Mathematical modeling of the effect of the sarcoplasmic reticulum calcium pump function on load dependent myocardial...

Earlier, we developed a mathematical model of myocardial contraction-relaxation cycle regulation. A great number of mechanical experiments was simulated in the model, the phenomenon of load dependent relaxation (LDR) included. In the present work we used the same model to analyze experimental data revealing that high temperature leads to reduction of LDR. We simulated three main factors arising due to high temperature, which a priori may cause LDR reduction: increasing the cross-bridges cycling rate, decreasing the duration of the Ca transient ascending limb, and increasing Ca pumping rate. Indeed, these factors together result in LDR reduction; i.e., the model correctly simulates the effect of high temperature on LDR in general. At the same time, the sensitivity of LDR to the third factor is much higher than to the first and the second ones; i.e., increasing the rate of Ca pumping is sufficient to induce the observed effect in the framework of the model. This seems to contrast with the result of our previous study dealing with the simulation of LDR disappearance due to increasing Ca pumping rate as it happens during relatively severe cardiac hypertrophy. However, the model analysis shows that the specific mechanism underlying the change in Ca pumping rate in either case is extremely important for the effect on LDR. Particularly, the model predicts that LDR will reduce if this rate increases due to enhanced ATP hydrolysis rate by the Ca pump; and vice versa, if this rate increases due to decreasing retroinhibition of the pump ATPase, it may result in LDR increase. Probably, but the first mechanism is operational due to high temperature and makes LDR to reduce, whereas slowing down Ca pumping due to increasing retroinhibition results in LDR disappearance during severe cardiac hypertrophy.