Modeling acidosis on Ca²⁺ signaling and the AP (rabbit ventricular myocyte). All simulations were performed using the computational model of Shannon et al. (2004) for Ca²⁺ handling and ionic currents in the rabbit ventricular myocyte. The control parameters and code for the model were obtained from version 1.6.91 on the JSim website, developed as part of the Physiome Project. The model was paced at 0.5 Hz for 2 min for both simulations. (A; a) The simulations include the separate actions of H⁺_o and H⁺_i to modulate charge screening/binding of surface charge and P_Ca as described in Fig. 10 (A and B). Not depicted in the cartoon, but included in the simulations (C), is the action of intracellular acidosis to slow I_Ca,L inactivation. (b) The simulations also included additional inhibitory effects of H⁺ on NCX, SR Ca²⁺ release channels (RyR), SERCA, and transient outward current (I_to). (B) The simulated effects of extracellular acidosis on APD, I_Ca,L, CaT, SR Ca²⁺, and I_NCX were achieved by a 17% reduction in P_Ca (Fig. 10 A) and included the measured changes in V_1/2 and k for d_∞ and f_∞ (Tables S1 and S2; no BAPTA). In addition, I_NCX was reduced by 15% to simulate the actions of external protons on NaCa exchange (Egger and Niggli, 2000). All other parameters were set to default values. (C) The simulated effects of intracellular acidosis on APD, I_Ca,L, CaT, SR Ca²⁺, and I_NCX were achieved by a 24% reduction in P_Ca (Fig. 10 B) and applying the measured changes in V_1/2 and k for d_∞ and f_∞ (Tables S1 and S2; no BAPTA). Additional changes included: (a) 1.2-fold increase in the time constant of I_Ca,L inactivation (τ_f) to simulate slowing of inactivation (Fig. 7); (b) 40% reduction in SERCA pump rate (Kentish and Xiang, 1997); (c) a 40% reduction in SR calcium release flux (RyR activity) (Xu et al., 1996); and (d) a 20% reduction in I_NCX (Doering et al., 1996). In addition, both the slow and fast components of transient outward current were reduced by 50% in accord with our experimental findings in rabbit ventricular myocytes (Saegusa, N., V. Garg, and K.W. Spitzer. 2011. Transient outward current responds differently to external and internal protons in ventricular myocytes. Heart Rhythm Society Meeting. Abstr. S252). All other parameters were set to default values.