Integrative models of pH regulation and intracellular Ca2+ handling during cardiac acidosis

The effects of acidosis on cardiac electrophysiology, intracellular Ca2+ (Cai) and contraction have been studied extensively. However, significant uncertainty remains about the key mediators of the effects of acidosis on cardiac function. Acidosis decreases the strength of cardiac contraction; this is the net result of complex interactions between protons and a variety of intracellular processes, which cause an increase in diastolic Cai and the amplitude of the systolic Cai transient, and slow the decline of the transient. These effects have been attributed to an inhibitory effect of protons on Ca2+ uptake and release by the sarcoplasmic reticulum, to a rise of intracellular Na+ caused by activation of Na+/H+ exchange, and to decreased Ca2+ affinity of the low‐affinity Ca2+ binding sites on Troponin‐C. The relative contribution of each of these components is, however, difficult to establish experimentally. In this study these interactions are incorporated into a dynamical model of pH regulation and excitation‐contraction coupling at both the cellular and tissue level to provide a computationally integrative model of cardiac acidosis. This model reproduces experimental data on acid loading experiments and predicts the time course of changes of key ionic species during acidosis in the beating heart and the inhibitory effect of acidosis on contraction.