Sensitivity of Rabbit Ventricular Action Potential and Ca(2+) Dynamics to Small Variations in Membrane Currents and Ion Diffusion Coefficients

Little is known about how small variations in ionic currents and Ca(2+) and Na(+) diffusion coefficients impact action potential and Ca(2+) dynamics in rabbit ventricular myocytes. We applied sensitivity analysis to quantify the sensitivity of Shannon et al. model (Biophys. J., 2004) to 5%–10% changes in currents conductance, channels distribution, and ion diffusion in rabbit ventricular cells. We found that action potential duration and Ca(2+) peaks are highly sensitive to 10% increase in L-type Ca(2+) current; moderately influenced by 10% increase in Na(+)-Ca(2+) exchanger, Na(+)-K(+) pump, rapid delayed and slow transient outward K(+) currents, and Cl(−) background current; insensitive to 10% increases in all other ionic currents and sarcoplasmic reticulum Ca(2+) fluxes. Cell electrical activity is strongly affected by 5% shift of L-type Ca(2+) channels and Na(+)-Ca(2+) exchanger in between junctional and submembrane spaces while Ca(2+)-activated Cl(−)-channel redistribution has the modest effect. Small changes in submembrane and cytosolic diffusion coefficients for Ca(2+), but not in Na(+) transfer, may alter notably myocyte contraction. Our studies highlight the need for more precise measurements and further extending and testing of the Shannon et al. model. Our results demonstrate usefulness of sensitivity analysis to identify specific knowledge gaps and controversies related to ventricular cell electrophysiology and Ca(2+) signaling.