Quantitative analysis of cardiac cell volume regulation by experiments and simulation

Abstract

In general, animal cells tend to swell if Na/K pump is blocked. However, the volume of guinea-pig ventricular myocytes remained almost constant during 3 hours under 40 μM ouabain. The Na/K pump block simulation using the Kyoto model showed that the cell swelling is retarded in parallel to a decrease in the background membrane conductances for Cl⁻ and Na⁺, suggesting very low conductances for these ions in actual ventricular cells. In addition, it is suggested by the simulation that the active Ca²⁺ extrusion by sarcomlemmal Ca²⁺ pump (PMCA) has an important role in the delayed cell swelling. The transmembrane [Ca²⁺] gradient is partially maintained by PMCA, and this makes the Na/Ca exchanger extrudes Na⁺ in reverse mode, compensating for Na/K pump. In the experiment where the Cl⁻ leak was increased beyond these compensatory mechanisms by applying 5 μM isopreterenol, cell swelling could be induced, but only after a delay of about 55 min after ouabain application. The simulation revealed a gradual membrane depolarization during the delay, and finally it reached a voltage range of continuous opening of a significant fraction of L-type Ca²⁺ channels (window current). A rapid accumulation of Ca²⁺ subsequently activates Ca²⁺-dependent Na⁺ conductance, which finally initiates the rapid cell swelling. [J Physiol Sci. 2006;56 Suppl:S128]