To explore the physiological consequences of ion concentration changes in the transverse-axial tubular system (TATS) of rat and guinea-pig cardiac ventricular myocytes we have developed mathematical models of their electrical activity that include a quantitative description of the TATS (e.g. Pásek et al., 2003). The geometrical characteristics of the TATS, and the characteristics of ion transporters and their distribution between the surface and tubular membranes, were modelled using available experimental data from each species. In both models, transient depletion of tubular Ca²⁺ occurred during each action potential and decreased intracellular Ca²⁺ load and consequently systolic Ca²⁺ transient amplitude. However, the magnitude of this effect and its frequency dependence was different in the two species. In the rat model, the maximal depletion of tubular Ca²⁺ during a single period, at a stimulation rate of 1 Hz, was 7 %. With increasing stimulation frequency, tubular Ca²⁺ depletion increased, reaching 13.1 % at 5 Hz. This depletion induced a cumulative beat-to-beat decrease in SR Ca²⁺ content that resulted in ~3 % decrease of steady-state Ca²⁺ transient amplitude at 1 Hz and ~20 % decrease at 5 Hz. In the guinea pig model, the maximal depletion of tubular Ca²⁺ was 13.8 % at 1 Hz, which decreased with stimulation frequency, to 6.5 % at 5 Hz. The reduction of Ca²⁺ transient amplitude was lower than in rat: 3 % at 1 Hz and 1.2 % at 5 Hz. These differences arise because: (i) the fraction of I_Ca in the TATS, which is responsible for tubular Ca²⁺ depletion, is lower in the guinea-pig (64 %, Shepherd & McDonough, 1998) than in the rat (87 %, Brette & Orchard, 2003); (ii) the sensitivity of I_Ca to the changes of membrane potential induced by tubular Ca²⁺ depletion is lower in guinea pig; (iii) unlike the rat model, the magnitude of I_Ca decreases with stimulation frequency in the guinea pig model; (iv) ion diffusion between the tubular lumen and external space is significantly faster in the guinea pig model (τ_Ca= 240 ms; Shepherd and McDonough, 1998) than in the rat model (τ_Ca= 500 ms; Yao et al., 1997); however Blatter & Niggli (1998), suggest that τ_Ca may be > 1000 ms in guinea pig, which would increase Ca²⁺ depletion in guinea pig TATS. These data suggest that changes of ion concentrations occur in the TATS lumen and modulate cell function.