Abstract
We construct a detailed mathematical model for Ca$^2+$ 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 Ca$^2+$; 2) a model for the L-type Ca$^2+$ channel
that inactivates by mode switching; and 3) a restricted subspace
into which the RyRs and L-type Ca$^2+$ channels empty and interact
via Ca$^2+$. We add membrane currents from the Luo-Rudy Phase
II ventricular cell model to our description of Ca$^2+$ handling
to formulate a new model for ventricular action potentials and Ca$^2+$
regulation. The model can simulate Ca$^2+$ transients during
an action potential similar to those seen experimentally. The subspace
Ca$^2+$ rises more rapidly and reaches a higher level (10-30
microM) than the bulk myoplasmic Ca$^2+$ (peak Ca$^2+$i
approximately 1 microM). Termination of sarcoplasmic reticulum (SR)
Ca$^2+$ release is predominately due to emptying of the SR, but
is influenced by RyR adaptation. Because force generation is roughly
proportional to peak myoplasmic Ca$^2+$, we use Ca$^2+$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 Ca$^2+$ loading. This model, therefore,
shows improved behavior over existing models that lack detailed descriptions
of subcellular Ca$^2+$ regulatory mechanisms.
- 9512016
- action
- animals,
- calcium
- calcium,
- cardiovascular,
- channel
- channel,
- channels,
- chemical,
- contraction,
- electric
- factors,
- gating,
- gov't,
- guinea
- heart
- in
- ion
- kinetics,
- l-type,
- models,
- myocardial
- myocardium,
- non-p.h.s.,
- non-u.s.
- pigs,
- potentials,
- receptor
- release
- research
- reticulum,
- ryanodine
- sarcoplasmic
- stimulation,
- support,
- time
- u.s.
- ventricles,
- vitro,
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