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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/H787    most recent 00796.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sharikabad, M. N. Articles by Brørs, O. Search for Related Content PubMed PubMed Citation Articles by Sharikabad, M. N. Articles by Brørs, O.

Cardiomyocytes from postinfarction failing rat hearts have improved ischemia tolerance

¹Clinical Chemistry Department and ²Institute for Experimental Medical Research, Ullevål University Hospital, Oslo; ³Center for Heart Failure Research, University of Oslo, Oslo; and ⁴Department of Cardiology, Ullevål University Hospital, Oslo, Norway

Submitted 31 July 2008 ; accepted in final form 23 December 2008

Altered myocardial Ca²⁺ and Na⁺ handling in congestive heart failure (CHF) may be expected to decrease the tolerance to ischemia by augmenting reperfusion Ca²⁺ overload. The aim of the present study was to investigate tolerance to hypoxia-reoxygenation by measuring enzyme release, cell death, ATP level, and cell Ca²⁺ 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 Ca²⁺ and Na⁺ were determined with radioactive isotopes, and free intracellular Ca²⁺ concentration ([Ca²⁺]_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 [Ca²⁺]_i than sham cells during hypoxia (423 vs. 1,766 arbitrary units at 4 h of hypoxia), and exchangeable Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ accumulation in CHF after reoxygenation.

calcium; congestive heart failure; sodium