Mice deficient for both kinin receptors are normotensive and protected from endotoxin-induced hypotension.
Kinins play a central role in the modulation of cardiovascular function and in the pathophysiology of inflammation. These peptides mediate their effects by binding to two specific G-protein coupled receptors named B1 and B2. To evaluate the full functional relevance of the kallikrein-kinin system, we generated mice lacking both kinin receptors (B1B2-/-). Because of the close chromosomal position of both kinin receptor genes, B1B2-/- mice could not be obtained by simple breeding of the single knockout lines. Therefore, we inactivated the B1 receptor gene by homologous recombination in embryonic stem cells derived from B2-deficient animals. The B1B2-/- mice exhibited undetectable levels of mRNAs for both receptors and a lack of response to bradykinin (B2 agonist) and des-Arg9-bradykinin (B1 agonist), as attested by contractility studies with isolated smooth muscle tissues. B1B2-/- mice are healthy and fertile, and no sign of cardiac abnormality was detected. They are normotensive but exhibit a lower heart rate than controls. Furthermore, kinin receptor deficiency affects the pathogenesis of endotoxin-induced hypotension. While blood pressure decreased markedly in wild-type mice and B2-/- and moderately in B1-/- mice after bacterial lipopolysaccharide (LPS) injection, blood pressure remained unchanged in B1B2-/- mice. These results clearly demonstrate a pivotal role of kinins and their receptors in hypotension induced by endotoxemia in mice.
Cayla
Cécile
C
Max-Delbrück-Center for Molecular Medicine, D-13092 Berlin-Buch, Germany.
Todiras
Mihail
M
Iliescu
Radu
R
Saul
Vera V
VV
Gross
Volkmar
V
Pilz
Bernhard
B
Chai
Guixuan
G
Merino
Vanessa F
VF
Pesquero
João B
JB
Baltatu
Ovidiu C
OC
Bader
Michael
M
D000818:Animals; D001794:Blood Pressure; D007022:Hypotension / Q000139:chemically induced; D007705:Kinins / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D043783:Receptor, Bradykinin B1 / Q000172:deficiency / Q000502:physiology*; D043782:Receptor, Bradykinin B2 / Q000172:deficiency / Q000502:physiology*
D007705:Kinins; D008070:Lipopolysaccharides; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2