title: Mice deficient for both kinin receptors are normotensive and protected from endotoxin-induced hypotension.
abstract: 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.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, D-13092 Berlin-Buch, Germany.
authors.forename: Cécile
authors.initials: C
authors.lastname: Cayla
authors.forename: Mihail
authors.initials: M
authors.lastname: Todiras
authors.forename: Radu
authors.initials: R
authors.lastname: Iliescu
authors.forename: Vera V
authors.initials: VV
authors.lastname: Saul
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gross
authors.forename: Bernhard
authors.initials: B
authors.lastname: Pilz
authors.forename: Guixuan
authors.initials: G
authors.lastname: Chai
authors.forename: Vanessa F
authors.initials: VF
authors.lastname: Merino
authors.forename: João B
authors.initials: JB
authors.lastname: Pesquero
authors.forename: Ovidiu C
authors.initials: OC
authors.lastname: Baltatu
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
mesh_terms: 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*
chemical_list: D007705:Kinins; D008070:Lipopolysaccharides; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2