Activation of bradykinin B1 receptor by ACE inhibitors
Activation of bradykinin B1 receptor by ACE inhibitors
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DOI：
10.1016/s1567-5769(02)00146-7
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发表时间：
2002-12-01
影响因子：
5.6
通讯作者：
Erdös, EG
中科院分区：
文献类型：
--
作者：
Ignjatovic, T;Tan, FL;Erdös, EG
ACE或激氨酸酶II抑制剂是非常重要的，广泛用于治疗各种疾病的治疗药物。虽然它们抑制血管紧张素转换酶，从而抑制血管紧张素II的释放和缓激肽(BK)的失活，但这种抑制本身并不足以解释它们在医学实践中的成功应用。Enalaprilot和其他纳摩尔浓度的ACE抑制剂在没有ACE和多肽配体Des-Arg-kinins的情况下直接激活BK B-1受体。这些抑制剂在B-1的锌结合五聚体共有序列HEXXH(195-199)处激活，该基序也存在于ACE的活性中心，但不存在于BK B-2受体中。血管紧张素转换酶抑制剂，当激活B-1受体时，升高细胞内钙离子，并从培养的细胞中释放NO。血管紧张素转换酶抑制剂的激活可被B-1受体拮抗剂Ca-EDTA、代表B-1受体192-202序列的合成十一肽以及H-195对A的定点突变所阻断，除B受体阻断剂外，这些药物和突变不影响多肽配体Des-Arg(10)-Lys(1)-BK的作用。缺血和炎症细胞因子诱导B-1受体并上调其表达。血管紧张素转换酶抑制剂直接激活B-1受体可促进其治疗效果，例如，通过在血管床中释放一氧化氮，或其一些副作用。(C)2002年，爱思唯尔科学公司出版。
ACE or kininase II inhibitors are very important, widely used therapeutic agents for the treatment of a variety of diseases. Although they inhibit ACE, thus, angiotensin II release and bradykinin (BK) inactivation, this inhibition alone does not suffice to explain their successful application in medical practice. Enalaprilot and other ACE inhibitors at nanomolar concentrations activate the BK B-1 receptor directly in the absence of ACE and the peptide ligands, des-Arg-kinins. The inhibitors activate at the Zn-binding pentameric consensus sequence HEXXH (195 - 199) of B-1, a motif also present in the active centers of ACE but absent from the BK B-2 receptor. ACE inhibitors, when activating the B-1 receptor, elevate intracellular calcium [Ca2+](i) and release NO from cultured cells. Activation by ACE inhibitor was abolished by Ca-EDTA, a B-1 receptor antagonist, by a synthetic undecapeptide representing the 192 - 202 sequence in the B-1 receptor, and by site-directed mutagenesis of H-195 to A. With the exception of the B, receptor blocker, these agents and the mutation did not affect the actions of the peptide ligand des-Arg(10) -Lys(1)-BK. Ischemia and inflammatory cytokines induce B-1 receptors and elevate its expression. Direct activation of the B-1 receptor by ACE inhibitors can contribute to their therapeutic efficacy, for example, by releasing NO in vascular beds, or to some of their side effects. (C) 2002 Published by Elsevier Science B.V.