title: Intermittent losartan administration triggers cardiac post-conditioning in isolated rat hearts: role of BK2 receptors.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro," Bari, Italy.
authors: Luca
authors: L
authors: Sgarra
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro," Bari, Italy.
authors: Valentina
authors: V
authors: Leo
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro," Bari, Italy.
authors: Francesco
authors: F
authors: Addabbo
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro," Bari, Italy.
authors: Dominga
authors: D
authors: Iacobazzi
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro," Bari, Italy.
authors: Maria Rosaria
authors: MR
authors: Carratù
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro," Bari, Italy.
authors: Monica
authors: M
authors: Montagnani
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro," Bari, Italy.
authors: Maria Assunta
authors: MA
authors: Potenza
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D001920:Bradykinin / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D000077405:Irbesartan; D057775:Ischemic Postconditioning; D019808:Losartan / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D013599:Systole / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D002316:Cardiotonic Agents; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D013777:Tetrazoles; D020928:Mitogen-Activated Protein Kinases; C426604:RISK-1 kinase, Aplysia; D000077405:Irbesartan; D019808:Losartan; D001920:Bradykinin