Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor

J Clin Invest. 2002 Apr;109(8):1057-63. doi: 10.1172/JCI14211.


Heterozygosity for C1 inhibitor (C1INH) deficiency results in hereditary angioedema. Disruption of the C1INH gene by gene trapping enabled the generation of homozygous- and heterozygous-deficient mice. Mating of heterozygous-deficient mice resulted in the expected 1:2:1 ratio of wild-type, heterozygous, and homozygous-deficient offspring. C1INH-deficient mice showed no obvious phenotypic abnormality. However, following injection with Evans blue dye, both homozygous and heterozygous C1INH-deficient mice revealed increased vascular permeability in comparison with wild-type littermates. This increased vascular permeability was reversed by treatment with intravenous human C1INH, with a Kunitz domain plasma kallikrein inhibitor (DX88), and with a bradykinin type 2 receptor (Bk2R) antagonist (Hoe140). In addition, treatment of the C1INH-deficient mice with an angiotensin-converting enzyme inhibitor (captopril) increased the vascular permeability. Mice with deficiency of both C1INH and Bk2R demonstrated diminished vascular permeability in comparison with C1INH-deficient, Bk2R-sufficient mice. These data support the hypothesis that angioedema is mediated by bradykinin via Bk2R.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angioedema / genetics
  • Angioedema / physiopathology
  • Animals
  • Bradykinin / analogs & derivatives*
  • Bradykinin / pharmacology
  • Bradykinin Receptor Antagonists
  • Capillary Permeability / drug effects
  • Capillary Permeability / physiology*
  • Complement C1 Inactivator Proteins / deficiency*
  • Complement C1 Inactivator Proteins / genetics
  • Complement C1 Inactivator Proteins / pharmacology
  • Complement C1 Inactivator Proteins / physiology
  • Disease Models, Animal
  • Heterozygote
  • Homozygote
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor, Bradykinin B2
  • Receptors, Bradykinin / deficiency
  • Receptors, Bradykinin / genetics
  • Receptors, Bradykinin / physiology*


  • Bradykinin Receptor Antagonists
  • Complement C1 Inactivator Proteins
  • Receptor, Bradykinin B2
  • Receptors, Bradykinin
  • icatibant
  • Bradykinin