Contribution of angiotensin receptor type II to dermal extravasation caused by bradykinin in mice: Implications for sartan-induced angioedema

Background While non-allergic angioedema induced by ACE inhibitors and sacubitril are caused by reduced bradykinin degradation and over-activation of bradykinin receptor type 2 (B2), the pathophysiology of sartan-induced angioedema is not fully understood. As angiotensin II receptor (AT) type 1 blockers (sartans) increase circulating angiotensin II, enhanced activation of AT2 by angiotensin II likely occurs. The aim of this study was to investigate whether the AT2 agonist compound 21 (C21) inhibits ACE activity and increases bradykinin-induced dermal extravasation. Methods Increased plasma angiotensin II by telmisartan was measured at a dose that reduced systolic blood pressure by 20 mmHg. C21 was synthesized and its biological activity assessed by vasorelaxation of aortic rings of control mice which was absent in rings of AT2 -/y mice. As for Miles Assays AT2 -/y mice were backcrossed to C57BL/6 J (AT2 -/y -C57). Blood pressure remained unchanged by C21. Results In Miles assays in C57BL/6 J, but not in AT2 -/y -C57, C21 potentiated dermal extravasation induced by bradykinin that was inhibited by the AT2 antagonist PD123319, while extravasation by the ACE resistant B2 agonist labradimil remained. Pre-treatment of human endothelial cells with C21 strongly reduced ACE activity in cell homogenates in an AT2 dependent manner suggesting a cellular loss of ACE and indicating reduced tissue ACE activity. Correspondingly, increased ACE activity in plasma occurred following treatment with C21. Conclusion These data suggest an increase of bradykinin-induced skin extravasation due to direct AT2 activation which may contribute to explaining the molecular mechanism underlying the occurrence of sartan-induced non-allergic angioedema.