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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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Related in: MedlinePlus

Verification of ion conductance sensitivity predictions. Steady-state AP and Ca2+ transients (recorded 9-10 s) in each of the three non-SR compartments in response to 1 Hz stimulus. The predicted changes in APD60 and Ca2+ peaks (see Insets also) are consistent with the generated by Nimrod/E and PLS outputs with respect to 10% increases in transporters' conductance. Control conductance values (black solid line) and 10% increases in KNCX (black dashed line), PCaL (black dash-dot line), GKr (gray dash-dot line), Gto (gray solid line), KNaK(gray dotted line), and GClBk (black dotted line).
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fig3: Verification of ion conductance sensitivity predictions. Steady-state AP and Ca2+ transients (recorded 9-10 s) in each of the three non-SR compartments in response to 1 Hz stimulus. The predicted changes in APD60 and Ca2+ peaks (see Insets also) are consistent with the generated by Nimrod/E and PLS outputs with respect to 10% increases in transporters' conductance. Control conductance values (black solid line) and 10% increases in KNCX (black dashed line), PCaL (black dash-dot line), GKr (gray dash-dot line), Gto (gray solid line), KNaK(gray dotted line), and GClBk (black dotted line).

Mentions: The increase in L-type Ca2+ channel permeability (PCaL) had the most pronounced effects on APD60 and Ca2+ signals, by increasing action potential duration and enhancing maximum Ca2+ peaks. The effects of GKr, Gto, and KNCX, while less pronounced than PCaL, were still significant. Figure 2 also shows that 10% increases in GKr and Gto decreased APD60 and Ca2+ peaks while 10% increase in KNCX decreased Ca2+ peaks but increased APD60. The increase in maximal NaK pump rate (KNaK) had still detectable but minor effect, by decreasing both APD60 and Ca2+ peaks. The changes in SR parameters (Krel⁡, Kup, and Kleak) by 10% had negligible effects on APD60 and Δ[Ca]i whereas the submembrane and junctional Ca2+ peaks (e.g., Δ[Ca]SL and Δ[Ca]jct) were most affected. Figure 2 shows that 10% increases in Krel⁡ and Kup increased Δ[Ca]SL and Δ[Ca]jct while Kleak had the opposite effect. Interestingly, 10% increase in background Cl− conductance (GClBk) showed similar magnitude as GKr and Gto and demonstrated the same effects in decreasing APD60 and Ca2+ peaks. Furthermore, Nimrod/E had the advantage in predicting how 10% increases in two-parameter group can affect the model outputs. Nimrod/E predicts here that PCaL and KNCX combined, as well all other two-parameter group combinations (not shown in Figure 2), had slight or no effect on the selected cellular biomarkers (APD60, Δ[Ca]i, Δ[Ca]SL, and Δ[Ca]jct). The plots in Figure 3 confirm further the specific, quantitative predictions made by PLS and Nimrod/E for the effects of 10% increases in PCaL, KNCX, GKr, Gto, KNaK, and GClBk 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 ion conductance sensitivity predictions. Steady-state AP and Ca2+ transients (recorded 9-10 s) in each of the three non-SR compartments in response to 1 Hz stimulus. The predicted changes in APD60 and Ca2+ peaks (see Insets also) are consistent with the generated by Nimrod/E and PLS outputs with respect to 10% increases in transporters' conductance. Control conductance values (black solid line) and 10% increases in KNCX (black dashed line), PCaL (black dash-dot line), GKr (gray dash-dot line), Gto (gray solid line), KNaK(gray dotted line), and GClBk (black dotted line).
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Verification of ion conductance sensitivity predictions. Steady-state AP and Ca2+ transients (recorded 9-10 s) in each of the three non-SR compartments in response to 1 Hz stimulus. The predicted changes in APD60 and Ca2+ peaks (see Insets also) are consistent with the generated by Nimrod/E and PLS outputs with respect to 10% increases in transporters' conductance. Control conductance values (black solid line) and 10% increases in KNCX (black dashed line), PCaL (black dash-dot line), GKr (gray dash-dot line), Gto (gray solid line), KNaK(gray dotted line), and GClBk (black dotted line).
Mentions: The increase in L-type Ca2+ channel permeability (PCaL) had the most pronounced effects on APD60 and Ca2+ signals, by increasing action potential duration and enhancing maximum Ca2+ peaks. The effects of GKr, Gto, and KNCX, while less pronounced than PCaL, were still significant. Figure 2 also shows that 10% increases in GKr and Gto decreased APD60 and Ca2+ peaks while 10% increase in KNCX decreased Ca2+ peaks but increased APD60. The increase in maximal NaK pump rate (KNaK) had still detectable but minor effect, by decreasing both APD60 and Ca2+ peaks. The changes in SR parameters (Krel⁡, Kup, and Kleak) by 10% had negligible effects on APD60 and Δ[Ca]i whereas the submembrane and junctional Ca2+ peaks (e.g., Δ[Ca]SL and Δ[Ca]jct) were most affected. Figure 2 shows that 10% increases in Krel⁡ and Kup increased Δ[Ca]SL and Δ[Ca]jct while Kleak had the opposite effect. Interestingly, 10% increase in background Cl− conductance (GClBk) showed similar magnitude as GKr and Gto and demonstrated the same effects in decreasing APD60 and Ca2+ peaks. Furthermore, Nimrod/E had the advantage in predicting how 10% increases in two-parameter group can affect the model outputs. Nimrod/E predicts here that PCaL and KNCX combined, as well all other two-parameter group combinations (not shown in Figure 2), had slight or no effect on the selected cellular biomarkers (APD60, Δ[Ca]i, Δ[Ca]SL, and Δ[Ca]jct). The plots in Figure 3 confirm further the specific, quantitative predictions made by PLS and Nimrod/E for the effects of 10% increases in PCaL, KNCX, GKr, Gto, KNaK, and GClBk 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