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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 transporter distribution sensitivity predictions. Steady-state model outputs (recorded 9-10 s) in response to 1 Hz periodic pulse. The predicted alterations in APD60 and Ca2+ peaks (see Insets also) are consistent with the generated by Nimrod/E and PLS results with respect to 5% increases in transporters' fraction in the junctional cleft. Default j-currents' fractions in junctional cleft (black solid line) and 5% increases in FxCaL(jct) (black dashed line), FxCl(Ca)(jct) (grey dotted line), FxNCX(jct) (black dash-dot line).
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fig5: Verification of transporter distribution sensitivity predictions. Steady-state model outputs (recorded 9-10 s) in response to 1 Hz periodic pulse. The predicted alterations in APD60 and Ca2+ peaks (see Insets also) are consistent with the generated by Nimrod/E and PLS results with respect to 5% increases in transporters' fraction in the junctional cleft. Default j-currents' fractions in junctional cleft (black solid line) and 5% increases in FxCaL(jct) (black dashed line), FxCl(Ca)(jct) (grey dotted line), FxNCX(jct) (black dash-dot line).

Mentions: To examine how the changes in ion transporter distributions affect the selected cellular biomarkers (APD60, Δ[Ca]i, Δ[Ca]SL, and Δ[Ca]jct), we performed systematic analysis, increasing by 5% the basic Fxj(jct) while decreasing Fxj(SL) to keep total number of transporter protein complexes within the sarcolemma unchanged; that is, Fxj(jct) + Fxj(SL) = 1 (the appendix, Table 2). Figure 4 shows that PLS and Nimrod/E analysis again showed consistent results. The 5% increase in L-type Ca2+ channels fraction in the junctional cleft (FxCaL(jct) = 0.945) had the most pronounced effect on the model outputs, decreasing APD60 and Ca2+ peaks. The results also suggest that 5% increase in the junctional Na+-Ca2+ current (FxNCX(jct) = 0.1155) prolonged APD60 while slightly affected Ca2+ peaks in the junctional cleft and subsarcolemmal and bulk cytosol compartments. The 5% increase in the junctional ICl(Ca) (FxCl(Ca)(jct) = 0.1155) had similar effect on all model outputs as the increase in FxCaL(jct) but with much smaller magnitude. Results in Lenth plot (Figure 4) for the four model outputs reveal that “FxNCX(jct)FxCaL(jct) combination” as well all other two-parameter combinations had insignificant impact (not shown in Figure 4). Additional analysis of the data has been done by increasing each Fxj(jct) by 5% and decreasing Fxj(SL) (j = CaL, NCX, Cl(Ca)) while keeping all other model parameters constant. The results in Figure 5 confirm the predictions made by both PLS and Nimrod/E methods.


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 transporter distribution sensitivity predictions. Steady-state model outputs (recorded 9-10 s) in response to 1 Hz periodic pulse. The predicted alterations in APD60 and Ca2+ peaks (see Insets also) are consistent with the generated by Nimrod/E and PLS results with respect to 5% increases in transporters' fraction in the junctional cleft. Default j-currents' fractions in junctional cleft (black solid line) and 5% increases in FxCaL(jct) (black dashed line), FxCl(Ca)(jct) (grey dotted line), FxNCX(jct) (black dash-dot line).
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Verification of transporter distribution sensitivity predictions. Steady-state model outputs (recorded 9-10 s) in response to 1 Hz periodic pulse. The predicted alterations in APD60 and Ca2+ peaks (see Insets also) are consistent with the generated by Nimrod/E and PLS results with respect to 5% increases in transporters' fraction in the junctional cleft. Default j-currents' fractions in junctional cleft (black solid line) and 5% increases in FxCaL(jct) (black dashed line), FxCl(Ca)(jct) (grey dotted line), FxNCX(jct) (black dash-dot line).
Mentions: To examine how the changes in ion transporter distributions affect the selected cellular biomarkers (APD60, Δ[Ca]i, Δ[Ca]SL, and Δ[Ca]jct), we performed systematic analysis, increasing by 5% the basic Fxj(jct) while decreasing Fxj(SL) to keep total number of transporter protein complexes within the sarcolemma unchanged; that is, Fxj(jct) + Fxj(SL) = 1 (the appendix, Table 2). Figure 4 shows that PLS and Nimrod/E analysis again showed consistent results. The 5% increase in L-type Ca2+ channels fraction in the junctional cleft (FxCaL(jct) = 0.945) had the most pronounced effect on the model outputs, decreasing APD60 and Ca2+ peaks. The results also suggest that 5% increase in the junctional Na+-Ca2+ current (FxNCX(jct) = 0.1155) prolonged APD60 while slightly affected Ca2+ peaks in the junctional cleft and subsarcolemmal and bulk cytosol compartments. The 5% increase in the junctional ICl(Ca) (FxCl(Ca)(jct) = 0.1155) had similar effect on all model outputs as the increase in FxCaL(jct) but with much smaller magnitude. Results in Lenth plot (Figure 4) for the four model outputs reveal that “FxNCX(jct)FxCaL(jct) combination” as well all other two-parameter combinations had insignificant impact (not shown in Figure 4). Additional analysis of the data has been done by increasing each Fxj(jct) by 5% and decreasing Fxj(SL) (j = CaL, NCX, Cl(Ca)) while keeping all other model parameters constant. The results in Figure 5 confirm the predictions made by both PLS and Nimrod/E methods.

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