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

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

*Corresponding author for this work

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Abstract

BACKGROUND AND PURPOSE Non-allergic angio-oedema is a life-threatening disease mediated by activation of bradykinin type 2 receptors (B-2 receptors). The aim of this study was to investigate whether activation of B-2 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. EXPERIMENTAL APPROACH We generated a new transgenic mouse model characterized by endothelium-specific overexpression of the B-2 receptor (B2(tg)) and established a non-invasive two-photon laser microscopy approach to measure the kinetics of spontaneous extravasation in vivo. The B2(tg) mice showed normal morphology and litter size as compared with their transgene-negative littermates (B2(n)). KEY RESULTS Overexpression of B-2 receptors was functional in conductance vessels and resistance vessels as evidenced by B-2 receptor-mediated aortic dilation to bradykinin in presence of non-specific COX inhibitor diclofenac and by significant hypotension in B2(tg) respectively. Measurement of dermal extravasation by Miles assay showed that bradykinin induced extravasation was significantly increased in B2(tg) as compared with B2(n). However, neither endothelial overexpression of B-2 receptors nor treatment with the ACEi moexipril or B-2 antagonist icatibant had any effect on spontaneous extravasation measured by two-photon laser microscopy. CONCLUSIONS AND IMPLICATIONS Activation of B-2 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.
Original languageEnglish
Pages (from-to)1607-1620
Number of pages14
JournalBritish Journal of Pharmacology
Volume175
Issue number10
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • NITRIC-OXIDE SYNTHASE
  • CONVERTING-ENZYME INHIBITOR
  • INCREASED VASCULAR-PERMEABILITY
  • HIGH-RISK PATIENTS
  • BLOOD-PRESSURE
  • IN-VIVO
  • HEREDITARY ANGIOEDEMA
  • CARDIOVASCULAR EVENTS
  • MEDIATED ANGIOEDEMA
  • HYDROGEN-PEROXIDE

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