-like peptide levels in the IPC group vs the control group were 105 vs 86.1 pg ml(-1). By the 30 min ischaemia the creatine kinase activity in the IPC group increased from 0.367 to 8.93 U l(-1) (before and 10-30 min after ischaemia). In the control group during the same time period the creatine kinase levels increased from 0.277 to 34.9 U l(-1). The low increase in creatine kinase activity following IPC was taken as equivalent of the cardioprotective action. A KAL antibody or HOE140 (kinin B(2)-receptor antagonist) completely abolished this beneficial effect of IPC (36.6 and 53.0 U l(-1)) when added to the perfusion medium during the reperfusion cycles of IPC prior to the 30 min ischaemia. Our data suggest that in rat hearts KAL-like peptide rather than bradykinin is the physiological compound activated by IPC and acting via the cardiac kinin B(2)-receptor. Thus, endogenously generated KAL-like peptide seems to play a major role in the cardioprotection of IPC.
缓激肽被认为在缺血预处理（IPC）的内源性心脏保护候选物质中起主要作用。组织激肽释放酶-激肽系统的生理介质可能是组织激肽（KAL）而非缓激肽这一事实却很少受到关注。为了评估这两种肽各自的重要性，研究了IPC后分离的大鼠心脏中两种激肽的释放及作用。用两种不同的特异性放射免疫分析法测定大鼠离体Langendorff心脏流出液中的缓激肽和一种KAL样肽。流出液中的肌酸激酶活性被判定为缺血所致的心脏损伤程度。在IPC过程中，即在30分钟缺血前包括三个5分钟无血流和5分钟再灌注周期，流出液中的缓激肽水平无显著变化（15.4 - 19.4 pg ml⁻¹）。对照组中的缓激肽水平为15.9 - 16.6 pg ml⁻¹。在IPC过程中，最近经质谱验证的KAL样肽（Arg¹ - ，而非Lys¹ - KAL），其在流出液中的水平升高5.8倍，且在相同时间间隔内从90.4显著增加至189 pg ml⁻¹。30分钟缺血后，IPC组中的缓激肽水平与对照组无显著差异（18.7 vs 14.4 pg ml⁻¹）。IPC组与对照组中的KAL样肽水平分别为105 vs 86.1 pg ml⁻¹。到30分钟缺血时，IPC组中的肌酸激酶活性从0.367升至8.93 U l⁻¹（缺血前及缺血后10 - 30分钟）。对照组在同一时期内肌酸激酶水平从0.277升至34.9 U l⁻¹。IPC后肌酸激酶活性的低升高被视为等同于心脏保护作用。当在30分钟缺血前IPC的再灌注周期期间将KAL抗体或HOE140（激肽B₂受体拮抗剂）添加到灌注培养基中时，它们完全消除了IPC的这种有益作用（36.6和53.0 U l⁻¹）。我们的数据表明，在大鼠心脏中，KAL样肽而非缓激肽是由IPC激活并通过心脏激肽B₂受体起作用的生理化合物。因此，内源性产生的KAL样肽似乎在IPC的心脏保护中起主要作用。
