title: Flow-dependent dilation mediated by endogenous kinins requires angiotensin AT2 receptors.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unit 541, Hôpital Lariboisière, Paris, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Bergaya
authors.forename: Rob H P
authors.initials: RH
authors.lastname: Hilgers
authors.forename: Pierre
authors.initials: P
authors.lastname: Meneton
authors.forename: You
authors.initials: Y
authors.lastname: Dong
authors.forename: May
authors.initials: M
authors.lastname: Bloch-Faure
authors.forename: Tadashi
authors.initials: T
authors.lastname: Inagami
authors.forename: François
authors.initials: F
authors.lastname: Alhenc-Gelas
authors.forename: Bernard I
authors.initials: BI
authors.lastname: Lévy
authors.forename: Chantal M
authors.initials: CM
authors.lastname: Boulanger
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D002339:Carotid Arteries / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D018056:Hemorheology; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010656:Phenylephrine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044139:Receptor, Angiotensin, Type 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D043782:Receptor, Bradykinin B2 / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D020840:Tissue Kallikreins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D065094:Bradykinin B2 Receptor Antagonists; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D013777:Tetrazoles; D014665:Vasodilator Agents; C073402:PD 123319; D010656:Phenylephrine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C065679:icatibant; D020840:Tissue Kallikreins; D019808:Losartan; D000109:Acetylcholine; C081643:candesartan; D001920:Bradykinin