Flow-dependent dilation mediated by endogenous kinins requires angiotensin AT2 receptors

The vascular kallikrein-kinin system contributes to about one third of flow-dependent dilation in mice carotid arteries, by activating bradykinin B-2 receptors coupled to endothelial nitric oxide (NO) release. Because the bradykinin/NO pathway may mediate some of the effects of angiotensin II AT(2) receptors, we examined the possible contribution of AT(2) 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 AT(2) 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 AT(1) receptors with losartan or candesartan did not affect the response to flow. Inhibition of AT(2) receptors with PD123319 reduced significantly flow-induced dilation in TK+/+ mice, but had no significant effect in TK-/- mice. Combining PD123319 with the bradykinin B-2 receptor antagonist HOE-140 had no additional effect to AT(2) receptor blockade alone in TK+/+ arteries. Flow-dependent-dilation was also impaired in AT(2) receptor deficient mice (AT(2)(-/-)) when compared with wild-type littermates. Furthermore, HOE-140 significantly reduced the response to flow in the AT(2)(+/+), but not in AT(2)(-/-) mice. In conclusion, this study demonstrates that the presence of functional AT(2) receptors is necessary to observe the contribution of the vascular kinin-kallikrein system to flow-dependent dilation.