Published online before print May 6, 2004, doi: 10.1161/01.RES.0000131497.73744.1a
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Submitted on January 22, 2003
Revised on April 1, 2004
Accepted on April 27, 2004
Flow-Dependent Dilation Mediated by Endogenous Kinins Requires Angiotensin AT2 Receptors
Sonia Bergaya ;
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, 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.
* To whom correspondence should be addressed. 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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