Dipeptidyl peptidase IV deficiency increases susceptibility to angiotensin-converting enzyme inhibitor-induced peritracheal edema

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:120

Article

Byrd, James Brian ; Shreevatsa, Ajai ; Putlur, Pradeep ; Foretia, Denis ; McAlexander, Laurie ; Sinha, Tuhin ; Does, Mark D. ; Brown, Nancy J.

关键词: angioedema;    angiotensin-converting enzyme inhibitor;    dipeptidyl peptidase IV;    trachea;    larynx;    magnetic resonance imaging;    pharmacogenetics;    substance P;    neurokinin;    spantide;   

DOI  :  10.1016/j.jaci.2007.04.012

来源: Elsevier

【 摘 要 】

Background: 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. Objectives: 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. Methods: 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 mu g/kg) by using serial T2-weighted magnetic resonance imaging. Results: 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). Conclusions: 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. Clinical implications: Genetic or environmental factors that decrease DPPIV activity might increase the risk of ACE inhibitor-associated angioedema.

【 授权许可】

Free