Simulation of Action Potentials From Metabolically Impaired Cardiac Myocytes

Abstract

The role of the ATP-sensitive K+ current (IK-ATP) and its contribution to electrophysiological changes that occur during metabolic impairment in cardiac ventricular myocytes is still being discussed. The aim of this work was to quantitatively study this issue by using computer modeling. A model of IK-ATP is formulated and incorporated into the Luo-Rudy ionic model of the ventricular action potential. Action potentials under different degrees of activation of IK-ATP are simulated. Our results show that in normal ionic concentrations, only approximately 0.6% of the KATP channels, when open, should account for a 50% reduction in action potential duration. However, increased levels of intracellular Mg2+ counteract this shortening. Under conditions of high [K+]0, such as those found in early ischemia, the activation of only approximately 0.4% of the KATP channels could account for a 50% reduction in action potential duration. Thus, our results suggest that opening of IK-ATP channels should play a significant role in action potential shortening during hypoxic/ischemic episodes, with the fraction of open channels involved being very low ( < 1%). However, the results of the model suggest that activation of IK-ATP alone does not quantitatively account for the observed K+ efflux in metabolically impaired cardiac myocytes. Mechanisms other than KATP channel activation should be responsible for a significant part of the K+ efflux measured in hypoxic/ischemic situations.

Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II

“…We previously demonstrated that a higher density of surface sarcolemmal K ATP channels results in a more rapid adjustment of ventricular action potential duration and thus higher fidelity matching of energy consumption to available metabolic resources under a sudden increase in cardiac workload or under metabolic insult (24,25). However, during persistent, intense cardiac performance and augmented energy consumption, a high surface density of K ATP channels could be a liability for the cell as the continued recruitment of K ATP channel current could render the membrane less excitable (1,5,6,57). A reduction in the overall surface abundance of K ATP channels through endocytosis promoted by CaMKII activation would effectively reduce the gain in the energetic feedback circuit, thereby supporting enhanced myocardial performance, whereas the rapid restoration of K ATP channel surface density when CaMKII activation is abated would permit the cell to "reset" to its base-line level of action potential responsiveness.…”

Vulnerability to reentry during the acute phase of myocardial ischemia: a simulation study

“…In this paper, we present a theoretical study of the mechanisms of figure-of-eight reentry during the acute phase of regional myocardial ischemia, focusing on the influence of the degree of hypoxia (and, therefore, the degree of activation of the ATP -sensitive K + current, I K(ATP) [9,10]), acidosis and hyperkalemia on the vulnerability to reentry. Mathematical models were used to simulate electrical activity of a virtual tissue which imitated the conditions of regional acute ischemia.…”

The effects of ischemia on the ectopic activity induced by EADs computer simulation

“…I K(ATP) currents, as formulated by Ferrero et al, was included in the basic LuoRudy model in order to simulate Hypoxia in the BZ and CZ [7]. The final model represents the basic features of AP and the electrical currents through the sarcolemma with a great degree of electrophysiological detail.…”