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Received March 28, 2002
Accepted after revision June 11, 2002
1 University of Glasgow Veterinary School, Glasgow G12 8QQ, UK
2 Department of Medical Cardiology, University of Glasgow, Glasgow G12 8QQ, UK
3 West Medical Building, University of Glasgow, UK
* To whom correspondence should be addressed. E-mail: g.smith{at}bio.gla.ac.uk.
Spontaneous sarcoplasmic reticulum (SR) Ca2+ release and propagated intracellular Ca2+ waves are a consequence of cellular Ca2+ overload in cardiomyocytes. We examined the relationship between average intracellular [Ca2+] and Ca2+ wave characteristics. The amplitude, time course and propagation velocity of Ca2+ waves were measured using line-scan confocal imaging of ß-escin-permeabilised cardiomyocytes perfused with 10 µM Fluo-3 or Fluo-5F. Spontaneous Ca2+ waves were evident at cellular [Ca2+] > 200 nM. Peak [Ca2+] during a wave was 2.0-2.2 µM; the minimum [Ca2+] between waves was 120-160 nM; wave frequency was ~0.1 Hz. Raising mean cellular [Ca2+] caused increases in all three parameters, particularly Ca2+ wave frequency. Increases in the rate of SR Ca2+ release and Ca2+ uptake were observed at higher cellular [Ca2+], indicating calcium-sensitive regulation of these processes. At extracellular [Ca2+] > 2 µM, the mean [Ca2+] inside the permeabilised cell did not increase above 1.5 µM. This extracellular-intracellular Ca2+ gradient could be maintained for periods of up to 5 min before the cardiomyocyte developed a sustained and irreversible hypercontraction. Inclusion of mitochondrial inhibitors (2 µM carbonyl cyanide m-chlorophenylhydrazone and 2 µM oligomycin) while perfusing with > 2 µM Ca2+ abolished the extracellular-intracellular Ca2+ gradient through the generation of Ca2+ waves with a higher peak [Ca2+] compared to control conditions. Under these conditions, cardiomyocytes rapidly (< 2 min) developed a sustained and irreversible contraction. These results suggest that mitochondrial Ca2+ uptake acts to delay an increase in [Ca2+] by blunting the peak of the Ca2+ wave.
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