title: Ranolazine triggers pharmacological preconditioning and postconditioning in anesthetized rabbits through activation of RISK pathway.
abstract: We tested the hypothesis that ranolazine (Ran) is cardioprotective in a model of ischemia /reperfusion and we elucidated the intracellular mechanism. Anesthetized rabbits were subjected to is chemia and reperfusion and were divided into 5 groups: 1) Control, 2) Preconditioning (PreC), 3) Postconditioning (PostC), 4) RanA and 5) RanB, respectively treated with intravenous ranolazine, either 10min before or during index ischemia. Ranolazine was initially given over 60s and then from the beginning and throughout the whole reperfusion period. The infarcted to the risk ratio was calculated (%I/R). In a second series consisting of respective to the first series groups, the animals were subjected to the same interventions up to the 10th min of reperfusion where tissue samples were taken for immunoblotting of Akt, eNOS, ERK½ and GSK3β (RISK pathway). In a third series, RanA+Wort, RanB+Wort and Wort groups were treated with ranolazine as RanA and RanB groups but with the addition of the PI3 inhibitor Wortmaninn (Wort) and %I/R calculated. Ranolazine reduced the % I/R in RanA and RanB compared to the Control (23.1±1.7%, 17.6±2.0% vs 47.6±1.0%, P<0.05). %I/R reduction achieved in the RanA and RanB groups was comparable to that observed in PreC and PostC (16.3±2.1%, 26.2±2.1%, respectively P<0.05 vs Control). Phosphorylation of Akt, ERK½, eNOS and GSK3β were higher in PreC, PostC and in both ranolazine treated groups. Wortmannin abrogated ranolazine's %I/R reduction (RanA+Wort 31.4±1.7%, RanB+Wort 32.4±2.4%). Ranolazine reduces %I/R and triggers cardioprotection with a similar to conditioning mechanism which upregulates the RISK pathway.
authors: Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, School of Pharmacy, Athens, Greece.
authors: Panagiotis
authors: P
authors: Efentakis
authors: Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, School of Pharmacy, Athens, Greece. Electronic address: jandread@pharm.uoa.gr.
authors: Ioanna
authors: I
authors: Andreadou
authors: Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, School of Pharmacy, Athens, Greece.
authors: Sophia-Iris
authors: SI
authors: Bibli
authors: Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, School of Pharmacy, Athens, Greece.
authors: Styliani
authors: S
authors: Vasileiou
authors: Second Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Attikon University Hospital, Athens, Greece.
authors: Nikolaos
authors: N
authors: Dagres
authors: Second Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Attikon University Hospital, Athens, Greece.
authors: Anastasia
authors: A
authors: Zoga
authors: Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, School of Pharmacy, Athens, Greece.
authors: Nikolaos
authors: N
authors: Lougiakis
authors: Second Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Attikon University Hospital, Athens, Greece.
authors: Dimitrios Th
authors: DT
authors: Kremastinos
authors: Second Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Attikon University Hospital, Athens, Greece.
authors: Efstathios K
authors: EK
authors: Iliodromitis
mesh_terms: D000758:Anesthesia; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D057775:Ischemic Postconditioning / Q000379:methods*; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011817:Rabbits; D000069458:Ranolazine / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D000069458:Ranolazine; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Cardioprotection; Postconditioning; Preconditioning; RISK pathway; Ranolazine