The role of bradykinin receptor type 2 in spontaneous extravasation in mice skin: implications for non-allergic angio-oedema.

Marion Bisha, Vu Thao-Vi Dao, Ehsan Gholamreza-Fahimi, Michael Vogt, Marc van Zandvoort, Sarah Weber, Murat Bas, Farbod Khosravani, Georg Kojda, Tatsiana Suvorava

British journal of pharmacology 2018 May

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Non-allergic angio-oedema is a life-threatening disease mediated by activation of bradykinin type 2 receptors (B2 receptors). The aim of this study was to investigate whether activation of B2 receptors by endogenous bradykinin contributes to physiological extravasation. This may shed new light on the assumption that treatment with an angiotensin converting enzyme inhibitor (ACEi) results in an alteration in the vascular barrier function predisposing to non-allergic angio-oedema. We generated a new transgenic mouse model characterized by endothelium-specific overexpression of the B2 receptor (B2tg ) and established a non-invasive two-photon laser microscopy approach to measure the kinetics of spontaneous extravasation in vivo. The B2tg mice showed normal morphology and litter size as compared with their transgene-negative littermates (B2n ). Overexpression of B2 receptors was functional in conductance vessels and resistance vessels as evidenced by B2 receptor-mediated aortic dilation to bradykinin in presence of non-specific COX inhibitor diclofenac and by significant hypotension in B2tg respectively. Measurement of dermal extravasation by Miles assay showed that bradykinin induced extravasation was significantly increased in B2tg as compared with B2n . However, neither endothelial overexpression of B2 receptors nor treatment with the ACEi moexipril or B2 antagonist icatibant had any effect on spontaneous extravasation measured by two-photon laser microscopy. Activation of B2 receptors does not appear to be involved in spontaneous extravasation. Therefore, the assumption that treatment with an ACEi results in an alteration in the physiological vascular barrier function predisposing to non-allergic angio-oedema is not supported by our findings. © 2018 The British Pharmacological Society.

Citation

Marion Bisha, Vu Thao-Vi Dao, Ehsan Gholamreza-Fahimi, Michael Vogt, Marc van Zandvoort, Sarah Weber, Murat Bas, Farbod Khosravani, Georg Kojda, Tatsiana Suvorava. The role of bradykinin receptor type 2 in spontaneous extravasation in mice skin: implications for non-allergic angio-oedema. British journal of pharmacology. 2018 May;175(10):1607-1620