Kokkonen J O, Kuoppala A, Saarinen J, Lindstedt K A, Kovanen P T
Wihuri Research Institute, Helsinki, Finland.
Circulation. 1999 Apr 20;99(15):1984-90. doi: 10.1161/01.cir.99.15.1984.
Since kinins kallidin (KD) and bradykinin (BK) appear to have cardioprotective effects ranging from improved hemodynamics to antiproliferative effects, inhibition of kinin-degrading enzymes should potentiate such effects. Indeed, it is believed that this mechanism is partly responsible for the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors. In the heart, enzymes other than ACE may contribute to local degradation of kinins. The purpose of this study was to investigate which enzymes are responsible for the degradation of KD and BK in human heart tissue.
Cardiac membranes were prepared from the left ventricles of normal (n=5) and failing (n=10) hearts. The patients had end-stage congestive heart failure as the result of coronary heart disease or idiopathic dilated cardiomyopathy. Heart tissue was incubated with KD or BK in the presence or absence of enzyme inhibitors. We found no difference in the enzymes responsible for kinin metabolism or their activities between normal and failing hearts. Thus KD was mostly converted into BK by the aminopeptidase M-like activity. When BK was used as substrate, it was converted into an inactive metabolite BK-(1-7) mostly (80% to 90%) by the neutral endopeptidase (NEP) activity, with ACE unexpectedly playing only a minor role. The low enzymatic activity of ACE in the cardiac membranes, compared with that of NEP, was not due to chronic ACE inhibitor therapy, because the cardiac ACE activities of patients, whether receiving ACE inhibitors or not, and of normal subjects were all equal.
The present in vitro study shows that in human cardiac membranes, the most critical step in kinin metabolism, that is, inactivation of BK, appears to be mediated mostly by NEP. This observation suggests a role for NEP in the local control of BK concentration in heart tissue. Thus inhibition of cardiac NEP activity could be cardioprotective by elevating the local concentration of BK in the heart.
由于激肽缓激肽原（KD）和缓激肽（BK）似乎具有从改善血流动力学到抗增殖作用等多种心脏保护作用，抑制激肽降解酶应能增强此类作用。事实上，人们认为这种机制部分解释了血管紧张素转换酶（ACE）抑制剂的有益作用。在心脏中，除ACE外的其他酶可能参与激肽的局部降解。本研究的目的是调查哪些酶负责人类心脏组织中KD和BK的降解。
从正常心脏（n = 5）和衰竭心脏（n = 10）的左心室制备心脏膜。这些患者因冠心病或特发性扩张型心肌病导致终末期充血性心力衰竭。将心脏组织在有或没有酶抑制剂的情况下与KD或BK一起孵育。我们发现正常心脏和衰竭心脏中负责激肽代谢的酶及其活性没有差异。因此，KD主要通过氨肽酶M样活性转化为BK。当以BK为底物时，它主要（80%至90%）通过中性内肽酶（NEP）活性转化为无活性代谢物BK-(1-7)，出乎意料的是，ACE仅起次要作用。与NEP相比，心脏膜中ACE的酶活性较低，这并非由于长期使用ACE抑制剂治疗，因为无论是否接受ACE抑制剂治疗的患者以及正常受试者的心脏ACE活性都是相等的。
目前的体外研究表明，在人心脏膜中，激肽代谢的最关键步骤，即BK的失活，似乎主要由NEP介导。这一观察结果提示NEP在心脏组织中BK浓度的局部控制中发挥作用。因此，抑制心脏NEP活性可能通过提高心脏中BK的局部浓度而具有心脏保护作用。
