Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor.
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.
Han
Eun D
ED
Center for Blood Research, Harvard Medical School, 800 Huntington Avenue, Boston, MA 02115, USA.
MacFarlane
Ryan C
RC
Mulligan
Aideen N
AN
Scafidi
Jennifer
J
Davis
Alvin E
AE
D000799:Angioedema / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D003174:Complement C1 Inactivator Proteins / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D004195:Disease Models, Animal; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D065168:Bradykinin Receptor Antagonists; D003174:Complement C1 Inactivator Proteins; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; C065679:icatibant; D001920:Bradykinin