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The balance between inactivation and activation of the Na⁺-K⁺ pump underlies the triphasic accumulation of extracellular K⁺ during myocardial ischemia

¹Auckland Bioengineering Institute and ²Department of Engineering Science, University of Auckland, Auckland, New Zealand; and ³Computing Laboratory, University of Oxford, Oxford, United Kingdom

Submitted 4 July 2007 ; accepted in final form 11 September 2007

Ischemia-induced hyperkalemia (accumulation of extracellular K⁺) predisposes the heart to the development of lethal reentrant ventricular arrhythmias. This phenomenon exhibits a triphasic time course and is thought to be mediated by a combination of three mechanisms: 1) increased cellular K⁺ efflux, 2) decreased cellular K⁺ influx, and 3) shrinkage of the extracellular space. These ischemia-induced electrophysiological changes are driven by an impaired cellular metabolism. However, the relative contributions of these mechanisms, as well as the origin of the triphasic profile, have proven to be difficult to determine experimentally. In this study, the changes in metabolite concentrations that arise during 15 min of zero-flow global ischemia were incorporated into a dynamic model of cellular electrophysiology, which was extended to include a metabolically sensitive description of the Na⁺-K⁺ pump and ATP-sensitive K⁺ channel, in addition to cell volume regulation. The coupling of altered K⁺ fluxes and cell volume regulation enables an integrative simulation of ischemic hyperkalemia. These simulations were able to quantitatively reproduce experimental measurements of the accumulation of extracellular K⁺ during 15 min of simulated ischemia, both with respect to the degree of K⁺ loss as well as the triphasic time course. Analysis of the model indicates that the inhibition of the Na⁺-K⁺ pump is the dominant factor underlying this hyperkalemic behavior, accounting for 85% of the observed extracellular K⁺ accumulation. It was found that the balance between activation and inhibition of the Na⁺-K⁺ pump, affected by the changing metabolite and ion concentrations (in particular, [ADP]), give rise to the triphasic profile associated with ischemic hyperkalemia.

heart; mathematical model; extracellular potassium accumulation

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