Functionally Isolated Sarcoplasmic Reticulum in Cardiomyocytes: Experimental and Mathematical Models.

The interaction among the various Ca 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 Ca cycling between the cytosol and the sarcoplasmic reticulum (SR), the main source of Ca for contraction in mammalian cardiomyocytes. In FISRM, the main transmembrane Ca transport pathways are eliminated by using a Na, Ca-free extracellular medium, and SR Ca release is elicited by a train of brief caffeine pulses. Two compounds that exert opposite effects on the SR Ca uptake were characterized by this approach in isolated rat ventricular cardiomyocytes. The experimental FISRM was simulated with a simple mathematical model of Ca 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 Ca fluxes occur across the SR membrane. Thus, the FISRM seems to be a valuable framework to investigate the SR Ca transport in intact cardiomyocytes under physiological and pathophysiological conditions, and to test therapeutic approaches targeting SR proteins.