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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^* and Michael Bader^*,1

^* Max-Delbrück-Center for Molecular Medicine (MDC) and

Helios-Klinikum Berlin, Franz-Volhard-Clinic, Berlin-Buch, Germany; and

Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil

¹Correspondence: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, D-13092 Berlin-Buch, Germany. E-mail: mbader{at}mdc-berlin.de

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, C., Todiras, M., Iliescu, R., Saul, V. V., Gross, V., Pilz, B., Chai, G., Merino, V. F., Pesquero, J. B., Baltatu, O. C., Bader, M. Mice deficient for both kinin receptors are normotensive and protected from endotoxin-induced hypotension.

Key Words: bradykinin • blood pressure • endotoxemia

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