Koch Matthias, Spillmann Frank, Dendorfer Andreas, Westermann Dirk, Altmann Christine, Sahabi Merdad, Linthout Sophie Van, Bader Michael, Walther Thomas, Schultheiss Heinz-Peter, Tschöpe Carsten
Department of Cardiology and Pneumology, Charité -- University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12220 Berlin, Germany.
Eur J Pharmacol. 2006 Nov 21;550(1-3):143-8. doi: 10.1016/j.ejphar.2006.08.054. Epub 2006 Sep 7.
Bradykinin coronary outflow, left ventricular performance and left ventricular dimensions of transgenic rats harboring the human tissue kallikrein-1 gene TGR(hKLK1) were investigated under basal and ischemic conditions. Bradykinin content in the coronary outflow of buffer-perfused, isolated hearts of controls and TGR(hKLK1) was measured by specific radioimmunoassay before and after global ischemia. Left ventricular function and left ventricular dimensions were determined in vivo using a tip catheter and echocardiography 6 days and 3 weeks after induction of myocardial infarction. Left ventricular type I collagen mRNA expression was analyzed by RNase protection assay. Compared to controls, basal bradykinin outflow was 3.5 fold increased in TGR(hKLK1). Ischemia induced an increase of bradykinin coronary outflow in controls but did not induce a further increase in TGR(hKLK1). However, despite similar unchanged infarction sizes, left ventricular function and remodeling improved in TGR(hKLK1) after myocardial infarction, indicated by an increase in left ventricular pressure (+34%; P<0.05), contractility (dp/dt max. +25%; P<0.05), and in ejection fraction (+20%; P<0.05) as well as by a reduction in left ventricular enddiastolic pressure (-49%, P<0.05), left ventricular enddiastolic diameter (-20%, P<0.05), and collagen mRNA expression (-15%, P<0.05) compared to controls. A chronically activated transgenic kallikrein kinin system with expression of human kallikrein-1 gene counteracts the progression of left ventricular contractile dysfunction after experimental myocardial infarction. Further studies have to show whether these results can be caused by other therapeutically options. Long acting bradykinin receptor agonists might be an alternative option to improve ischemic heart disease.
在基础状态和缺血条件下，研究了携带人组织激肽释放酶-1基因的转基因大鼠（TGR(hKLK1)）的缓激肽冠脉流出量、左心室功能和左心室尺寸。通过特异性放射免疫分析法在全心缺血前后测量对照大鼠和TGR(hKLK1)大鼠经缓冲液灌注的离体心脏冠脉流出液中的缓激肽含量。在心肌梗死诱导后6天和3周，使用顶端导管和超声心动图在体内测定左心室功能和左心室尺寸。通过核糖核酸酶保护试验分析左心室I型胶原mRNA表达。与对照相比，TGR(hKLK1)的基础缓激肽流出量增加了3.5倍。缺血导致对照大鼠冠脉缓激肽流出量增加，但未使TGR(hKLK1)进一步增加。然而，尽管梗死面积相似且无变化，但心肌梗死后TGR(hKLK1)的左心室功能和重塑得到改善，表现为左心室压力增加（+34%；P<0.05）、收缩力增加（dp/dt max. +25%；P<0.05）、射血分数增加（+20%；P<0.05），以及左心室舒张末期压力降低（-49%，P<0.05）、左心室舒张末期直径降低（-20%，P<0.05）和胶原mRNA表达降低（-15%，P<0.05）。具有人激肽释放酶-1基因表达的慢性激活的转基因激肽释放酶-激肽系统可对抗实验性心肌梗死后左心室收缩功能障碍的进展。进一步的研究必须表明这些结果是否可由其他治疗选择引起。长效缓激肽受体激动剂可能是改善缺血性心脏病的另一种选择。
