Reassessment of mechanical restitution in guinea pig cardiomyocytes through refined computational modelling

Mechanical restitution (MR) represents the time recovery of the heart muscle's ability to contract. Despite intensive research, some aspects of MR remain unclear. To describe MR in guinea pig cardiac muscle, we modified our published mathematical model of guinea pig ventricular cardiomyocyte and supplemented it with a description of cellular contraction. To achieve the best agreement between the model simulations and available experimental data, some model parameters were optimised. The model enables the simulation of the experimentally observed fast onset of recovery of action potential duration, L-type Ca²⁺ current amplitude, and isometric force. The performed simulations and analyses of model data showed that the high time constant of voltage-dependent inactivation of L-type Ca²⁺ channels used in previously published models (~ 600 ms at resting voltage) is not consistent with the initial steep rise of the MR curve in guinea pig cardiomyocytes. It also suggests that the adaptation rate of ryanodine receptors, which was set differently in the previous models, is fast (~ 100 s^- 1). Finally, analysis of the effect of a 50% reduction in membrane currents on MR revealed a marked dependence on stimulation frequency. At 1 Hz, only the reduction of I_NaCa and I_NaK significantly affected the MR course.