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Little is known about how small variations in ionic currents and Ca²⁺ and Na⁺ diffusion coefficients impact action potential and Ca²⁺ 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 Ca²⁺ peaks are highly sensitive to 10% increase in L-type Ca²⁺ current; moderately influenced by 10% increase in Na⁺-Ca²⁺ 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 Ca²⁺ fluxes. Cell electrical activity is strongly affected by 5% shift of L-type Ca²⁺ channels and Na⁺-Ca²⁺ exchanger in between junctional and submembrane spaces while Ca²⁺-activated Cl⁻-channel redistribution has the modest effect. Small changes in submembrane and cytosolic diffusion coefficients for Ca²⁺, 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 Ca²⁺ signaling.

There is a growing body of experimental evidence suggesting that the Ca(2+) signaling in ventricular myocytes is characterized by a high gradient near the cell membrane and a more uniform Ca(2+) distribution in the cell interior [1]--[7]. An important reason for this phenomenon might be that in these cells the t-tubular system forms a network of extracellular space, extending deep into the cell interior. This allows the electrical signal, that propagates rapidly along the cell membrane, to reach the vicinity of the sarcoplasmic reticulum (SR), where intracellular Ca(2+) required for myofilament activation is stored [1], [8]--[11]. Early studies of cardiac muscle showed that the t-tubules are found at intervals of about 2 lm along the longitudinal cell axis in close proximity to the Z-disks of the sarcomeres [12]. Subsequent studies have demonstrated that the t-tubular system has also longitudinal extensions [9]--[11], [13].

A tight coupling between ionic currents, intracellular Ca2+ homeostasis, cytosolic [ADP] and deltaG of ATP hydrolysis underlies the regulation of cardiac cell function. As more experimental detail on the biochemistry and biophysics of these complex processes and their interactions accumulates, the intuitive interpretation of the new findings becomes increasingly impractical. For this reason we developed detailed biophysical model that couples Ca2+ signaling, cell electrophysiology and bioenergetics with the main interactions between phosphorylated species (ATP, ADP, AMP, PCr, Cr, P(i)) and Lewis cytosolic acids (Na+, K+, Mg2+, H+). The results indicate that the increase in free cytosolic Mg2+ (0.2-5 mM) systematically shortens the action potential duration. The analysis suggests that that under physiological conditions a pH decrease accompanied by a free Mg2+ increase tends to counteract an [ADP] increase due to PCr depletion. The model reproduces qualitatively a sequence of events that correlates well with the experimental data.