Document Detail


Ranolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts.
MedLine Citation:
PMID:  21741479     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Ranolazine is a clinically approved drug for treating cardiac ventricular dysrhythmias and angina. Its mechanism(s) of protection is not clearly understood but evidence points to blocking the late Na+ current that arises during ischemia, blocking mitochondrial complex I activity, or modulating mitochondrial metabolism. Here we tested the effect of ranolazine treatment before ischemia at the mitochondrial level in intact isolated hearts and in mitochondria isolated from hearts at different times of reperfusion. Left ventricular (LV) pressure (LVP), coronary flow (CF), and O2 metabolism were measured in guinea pig isolated hearts perfused with Krebs-Ringer's solution; mitochondrial (m) superoxide (O2·-), Ca2+, NADH/FAD (redox state), and cytosolic (c) Ca2+ were assessed on-line in the LV free wall by fluorescence spectrophotometry. Ranolazine (5 μM), infused for 1 min just before 30 min of global ischemia, itself did not change O2·-, cCa2+, mCa2+ or redox state. During late ischemia and reperfusion (IR) O2·- emission and m[Ca2+] increased less in the ranolazine group vs. the control group. Ranolazine decreased c[Ca2+] only during ischemia while NADH and FAD were not different during IR in the ranolazine vs. control groups. Throughout reperfusion LVP and CF were higher, and ventricular fibrillation was less frequent. Infarct size was smaller in the ranolazine group than in the control group. Mitochondria isolated from ranolazine-treated hearts had mild resistance to permeability transition pore (mPTP) opening and less cytochrome c release than control hearts. Ranolazine may provide functional protection of the heart during IR injury by reducing cCa2+ and mCa2+ loading secondary to its effect to block the late Na+ current. Subsequently it indirectly reduces O2·- emission, preserves bioenergetics, delays mPTP opening, and restricts loss of cytochrome c, thereby reducing necrosis and apoptosis.
Authors:
Mohammed Aldakkak; Amadou K S Camara; James S Heisner; Meiying Yang; David F Stowe
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-06-29
Journal Detail:
Title:  Pharmacological research : the official journal of the Italian Pharmacological Society     Volume:  64     ISSN:  1096-1186     ISO Abbreviation:  Pharmacol. Res.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-09-19     Completed Date:  2012-01-19     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  8907422     Medline TA:  Pharmacol Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  381-92     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Ltd. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Acetanilides / pharmacology,  therapeutic use*
Animals
Calcium / metabolism*
Enzyme Inhibitors / pharmacology,  therapeutic use*
Guinea Pigs
Heart / drug effects
Membrane Potential, Mitochondrial / drug effects
Mitochondria, Heart / drug effects*,  metabolism
Myocardial Reperfusion Injury / metabolism,  prevention & control*
Oxidative Stress / drug effects*
Piperazines / pharmacology,  therapeutic use*
Grant Support
ID/Acronym/Agency:
R01 HL089514/HL/NHLBI NIH HHS; R01 HL089514/HL/NHLBI NIH HHS; R01 HL089514-02/HL/NHLBI NIH HHS; R01 HL095122/HL/NHLBI NIH HHS; R01 HL095122/HL/NHLBI NIH HHS; R01 HL095122-02/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Acetanilides; 0/Enzyme Inhibitors; 0/Piperazines; 110445-25-5/ranolazine; SY7Q814VUP/Calcium
Comments/Corrections

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