INTRODUCTION. Hyperkalemia (the increase of extracellular potassium concentration, [K+]o) is known to be one of the components of acute myocardial ischemia that most favours re-entrant arrhythmias. However, its causes are not completely understood. Indeed, the relative contributions of the different ion channels and pumps are not established. The aim of this work is to use computer simulations to throw some light on the mechanisms that cause hyperkalemia at the cellular level.
METHODS. The O’Hara-Rudy model of the ventricular action potential was used to quantify the contributions of different ionic mechanisms to hyperkalemia. The model was modified to include the IK(ATP) current, the effects of intracellular ATP and ADP on ionic pumps, the effects of pH, and to allow dynamic computing of [K+]o. A simulated isolated cell was paced for 10 minutes in control conditions, followed by 15 minutes of progressive ischemia.
RESULTS. [K+]o begins to rise immediately after the onset of simulated ischemia from its normoxic value of 5.4mmol/L and reaches 11.2mmol/L after 8 minutes, after which it plateaus. This result nicely agrees with experimental observations. During the first 8 minutes, net potassium efflux increases to 0.055 mmol/(g.min), due to a net increase in potassium efflux through IK(ATP) (0.083) and IK1 (0.038), a net decrease in IKr (0.041), IKs (0.015) and Ito (0.008) and a decreased influx through INaK (0.013). However, [K+]o only reaches a value of 7.6 mmol/L if the changes in INaK are knocked-down. The plateau in [K+]o occurs when the action potential (AP) begins to alternate (with AP durations alternating between 155 and 101 ms) and is mediated by IK(ATP).
CONCLUSIONS. Hyperkalemia is mainly caused by an increased potassium efflux through IK(ATP) and IK1. The reduced influx through the sodium-potassium pump is quantitively lower. Action potential alternans may be the cause of the hyperkalemic plateau.