Page 9 - CBAC Newsletter 2013

While the molecular composition of K is critical to its physiology, just as relevant is the potentially heterogeneous
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response of the myocardium to K activation. Therefore, we decided to test the response to an injected, simulated
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K current in myocytes isolated from atria and ventricle via dynamic clamp. The pattern that emerged from these ex-
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periments was preferential shortening in cells with longer APDs. This finding was consistent with previous work showing
greater rate adaptation in M-cells as well as with the concept of the “repolarization reserve”, which states that cells
with reduced repolarizing currents will show greater prolongation when the remaining currents are blocked (Roden and
Abraham 2011). Two phases of K activation can now be defined - the first that preferentially affects cells with longer
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APDs such as M-cells and the second phase that can lead to early termination of APs in cells carrying large I currents.
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Simulating K ATP

Once the molecular composition, heterogeneous expression and functional consequences of K activation have been
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identified, a quantitative integrative model of its physiology is tenable. Our first step was to test whether an existing,
modern model of the canine ventricular myocyte (HRd2010) (Decker and Rudy 2010) could account for its behavior.
Qualitatively, the results matched experiment with greater shortening observed for cells with longer APD and less
shortening observed at faster cycle lengths. However, 5x more injected current was required to see equivalent short-
ening, which implies that the ability of the model to sustain its plateau may be overly robust and should be noted when
ionic perturbations are being simulated. Notably, the more recent O’Hara - Rudy (ORd) model of the human ventricular
myocyte was shown to accurately simulate reduction in repolarizing currents, and is therefore more likely to accurately
simulate this type of experiment (O’Hara, Virag et al. 2011).

In cardiac myocytes, K is typically assumed to be inactive unless the acute consequences of ischemia are being
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simulated. In contrast, K in healthy pancreatic beta cells is regularly activated when blood glucose drops, preventing
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bursting and insulin release. Simulation results from beta cells can provide vital experience regarding the path forward
in cardiac myocytes. The dependence of bursting on K has been modeled. However, until recently, models of beta
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cell excitability lacked dynamic simulation of intracellular ion concentration, long a feature of second generation cardi-
ac models. In 2011, Cha et al. introduced a second generation beta cell model that also has the ability to accurately
simulate the glucose-dependence of bursting (Cha, Nakamura et al. 2011).

In the past decade, transgenic mouse models have provided quantitative experimental data that also shows a
dependence of bursting on K expression. In the extreme case of K ATP conductance being abolished, beta cells are
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constitutively active, bursting even at very low glucose concentrations. The beta cell model of Cha et al. provides a
means to simulate these results in silico. However, our initial attempts to reproduce K dependence of bursting with
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the published Cha et al. model were unsuccessful. Examination of experimental data on which the model was based,
led us to conclude that other nucleotide-sensitive components such as the Na -K pump and the L-type Ca channel
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were overly responsive to intracellular ATP concentration. Adjusting parameters in the formulation of these model com-
ponents to better match experimentally measured ATP sensitivity resulted in reasonably accurate reproduction of K
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dependence of bursting (Silva and Nichols 2013).
Accurate reproduction of the K dependence of bursting in beta cells required careful quantitation. In cardiac myo-
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cytes, a similar effort will be required to accurately simulate K consequences on cellular electrophysiology. To date,
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computational models simulating metabolic interaction with the AP have been primarily focused on the consequenc-
es of increased K conductance. Experience with beta cell modeling has proven that a careful accounting of ATP
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interaction with other major components such as the L-type Ca channel and the Na -K pump is also warranted.
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