Control of Ca2+ release by action potential configuration in normal and failing murine cardiomyocytes.
Cardiomyocytes from failing hearts exhibit spatially nonuniform or dyssynchronous sarcoplasmic reticulum (SR) Ca(2+) release. We investigated the contribution of action potential (AP) prolongation in mice with congestive heart failure (CHF) after myocardial infarction. AP recordings from CHF and control myocytes were included in a computational model of the dyad, which predicted more dyssynchronous ryanodine receptor opening during stimulation with the CHF AP. This prediction was confirmed in cardiomyocyte experiments, when cells were alternately stimulated by control and CHF AP voltage-clamp waveforms. However, when a train of like APs was used as the voltage stimulus, the control and CHF AP produced a similar Ca(2+) release pattern. In this steady-state condition, greater integrated Ca(2+) entry during the CHF AP lead to increased SR Ca(2+) content. A resulting increase in ryanodine receptor sensitivity synchronized SR Ca(2+) release in the mathematical model, thus offsetting the desynchronizing effects of reduced driving force for Ca(2+) entry. A modest nondyssynchronous prolongation of Ca(2+) release was nevertheless observed during the steady-state CHF AP, which contributed to increased time-to-peak measurements for Ca(2+) transients in failing cells. Thus, dyssynchronous Ca(2+) release in failing mouse myocytes does not result from electrical remodeling, but rather other alterations such as T-tubule reorganization.
Louch
William E
WE
Institute for Experimental Medical Research, Oslo University Hospital Ullevaal, Oslo, Norway. w.e.louch@medisin.uio.no
Hake
Johan
J
Jølle
Guro Five
GF
Mørk
Halvor K
HK
Sjaastad
Ivar
I
Lines
Glenn T
GT
Sejersted
Ole M
OM
D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D016764:Cell Polarity; D005260:Female; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D002118:Calcium
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