title: Aliskiren reduces myocardial ischemia-reperfusion injury by a bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanism.
abstract: Angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers reduce myocardial ischemia-reperfusion injury via bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanisms. The renin inhibitor aliskiren increases cardiac tissue kallikrein and bradykinin levels. In the present study, we investigated the effect of aliskiren on myocardial ischemia-reperfusion injury and the roles of B2 and AT2 receptors in this effect. Female Sprague-Dawley rats were treated with aliskiren (10 mg/kg per day) and valsartan (30 mg/kg per day), alone or in combination, together with the B2 receptor antagonist icatibant (0.5 mg/kg per day) or the AT2 receptor antagonist PD123319 (30 mg/kg per day), for 4 weeks before myocardial ischemia-reperfusion injury. Aliskiren increased cardiac bradykinin levels and attenuated valsartan-induced increases in plasma angiotensin II levels. In vehicle-treated rats, myocardial infarct size (% area at risk, mean±SEM, n=7-13) was 43±3%. This was reduced to a similar extent by aliskiren, valsartan, and their combination to 24±3%, 25±3%, and 22±2%, respectively. Icatibant reversed the cardioprotective effects of aliskiren and the combination of aliskiren plus valsartan, but not valsartan alone, indicating that valsartan-induced cardioprotection was not mediated by the B2 receptor. PD123319 reversed the cardioprotective effects of aliskiren, valsartan, and the combination of aliskiren plus valsartan. Aliskiren protects the heart from myocardial ischemia-reperfusion injury via a B2 receptor- and AT2 receptor-mediated mechanism, whereas cardioprotection by valsartan is mediated via the AT2 receptor. In addition, aliskiren attenuates valsartan-induced increases in angiotensin II levels, thus preventing AT2 receptor-mediated cardioprotection by valsartan.
authors.affiliation: St Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia. dcampbell@svi.edu.au.
authors.forename: Suang Suang
authors.initials: SS
authors.lastname: Koid
authors.forename: James
authors.initials: J
authors.lastname: Ziogas
authors.forename: Duncan John
authors.initials: DJ
authors.lastname: Campbell
mesh_terms: D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005650:Fumarates / Q000494:pharmacology / Q000627:therapeutic use*; D007093:Imidazoles / Q000494:pharmacology; D023421:Models, Animal; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects / Q000502:physiology*; D043782:Receptor, Bradykinin B2 / Q000187:drug effects / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan
chemical_list: D000577:Amides; D057912:Angiotensin II Type 2 Receptor Blockers; D000959:Antihypertensive Agents; D065094:Bradykinin B2 Receptor Antagonists; D002316:Cardiotonic Agents; D005650:Fumarates; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D013777:Tetrazoles; C073402:PD 123319; C446481:aliskiren; C065679:icatibant; D000068756:Valsartan; D014633:Valine; D001920:Bradykinin
keywords: aliskiren; angiotensins; bradykinin; myocardial infarction