title: Cardiomyocytes from postinfarction failing rat hearts have improved ischemia tolerance.
abstract: Altered myocardial Ca(2+) and Na(+) handling in congestive heart failure (CHF) may be expected to decrease the tolerance to ischemia by augmenting reperfusion Ca(2+) overload. The aim of the present study was to investigate tolerance to hypoxia-reoxygenation by measuring enzyme release, cell death, ATP level, and cell Ca(2+) and Na(+) in cardiomyocytes from failing rat hearts. CHF was induced in Wistar rats by ligation of the left coronary artery during isoflurane anesthesia, after which cardiac failure developed within 6 wk. Isolated cardiomyocytes were cultured for 24 h and subsequently exposed to 4 h of hypoxia and 2 h of reoxygenation. Cell damage was measured as lactate dehydrogenase (LD) release, cell death as propidium iodide uptake, and ATP by firefly luciferase assay. Cell Ca(2+) and Na(+) were determined with radioactive isotopes, and free intracellular Ca(2+) concentration ([Ca(2+)](i)) with fluo-3 AM. CHF cells showed less increase in LD release and cell death after hypoxia-reoxygenation and had less relative reduction in ATP level after hypoxia than sham cells. CHF cells accumulated less Na(+) than sham cells during hypoxia (117 vs. 267 nmol/mg protein). CHF cells maintained much lower [Ca(2+)](i) than sham cells during hypoxia (423 vs. 1,766 arbitrary units at 4 h of hypoxia), and exchangeable Ca(2+) increased much less in CHF than in sham cells (1.4 vs. 6.7 nmol/mg protein) after 120 min of reoxygenation. Ranolazine, an inhibitor of late Na(+) current, significantly attenuated both the increase in exchangeable Ca(2+) and the increase in LD release in sham cells after reoxygenation. This supports the suggestion that differences in Na(+) accumulation during hypoxia cause the observed differences in Ca(2+) accumulation during reoxygenation. Tolerance to hypoxia and reoxygenation was surprisingly higher in CHF than in sham cardiomyocytes, probably explained by lower hypoxia-mediated Na(+) accumulation and subsequent lower Ca(2+) accumulation in CHF after reoxygenation.
authors.affiliation: Dept. of Clinical Chemistry, Ullevål Univ. Hopital, 0407 Oslo, Norway. m.n.sharikabad@medisin.uio.no
authors.forename: Mohammad Nouri
authors.initials: MN
authors.lastname: Sharikabad
authors.forename: Jan Magnus
authors.initials: JM
authors.lastname: Aronsen
authors.forename: Espen
authors.initials: E
authors.lastname: Haugen
authors.forename: Janne
authors.initials: J
authors.lastname: Pedersen
authors.forename: Anne-Sophie W
authors.initials: AS
authors.lastname: Møller
authors.forename: Halvor Kjeang
authors.initials: HK
authors.lastname: Mørk
authors.forename: Hans C D
authors.initials: HC
authors.lastname: Aass
authors.forename: Ole M
authors.initials: OM
authors.lastname: Sejersted
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Odd
authors.initials: O
authors.lastname: Brørs
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D000069458:Ranolazine; D051381:Rats; D017208:Rats, Wistar; D012414:Rubidium Radioisotopes; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013997:Time Factors
chemical_list: D000083:Acetanilides; D010879:Piperazines; D012414:Rubidium Radioisotopes; D026941:Sodium Channel Blockers; D019831:Sodium-Calcium Exchanger; D000255:Adenosine Triphosphate; D012964:Sodium; D000069458:Ranolazine; D007770:L-Lactate Dehydrogenase; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium; D010100:Oxygen; D002118:Calcium