Byrd James Brian, Shreevatsa Ajai, Putlur Pradeep, Foretia Denis, McAlexander Laurie, Sinha Tuhin, Does Mark D, Brown Nancy J
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
J Allergy Clin Immunol. 2007 Aug;120(2):403-8. doi: 10.1016/j.jaci.2007.04.012. Epub 2007 May 25.
Serum dipeptidyl peptidase IV (DPPIV) activity is decreased in some individuals with ACE inhibitor-associated angioedema. ACE and DPPIV degrade substance P, an edema-forming peptide. The contribution of impaired degradation of substance P by DPPIV to the pathogenesis of ACE inhibitor-associated angioedema is unknown.
We sought to determine whether DPPIV deficiency results in increased edema formation during ACE inhibition. We also sought to develop an animal model using magnetic resonance imaging to quantify ACE inhibitor-induced edema.
The effect of genetic DPPIV deficiency on peritracheal edema was assessed in F344 rats after treatment with saline, captopril (2.5 mg/kg), or captopril plus the neurokinin receptor antagonist spantide (100 mug/kg) by using serial T2-weighted magnetic resonance imaging.
Serum dipeptidyl peptidase activity was dramatically decreased in DPPIV-deficient rats (P < .001). The volume of peritracheal edema was significantly greater in captopril-treated DPPIV-deficient rats than in saline-treated DPPIV-deficient rats (P = .001), saline-treated rats of the normal substrain (P < .001), or captopril-treated rats of the normal substrain (P = .001). Cotreatment with spantide attenuated peritracheal edema in captopril-treated DPPIV-deficient rats (P = .005 vs captopril-treated DPPIV-deficient rats and P = .57 vs saline-treated DPPIV-deficient rats).
DPPIV deficiency predisposes to peritracheal edema formation when ACE is inhibited through a neurokinin receptor-dependent mechanism. Magnetic resonance imaging is useful for modeling ACE inhibitor-associated angioedema in rats.
Genetic or environmental factors that decrease DPPIV activity might increase the risk of ACE inhibitor-associated angioedema.
在一些服用血管紧张素转换酶（ACE）抑制剂相关血管性水肿的个体中，血清二肽基肽酶IV（DPPIV）活性降低。ACE和DPPIV可降解P物质，一种可导致水肿的肽。DPPIV对P物质降解受损在ACE抑制剂相关血管性水肿发病机制中的作用尚不清楚。
我们试图确定DPPIV缺乏是否会导致ACE抑制期间水肿形成增加。我们还试图建立一种使用磁共振成像的动物模型来量化ACE抑制剂诱导的水肿。
通过连续T2加权磁共振成像，评估F344大鼠在接受生理盐水、卡托普利（2.5mg/kg）或卡托普利加神经激肽受体拮抗剂spantide（100μg/kg）治疗后，遗传性DPPIV缺乏对气管周围水肿的影响。
DPPIV缺乏的大鼠血清二肽基肽酶活性显著降低（P <.001）。卡托普利治疗的DPPIV缺乏大鼠的气管周围水肿体积显著大于生理盐水治疗的DPPIV缺乏大鼠（P =.001）、正常亚系的生理盐水治疗大鼠（P <.001）或正常亚系的卡托普利治疗大鼠（P =.001）。与spantide联合治疗可减轻卡托普利治疗的DPPIV缺乏大鼠的气管周围水肿（与卡托普利治疗的DPPIV缺乏大鼠相比，P =.005；与生理盐水治疗的DPPIV缺乏大鼠相比，P =.57）。
当通过神经激肽受体依赖性机制抑制ACE时，DPPIV缺乏易导致气管周围水肿形成。磁共振成像有助于在大鼠中建立ACE抑制剂相关血管性水肿模型。
降低DPPIV活性的遗传或环境因素可能会增加ACE抑制剂相关血管性水肿的风险。
