Ischemia alters sensitivity of action potential to the sodium-potassium pump

Ischemia increases extracellular concentration of potassium, [K⁺]_o, reduces the cytosolic ATP concentrations, and reduces cytosolic pH. The sodium-potassium pump, I_NaK, is an ATPase that maintains the ionic gradients across the cell membrane required to drive the action potential (AP) and depends on these parameters. The suitability of biophysically detailed mathematical models to study pathophysiological conditions is in their capability to produce physiological responses to parameter alterations. This study evaluated the sensitivity of I_NaK parameters and of [K⁺]_o to AP in a human ventricle cell model using forward sensitivity analysis. The derivative based forward sensitivity of the O´Hara et af. model AP to [K⁺]_o, ATP, and pH was estimated using diference quotient algorithms. The FSA was verified by computing I_NaK-concentration curves for each of the three parameters. AP alterations under small and large alterations of the parameters were also computed. The model´s AP has sensitivity to the ischemic parameters in agreement with experimental data. The sensitivity of the AP to pH, however, was found to be small. This could be improved by further developing the I_NaK formulation. FSA is a straightforward method serving as a first port of call to evaluate model suitability.