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Sensitivity of rabbit ventricular action potential and Ca²⁺ dynamics to small variations in membrane currents and ion diffusion coefficients.

Lo YH, Peachey T, Abramson D, McCulloch A, Michailova A - Biomed Res Int (2013)

Bottom Line: We applied sensitivity analysis to quantify the sensitivity of Shannon et al. model (Biophys.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, PFBH 241, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA.

ABSTRACT
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.

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Verification of Ca2+ and Na+ diffusion sensitivity predictions. Steady-state AP and Ca2+ transients (recorded 9-10 s) in three non-SR compartments in response to 1 Hz stimulus. The relative changes in APD60 and Ca2+ peaks (see Insets also) are consistent with predictions generated by Nimrod/E and PLS with respect to 10% increases in Ca2+ and Na+ diffusion constants. Control diffusion coefficients (black solid line) and 10% increases in DCa(jct-SL) (black dashed line), DCa(SL-i) (black dash-dot line), DNa(jct-SL) (gray dotted lines), DNa(SL-i) (light gray dotted lines).
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fig7: Verification of Ca2+ and Na+ diffusion sensitivity predictions. Steady-state AP and Ca2+ transients (recorded 9-10 s) in three non-SR compartments in response to 1 Hz stimulus. The relative changes in APD60 and Ca2+ peaks (see Insets also) are consistent with predictions generated by Nimrod/E and PLS with respect to 10% increases in Ca2+ and Na+ diffusion constants. Control diffusion coefficients (black solid line) and 10% increases in DCa(jct-SL) (black dashed line), DCa(SL-i) (black dash-dot line), DNa(jct-SL) (gray dotted lines), DNa(SL-i) (light gray dotted lines).

Mentions: The effects of changes in default parameters describing Ca2+ and Na+ diffusion between junctional and subsarcolemmal compartments and between subsarcolemmal and bulk compartments were also analyzed in this study (the appendix, Table 3). Figure 6 shows that 10% increases in basal DCa(jct-SL) altered all model outputs, prolonging APD60 and increasing Δ[Ca]i and Δ[Ca]SL but decreasing Δ[Ca]jct. Moreover 10% increases in basal DCa(SL-i) value shortened APD60 and increased Δ[Ca]i, Δ[Ca]jct, and Δ[Ca]SL. Interestingly, 10% increases in basal DNa(jct-SL) and DNa(SL-i) values in all three compartments had no effect on APD60 and Ca2+ peaks. Nimrod/E analysis also suggests that two-level interaction between DCa(jct-SL) and DCa(SL-i) had a minor effect on increasing Δ[Ca]i while APD60, Δ[Ca]SL, and Δ[Ca]jct were unaffected. Figure 7 additionally confirms the PLS and Nimrod/E predictions for the effects of 10% increases in DCa(jct-SL) and DCa(SL-i) on AP morphology and Ca2+ transients.


Sensitivity of rabbit ventricular action potential and Ca²⁺ dynamics to small variations in membrane currents and ion diffusion coefficients.

Lo YH, Peachey T, Abramson D, McCulloch A, Michailova A - Biomed Res Int (2013)

Verification of Ca2+ and Na+ diffusion sensitivity predictions. Steady-state AP and Ca2+ transients (recorded 9-10 s) in three non-SR compartments in response to 1 Hz stimulus. The relative changes in APD60 and Ca2+ peaks (see Insets also) are consistent with predictions generated by Nimrod/E and PLS with respect to 10% increases in Ca2+ and Na+ diffusion constants. Control diffusion coefficients (black solid line) and 10% increases in DCa(jct-SL) (black dashed line), DCa(SL-i) (black dash-dot line), DNa(jct-SL) (gray dotted lines), DNa(SL-i) (light gray dotted lines).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814049&req=5

fig7: Verification of Ca2+ and Na+ diffusion sensitivity predictions. Steady-state AP and Ca2+ transients (recorded 9-10 s) in three non-SR compartments in response to 1 Hz stimulus. The relative changes in APD60 and Ca2+ peaks (see Insets also) are consistent with predictions generated by Nimrod/E and PLS with respect to 10% increases in Ca2+ and Na+ diffusion constants. Control diffusion coefficients (black solid line) and 10% increases in DCa(jct-SL) (black dashed line), DCa(SL-i) (black dash-dot line), DNa(jct-SL) (gray dotted lines), DNa(SL-i) (light gray dotted lines).
Mentions: The effects of changes in default parameters describing Ca2+ and Na+ diffusion between junctional and subsarcolemmal compartments and between subsarcolemmal and bulk compartments were also analyzed in this study (the appendix, Table 3). Figure 6 shows that 10% increases in basal DCa(jct-SL) altered all model outputs, prolonging APD60 and increasing Δ[Ca]i and Δ[Ca]SL but decreasing Δ[Ca]jct. Moreover 10% increases in basal DCa(SL-i) value shortened APD60 and increased Δ[Ca]i, Δ[Ca]jct, and Δ[Ca]SL. Interestingly, 10% increases in basal DNa(jct-SL) and DNa(SL-i) values in all three compartments had no effect on APD60 and Ca2+ peaks. Nimrod/E analysis also suggests that two-level interaction between DCa(jct-SL) and DCa(SL-i) had a minor effect on increasing Δ[Ca]i while APD60, Δ[Ca]SL, and Δ[Ca]jct were unaffected. Figure 7 additionally confirms the PLS and Nimrod/E predictions for the effects of 10% increases in DCa(jct-SL) and DCa(SL-i) on AP morphology and Ca2+ transients.

Bottom Line: We applied sensitivity analysis to quantify the sensitivity of Shannon et al. model (Biophys.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, PFBH 241, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus