Mice deficient for both kinin receptors are normotensive and protected from endotoxin-induced hypotension

Cécile Cayla, Mihail Todiras, Radu Iliescu, Vera V. Saul, Volkmar Gross, Bernhard Pilz, Guixuan Chai, Vanessa F. Merino, João B. Pesquero, Ovidiu C. Baltatu, Michael Bader

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1689-1698
Number of pages10
JournalFASEB Journal
Volume21
Issue number8
DOIs
StatePublished - Jun 1 2007
Externally publishedYes

Keywords

  • Blood pressure
  • Bradykinin
  • Endotoxemia

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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