Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC139
Computer model of the rat ventricular myocyte with different ICa inactivation at the peripheral and t-tubule membranes
M. Pásek1,2, J. Šimurda2, C. H. Orchard3
1. Institute of Thermomechanics - branch Brno, Czech Academy of Science, Brno, Czech Republic. 2. Department of Physiology, Masaryk University, Brno, Czech Republic. 3. Department of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.
We have previously developed a mathematical model of electrical activity and ion handling in the rat ventricular myocyte (Pásek et al., 2006), which includes a quantitative description of the transverse-axial tubular system (TATS). The model has been used to explore the role of the t-tubules in determining the electrical and mechanical activity of the myocyte. However recent experimental data have shown that some aspects of trans-sarcolemmal Ca2+ flux and intracellular Ca2+ dynamics are more complex than formulated in the model, and that the tubular fractions of some trans-sarcolemmal ion fluxes are different from those used previously (Pásek et al., 2008; Chase & Orchard, 2011). We have, therefore, developed the model further, to incorporate a modified description of calcium current (ICa) and Ca2+ handling, in particular: (i) separating the original single dyadic space, and single sarcoplasmic reticulum (SR) release compartment, into two, one adjacent to peripheral membrane and the other adjacent to tubular membrane, and incorporating peripheral and tubular intracellular subspaces (Shannon et al., 2004); (ii) reformulating ICa inactivation to reflect enhanced Ca2+-dependent inactivation due to SR Ca2+ release at the TATS, compared with the peripheral membrane (Brette et al. 2004); (iii) incorporating a quantitative description of diffusion of exogenous Ca2+ buffers (e. g. EGTA, BAPTA) between the pipette and intracellular compartments; (iv) incorporating the most recent experimentally-derived tubular fractions of Ca2+ flux pathways (Chase & Orchard, 2011). The modified model is stable for at least 5 hours of simulated activity, with appropriate and reversible changes of ion concentrations with changes of activity. It reproduces the experimentally-observed effect of SR inhibition and exogenous Ca2+ buffers on ICa inactivation at the tubular and peripheral membranes, and has been used to explore the effects of activity-induced changes of ion concentrations in the tubular lumen on excitation-contraction coupling.
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