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 μM) than the bulk myoplasmic Ca²⁺ (peak [Ca²⁺]₁ ~ 1 μM). 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 propodional 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.