Institute of Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Düsseldorf, Germany.
Allergy. 2015 Mar;70(3):285-94. doi: 10.1111/all.12556. Epub 2014 Dec 24.
Little is known about factors which trigger and/or contribute to hereditary angioedema or ACE-inhibitor-mediated angioedema including variations in bradykinin type 2 receptor (B2R) expression and activity.
Protein and mRNA expression of B2R and the increase of intracellular calcium (iCa) in response to bradykinin were monitored in porcine and murine endothelial cells in response to NO donors or bradykinin. B2R protein expression was evaluated in skin, heart, and lung of (i) mice with endothelial-specific overexpression of eNOS (eNOS(tg) ), (ii) in eNOS(-/-) mice and (iii) in C57BL/6 mice treated with the NO donor pentaerythritol tetranitrate (PETN), the NOS inhibitor l-nitroarginine (L-NA), plasma pool C1-INH, and the B2R antagonist icatibant. Aortic reactivity to bradykinin was investigated including eNOS(-/-) mice.
B2R protein and mRNA expression remained unchanged in cells subjected to L-NA, NO donors, and bradykinin in a time- and concentration-dependent manner. Likewise, increases of iCa in murine brain endothelial cells remained unchanged. B2R protein levels were similar in eNOS(tg) and eNOS(-/-) as compared to transgene-negative littermates. Likewise, treatment of C57BL/6 mice with PETN, L-NA, C1-INH or icatibant did not change B2R protein expression. In aortic rings of C57BL/6 mice, bradykinin induced B2R-dependent constrictions which were attenuated by endothelial NO and abolished by diclofenac indicating the functional importance of B2R-induced activation of endothelial NO synthase and cyclooxygenase.
These data suggest that alterations of B2R protein expression induced by NO, bradykinin, C1-INH, or icatibant unlikely contribute to bradykinin-induced angioedema. This finding does not rule out a role for NO in bradykinin-induced extravasation and/or angioedema.
关于触发和/或导致遗传性血管性水肿或血管紧张素转换酶抑制剂介导的血管性水肿的因素知之甚少，包括缓激肽 B2 受体（B2R）表达和活性的变化。
监测猪和鼠内皮细胞对一氧化氮供体或缓激肽的反应中 B2R 的蛋白和 mRNA 表达以及细胞内钙（iCa）的增加。评估（i）内皮细胞特异性过表达 eNOS（eNOS(tg)）的小鼠、（ii）eNOS(-/-)小鼠和（iii）用一氧化氮供体五亚乙基六胺四硝酯（PETN）、一氧化氮合酶抑制剂 l-硝基精氨酸（L-NA）、血浆池 C1-INH 和 B2R 拮抗剂 icatibant 治疗的 C57BL/6 小鼠中皮肤、心脏和肺中的 B2R 蛋白表达。研究了缓激肽引起的主动脉反应，包括 eNOS(-/-)小鼠。
在时间和浓度依赖性方式中，L-NA、NO 供体和缓激肽处理的细胞中 B2R 蛋白和 mRNA 表达保持不变。同样，鼠脑内皮细胞中的 iCa 增加保持不变。与转基因阴性同窝仔相比，eNOS(tg)和 eNOS(-/-)中的 B2R 蛋白水平相似。同样，用 PETN、L-NA、C1-INH 或 icatibant 治疗 C57BL/6 小鼠不会改变 B2R 蛋白表达。在 C57BL/6 小鼠的主动脉环中，缓激肽诱导 B2R 依赖性收缩，内皮一氧化氮减弱，双氯芬酸消除，表明 B2R 诱导的内皮一氧化氮合酶和环加氧酶激活的功能重要性。
这些数据表明，NO、缓激肽、C1-INH 或 icatibant 诱导的 B2R 蛋白表达的改变不太可能导致缓激肽诱导的血管性水肿。这一发现并不排除 NO 在缓激肽诱导的渗出和/或血管性水肿中的作用。
