Figure 5.

Close Na⁺, K⁺-ATPase (NKA)-Na⁺-Ca²⁺ exchanger (NCX) crosstalk drives the biphasic Ca²⁺ transient response to hypokalemia. A mathematical model of the rat ventricular cardiomyocyte was employed to investigate the contribution of various ion channels and transporters to changes in cellular [Na⁺], SR Ca²⁺ content, and Ca²⁺ transients. A, With baseline model settings (blue lines), reducing [K⁺]_o from 5.0 to 2.7 mmol/L triggered a modest accumulation of intracellular [Na⁺], and a biphasic response of SR Ca²⁺ content and Ca²⁺ transients which occurred over a markedly longer time course than that observed experimentally. To simulate greater crosstalk between NCX and NKA, the fraction of NCX operating in reverse mode (NCX_rev) was increased in a step-wise manner, which produced an augmented and accelerated biphasic response (see also enlargement of the first 1000 s in [B], presented normalized to [K⁺]_o=5.0). Removing the NCX_rev contribution prevented any secondary rise in Ca²⁺ transients, in resemblance to experiments in untubulated cells. C, Sensitivity analyses were performed to examine the effects of modulating individual ion fluxes±5%. Reducing t-tubule-associated fluxes such as I_Na (g_Na) or the number of L-type-RyR units (LCC-RYR) did not inhibit the biphasic response, while changing NCX and NKA fluxes had proportionally opposite effects. D, In addition to augmenting the biphasic response to hypokalemia, increasing NCX_rev slowed Ca²⁺ transient decay at steady state.