Functionally Isolated Sarcoplasmic Reticulum in Cardiomyocytes: Experimental and Mathematical Models

The interaction among the various Ca²⁺ transporters complicates the assessment of isolated systems in an intact cell. This article proposes the functionally isolated SR model (FISRM), a hybrid (experimental and mathematical) approach to study Ca²⁺ cycling between the cytosol and the sarcoplasmic reticulum (SR), the main source of Ca²⁺ for contraction in mammalian cardiomyocytes. In FISRM, the main transmembrane Ca²⁺ transport pathways are eliminated by using a Na⁺, Ca²⁺-free extracellular medium, and SR Ca²⁺ release is elicited by a train of brief caffeine pulses. Two compounds that exert opposite effects on the SR Ca²⁺ uptake were characterized by this approach in isolated rat ventricular cardiomyocytes. The experimental FISRM was simulated with a simple mathematical model of Ca²⁺ fluxes across the SR membrane, based on a previous model adapted to the present conditions. To a fair extent, the theoretical model could reproduce the experimental results, and confirm the main assumption of the experimental model: that the only relevant Ca²⁺ fluxes occur across the SR membrane. Thus, the FISRM seems to be a valuable framework to investigate the SR Ca²⁺ transport in intact cardiomyocytes under physiological and pathophysiological conditions, and to test therapeutic approaches targeting SR proteins.