The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling
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The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling. / Bonde, Marie Mi; Olsen, Kristine Boisen; Erikstrup, Niels; Speerschneider, Tobias; Lyngsø, Christina; Haunsø, Stig; Nielsen, Morten Schak; Sheikh, Søren Paludan; Hansen, Jakob Lerche.
In: Regulatory Peptides, Vol. 167, No. 1, 2011, p. 21-25.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling
AU - Bonde, Marie Mi
AU - Olsen, Kristine Boisen
AU - Erikstrup, Niels
AU - Speerschneider, Tobias
AU - Lyngsø, Christina
AU - Haunsø, Stig
AU - Nielsen, Morten Schak
AU - Sheikh, Søren Paludan
AU - Hansen, Jakob Lerche
N1 - Copyright © 2010 Elsevier B.V. All rights reserved.
PY - 2011
Y1 - 2011
N2 - The angiotensin II type 1 receptor (AT1R) blocker (ARB) Losartan has cardioprotective effects during ischemia-reperfusion injury and inhibits reperfusion arrhythmias -effects that go beyond the benefits of lowering blood pressure. The renin-angiotensin and kallikrein-kinin systems are intricately connected and some of the cardioprotective effects of Losartan are abolished by blocking the bradykinin B2 receptor (B2R) signaling. In this study, we investigated the ability of six clinically available ARBs to specifically bind and activate the B2R. First, we investigated their ability to activate phosphoinositide (PI) hydrolysis in COS-7 cells transiently expressing the B2R. We found that only Losartan activated the B2R, working as a partial agonist compared to the endogenous ligand bradykinin. This effect was blocked by the B2R antagonist HOE 140. A competitive binding analysis revealed that Losartan does not significantly compete with bradykinin and does not change the binding affinity of bradykinin on the B2R. Furthermore, Losartan but not Candesartan mimicked the ability of bradykinin to increase the recovery of contractile force after metabolic stress in rat atrial tissue strips. In conclusion, Losartan is a partial agonist of the B2R through direct binding and activation, suggesting that B2R agonism could partly explain the beneficial effects of Losartan
AB - The angiotensin II type 1 receptor (AT1R) blocker (ARB) Losartan has cardioprotective effects during ischemia-reperfusion injury and inhibits reperfusion arrhythmias -effects that go beyond the benefits of lowering blood pressure. The renin-angiotensin and kallikrein-kinin systems are intricately connected and some of the cardioprotective effects of Losartan are abolished by blocking the bradykinin B2 receptor (B2R) signaling. In this study, we investigated the ability of six clinically available ARBs to specifically bind and activate the B2R. First, we investigated their ability to activate phosphoinositide (PI) hydrolysis in COS-7 cells transiently expressing the B2R. We found that only Losartan activated the B2R, working as a partial agonist compared to the endogenous ligand bradykinin. This effect was blocked by the B2R antagonist HOE 140. A competitive binding analysis revealed that Losartan does not significantly compete with bradykinin and does not change the binding affinity of bradykinin on the B2R. Furthermore, Losartan but not Candesartan mimicked the ability of bradykinin to increase the recovery of contractile force after metabolic stress in rat atrial tissue strips. In conclusion, Losartan is a partial agonist of the B2R through direct binding and activation, suggesting that B2R agonism could partly explain the beneficial effects of Losartan
U2 - 10.1016/j.regpep.2010.11.003
DO - 10.1016/j.regpep.2010.11.003
M3 - Journal article
C2 - 21115072
VL - 167
SP - 21
EP - 25
JO - Regulatory Peptides
JF - Regulatory Peptides
SN - 0167-0115
IS - 1
ER -
ID: 33811099