The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling.
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.
Laboratory for Molecular Cardiology, The Danish National Research Foundation Centre for Cardiac Arrhythmia, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Juliane Mariesvej 20, Section 9312, DK-2100 Copenhagen, Denmark.
Marie Mi
MM
Bonde
Kristine Boisen
KB
Olsen
Niels
N
Erikstrup
Tobias
T
Speerschneider
Christina
C
Lyngsø
Stig
S
Haunsø
Morten Schak
MS
Nielsen
Søren P
SP
Sheikh
Jakob Lerche
JL
Hansen
D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism / Q000494:pharmacology*; D000809:Angiotensins / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001667:Binding, Competitive; D001713:Biphenyl Compounds; D001920:Bradykinin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D065094:Bradykinin B2 Receptor Antagonists; D019556:COS Cells; D002522:Chlorocebus aethiops; D006868:Hydrolysis; D016234:Kallikrein-Kinin System / Q000502:physiology; D019808:Losartan / Q000378:metabolism / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000819:agonists / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D000809:Angiotensins; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D065094:Bradykinin B2 Receptor Antagonists; D010716:Phosphatidylinositols; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D013777:Tetrazoles; C065679:icatibant; D019808:Losartan; C081643:candesartan; D001920:Bradykinin