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Hypertension. 2003;41:611-617
Published online before print February 3, 2003, doi: 10.1161/01.HYP.0000054971.03046.9B
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(Hypertension. 2003;41:611.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Tissue Kallikrein Actions at the Rabbit Natural or Recombinant Kinin B2 Receptors

Steeve Houle; Giuseppe Molinaro; Albert Adam; François Marceau

From the Centre Hospitalier Universitaire de Québec, Centre de recherche du Pavillon l’Hôtel-Dieu de Québec (S.H., F.M.), and the Faculté de Pharmacie, Université de Montréal, Montréal (G.M., A.A.), Québec, Canada.

Correspondence to François Marceau, MD, PhD, CHUQ Research Center, Pavillon HDQ, 11 Côte-du-Palais, Québec, Canada G1R 2J6. E-mail francois.marceau{at}crhdq.ulaval.ca

We have examined whether exogenous human tissue kallikrein exerts pharmacological actions via the bradykinin B2 receptor; specifically, whether the protease can bind to, cleave, internalize, and/or activate a fusion protein composed of the rabbit B2 receptor conjugated to the green fluorescent protein (B2R-GFP). The enzyme partially digested the fusion protein at 1 µmol/L, but not 100 nmol/L, and promoted B2R-GFP endocytosis in HEK 293 cells (>=50 nmol/L). Trypsin and endoproteinase Lys-C, but not plasma kallikrein, also cleaved B2R-GFP. Phospholipase A2 was activated by 50 nmol/L tissue kallikrein in HEK 293 cells expressing B2R-GFP, and this was mediated by the receptor, as shown by the effect of a B2 receptor antagonist and by the lack of response in untransfected cells. However, 500 nmol/L kallikrein elicited a strong receptor-independent activation of phospholipase A2. Tissue kallikrein competed for [3H]bradykinin binding to B2R-GFP only at 1 µmol/L. A simulation involving kallikrein treatment of HEK 293 cells, pretreated or not with human plasma, evidenced the formation of immunoreactive bradykinin. The enzyme (50 nmol/L) contracted the rabbit isolated jugular vein via its endogenous B2 receptors, but the effect was tachyphylactic, and there was no cross-desensitization with bradykinin effects. Aprotinin prevented all pharmacological responses to tissue kallikrein, indicating that the enzyme activity is required for its effect. The local generation of kinins is a plausible mechanism for the pharmacological effects of lower concentrations of tissue kallikrein (50 to 100 nmol/L); higher levels (0.5 to 1 µmol/L) can not only initiate the degradation of rabbit B2 receptors but also exert nonreceptor-mediated effects.


Key Words: receptors, bradykinin • kallikrein • rabbits • fluorescence




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