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(Circulation Research. 2004;94:1623.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Flow-Dependent Dilation Mediated by Endogenous Kinins Requires Angiotensin AT₂ Receptors

Sonia Bergaya, Rob H.P. Hilgers, Pierre Meneton, You Dong, May Bloch-Faure, Tadashi Inagami, François Alhenc-Gelas, Bernard I. Lévy, Chantal M. Boulanger

From the Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 541, Hôpital Lariboisière, Paris, France. Present address for R.H.P.H. is the Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands; for P.M., M.B.-F., F.A.-G. is INSERM Unit 367, Paris, France; and for T.I. is the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Chantal M. Boulanger, PhD, INSERM Unit 541, Hôpital Lariboisière, 41 Bd de la Chapelle, F-75475 Paris Cedex 10, France. E-mail chantal.boulanger{at}larib.inserm.fr

The vascular kallikrein-kinin system contributes to about one third of flow-dependent dilation in mice carotid arteries, by activating bradykinin B₂ receptors coupled to endothelial nitric oxide (NO) release. Because the bradykinin/NO pathway may mediate some of the effects of angiotensin II AT₂ receptors, we examined the possible contribution of AT₂ receptors to the kinin-dependent response to flow. Changes in outer diameter after increases in flow rate were evaluated in perfused arteries from wild-type animals (TK^+/+) and in tissue kallikrein-deficient mice (TK^–/–) in which the presence of AT₂ receptor expression was verified. Saralasin, a nonselective angiotensin II receptor antagonist, impaired significantly flow-induced dilation in TK^+/+, whereas it had no effect in TK^–/– mice. In both groups, blockade of AT₁ receptors with losartan or candesartan did not affect the response to flow. Inhibition of AT₂ receptors with PD123319 reduced significantly flow-induced dilation in TK^+/+ mice, but had no significant effect in TK^–/– mice. Combining PD123319 with the bradykinin B₂ receptor antagonist HOE-140 had no additional effect to AT₂ receptor blockade alone in TK^+/+ arteries. Flow-dependent-dilation was also impaired in AT₂ receptor deficient mice (AT₂^–/–) when compared with wild-type littermates. Furthermore, HOE-140 significantly reduced the response to flow in the AT₂^+/+, but not in AT₂^–/– mice. In conclusion, this study demonstrates that the presence of functional AT₂ receptors is necessary to observe the contribution of the vascular kinin-kallikrein system to flow-dependent dilation.

Key Words: kinins • angiotensin II • flow-dependent vasodilation • angiotensin AT₂ receptor • bradykinin B₂ receptor

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