Cardiac Ca2+ dynamics: the roles of ryanodine receptor adaptation and sarcoplasmic reticulum load.
We construct a detailed mathematical model for Ca2+ regulation in the ventricular myocyte that includes novel descriptions of subcellular mechanisms based on recent experimental findings: 1) the Keizer-Levine model for the ryanodine receptor (RyR), which displays adaptation at elevated Ca2+; 2) a model for the L-type Ca2+ channel that inactivates by mode switching; and 3) a restricted subspace into which the RyRs and L-type Ca2+ channels empty and interact via Ca2+. We add membrane currents from the Luo-Rudy Phase II ventricular cell model to our description of Ca2+ handling to formulate a new model for ventricular action potentials and Ca2+ regulation. The model can simulate Ca2+ transients during an action potential similar to those seen experimentally. The subspace [Ca2+] rises more rapidly and reaches a higher level (10-30 microM) than the bulk myoplasmic Ca2+ (peak [Ca2+]i approximately 1 microM). Termination of sarcoplasmic reticulum (SR) Ca2+ release is predominately due to emptying of the SR, but is influenced by RyR adaptation. Because force generation is roughly proportional to peak myoplasmic Ca2+, we use [Ca2+]i in the model to explore the effects of pacing rate on force generation. The model reproduces transitions seen in force generation due to changes in pacing that cannot be simulated by previous models. Simulation of such complex phenomena requires an interplay of both RyR adaptation and the degree of SR Ca2+ loading. This model, therefore, shows improved behavior over existing models that lack detailed descriptions of subcellular Ca2+ regulatory mechanisms.
Jafri
M S
MS
Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. jafri@bme.jhu.edu
Rice
J J
JJ
Winslow
R L
RL
D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D020746:Calcium Channels, L-Type; D006352:Heart Ventricles; D007700:Kinetics; D008955:Models, Cardiovascular; D008956:Models, Chemical; D009206:Myocardium / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium