Session P35.1

Sodium Ion Diffusion Dependent Calcium Ion Handling in Rabbit Ventricular Myocytes

E Grandi*, F Wang, DM Bers

University of California
Davis, CA, USA

Intracellular Na+ concentration ([Na+] i) plays a pivotal role in modulating the electrical and contractile activity of the heart via Na+/Ca2+ (NCX) and Na+/H+ exchange mechanisms. Several studies showed that the general assumption that Na+ diffuses freely over the cytoplasm may not be correct, and that important [Na+] gradients exist close to the cell membrane. Thus, [Na+] sensed by the membrane transporters might be different from the bulk [Na+]i. For such gradients to exist, intracellular Na+ diffusion has to be slow with respect to the rates of Na+ transport across the sarcolemma. Here we extended our rabbit ventricular action potential and Ca2+ transient (CaT) model (Shannon-Bers) to establish intracellular [Na+] gradients directly inferred from experimental data. We tuned the Na+ diffusion coefficient between different compartments (e.g. junctional cleft to subsarcolemmal to cytosol). However, this change was not sufficient to account for the Na+/K+ pump (NKA) current sag: an initial rapid phase of current decline with minimal changes in [Na+]i after a period of pump blockade. We suggest that this may be due to local depletion of Na+ near NKA protein, i.e., NKA could sense a very local [Na+], and modified the formulation of NKA current accordingly. We also theoretically investigated certain indirect effects of altered local [Na+] on Ca2+ handling. We found that i) Na+ influx through the fast Na+ current can alter subsarcolemmal [Na+] and consequently alter NCX. ii) Abrupt inhibition of NKA decelerated caffeine-induced CaT and NCX current decline, suggesting that NKA influences NCX function in the absence of changes in total sarcoplasmic reticulum [Ca2+]. iii) Abrupt inhibition of NKA increased CaT peak and decreased CaT decline during depolarizing voltage pulses. The increased CaT peak was due to decreased NCX current without changing total sarcoplasmic reticulum [Ca2+]. We conclude that by slowing Na+ diffusion [Na+] gradient can significantly modulate Ca2+ handling through NCX.

(Abstract Control Number: 115)