Intermittent losartan administration triggers cardiac post-conditioning in isolated rat hearts: role of BK2 receptors

• Published in: PloS one Vol. 9; no. 2; p. e88542
• Main Authors: Sgarra, Luca, Leo, Valentina, Addabbo, Francesco, Iacobazzi, Dominga, Carratù, Maria Rosaria, Montagnani, Monica, Potenza, Maria Assunta
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10-02-2014; Public Library of Science (PLoS)
• Subjects: Activation; AKT protein; Angiotensin AT1 receptors; Angiotensin Receptor Antagonists - pharmacology; Angiotensin Receptor Antagonists - therapeutic use; Angiotensins; Animals; Binding sites; Biology; Biphenyl Compounds - pharmacology; Biphenyl Compounds - therapeutic use; Blood pressure; Bradykinin; Bradykinin - metabolism; Cardiac conditioning; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Compounds; Conditioning; Diastolic pressure; Heart; Heart - drug effects; Heart - physiopathology; Heart diseases; Hemodynamics - drug effects; In Vitro Techniques; Ischemia; Ischemic Postconditioning; Kinases; Laboratory animals; Losartan - administration & dosage; Losartan - pharmacology; Losartan - therapeutic use; Male; MAP kinase; Medicine; Mitochondria; Mitogen-Activated Protein Kinases - metabolism; Myocardial Infarction - drug therapy; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - physiopathology; Oncology; Permeability; Phosphorylation; Phosphotransferases; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2 - metabolism; Receptor, Bradykinin B2 - metabolism; Receptors; Reperfusion; Risk; Rodents; Signal transduction; Systole - drug effects; Tetrazoles - pharmacology; Tetrazoles - therapeutic use; Ventricle
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0088542

The angiotensin (Ang) and bradykinin (BK) tissue-system plays a pivotal role in post-conditioning, but the efficacy of angiotensin type 1 receptor (AT1R) blockers (ARBs) in post-ischemic strategies is still under investigation. We evaluated functional and morphological outcomes, together with activation of cytosolic RISK pathway kinases, in rat hearts subjected to losartan (LOS) or irbesartan (IRB) post-ischemic administration.
Isolated rat hearts underwent 30 min ischemia and 120 min reperfusion. Post-conditioning was obtained by intermittent (10 s/each) or continuous drug infusion during the first 3 min of reperfusion. Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (dLVP), coronary flow (CF), and left ventricular infarct mass (IM) were measured together with the activation status of RISK kinases Akt, p42/44 MAPK and GSK3β.
When compared to hearts subjected to ischemia/reperfusion (iI/R) alone, continuous IRB or LOS administration did not significantly reduce total infarct mass (cIRB or cLOS vs. iI/R, p = 0.2). Similarly, intermittent IRB (iIRB) was not able to enhance cardioprotection. Conversely, intermittent LOS administration (iLOS) significantly ameliorated cardiac recovery (iLOS vs iI/R, p<0.01). Differences between iLOS and iIRB persisted under continuous blockade of AT2R (iLOS+cPD vs. iIRB+cPD, p<0.05). Interestingly, iLOS cardioprotection was lost when BK2R was simultaneously blocked (iLOS+cHOE vs. iI/R, p = 0.6), whereas concurrent administration of iBK and iIRB replicated iLOS effects (iIRB+iBK vs. iLOS, p = 0.7). At the molecular level, iIRB treatment did not significantly activate RISK kinases, whereas both iLOS and iBK treatments were associated with activation of the Akt/GSK3β branch of the RISK pathways (p<0.05 vs. iI/R, for both).
Our results suggest that intermittent losartan is effective in mediating post-conditioning cardioprotection, whereas irbesartan is not. The infarct mass reduction by intermittent losartan seem mainly related on its specific ability to modulate BK2R, and only modestly associated on AT1R blocking properties.