Zusammenfassung
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.
- /&/
- acetanilides,
- adenosine
- animal;
- animals;
- atpase,
- blockers,
- calcium,
- cardiac,
- cell
- cells,
- channel
- complications/metabolism/pathology;
- control;
- cultured;
- death;
- dehydrogenase,
- disease
- drug
- effects/enzymology/metabolism/pathology;
- etiology/metabolism/pathology;
- etiology/metabolism/prevention
- exchanger,
- factors
- failure,
- heart
- hypoxia;
- infarction,
- injury,
- l-lactate
- male;
- metabolism;
- models,
- myocardial
- myocytes,
- oxygen,
- pharmacology;
- piperazines,
- potassium,
- radioisotopes;
- rats,
- rats;
- reperfusion
- rubidium
- sodium
- sodium,
- sodium-calcium
- sodium-potassium-exchanging
- time
- triphosphate,
Nutzer