Variability in timing of spontaneous calcium release in the intact rat heart is determined by the time course of sarcoplasmic reticulum calcium load.
BACKGROUND
Abnormalities in intracellular calcium (Ca) cycling during Ca overload can cause triggered activity because spontaneous calcium release (SCR) activates sufficient Ca-sensitive inward currents to induce delayed afterdepolarizations (DADs). However, little is known about the mechanisms relating SCR and triggered activity on the tissue scale.


RESULTS
Laser scanning confocal microscopy was used to measure the spatiotemporal properties of SCR within large myocyte populations in intact rat heart. Computer simulations were used to predict how these properties of SCR determine DAD magnitude. We measured the average and standard deviation of the latency distribution of SCR within a large population of myocytes in intact tissue. We found that as external [Ca] is increased, and with faster pacing rates, the average and SD of the latency distribution decreases substantially. This result demonstrates that the timing of SCR occurs with less variability as the sarcoplasmic reticulum (SR) Ca load is increased, causing more sites to release Ca within each cell. We then applied a mathematical model of subcellular Ca cycling to show that a decrease in SCR variability leads to a higher DAD amplitude and is dictated by the rate of SR Ca refilling following an action potential.


CONCLUSIONS
Our results demonstrate that the variability of the timing of SCR in a population of cells in tissue decreases with SR load and is dictated by the time course of the SR Ca content.
Wasserstrom
J Andrew
JA
Department of Medicine (Cardiology) and Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 310 E Superior Street, Chicago, IL 60611, USA. ja-wasserstrom@northwestern.edu
Shiferaw
Yohannes
Y
Chen
Wei
W
Ramakrishna
Satvik
S
Patel
Heetabh
H
Kelly
James E
JE
O'Toole
Matthew J
MJ
Pappas
Amanda
A
Chirayil
Nimi
N
Bassi
Nikhil
N
Akintilo
Lisa
L
Wu
Megan
M
Arora
Rishi
R
Aistrup
Gary L
GL
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D013997:Time Factors
D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium