CARDIAC CA2- THE ROLES OF RYANODINE RECEPTOR ADAPTATION AND SARCOPLASMIC-RETICULUM LOAD( DYNAMICS )

We construct a detailed mathematical model for Ca2+ regulation in the ventricular myocyte that includes novel descriptions of subcellular me chanisms based on recent experimental findings: 1) the Keizer-Levine m odel for the ryanodine receptor (RyR), which displays adaptation at el evated Ca2+; 2) a model for the L-type Ca2+ channel that inactivates b y mode switching; and 3) a restricted subspace into which the RyRs and L-type Ca2+ channels empty and interact via Ca2+. We add membrane cur rents from the Luo-Rudy Phase II ventricular cell model to our descrip tion 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 m u M) than the bulk myoplasmic Ca2+ (peak [Ca2+](i) approximate to 1 mu M). Termination of sarcoplasmic reticulum (SR) Ca2+ release is predom inately 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 r ate on force generation. The model reproduces transitions seen in forc e generation due to changes in pacing that cannot be simulated by prev ious models. Simulation of such complex phenomena requires an interpla y of both RyR adaptation and the degree of SR Ca2+ loading. This model , therefore, shows improved behavior over existing models that lack de tailed descriptions of subcellular Ca2+ regulatory mechanisms.