To investigate the hypothesis that Na⁺ concentration in subplasmalemmal microdomains regulates Ca²⁺ concentrations in cellular microdomains ([Ca]_md), cytosol ([Ca]cyt), and sarcoplasmic reticulum (SR, [Ca]_sr), we modeled transport events in those compartments. Inputs to the model were obtained from published measurements in descending vasa recta pericytes and other smooth muscle cells. The model accounts for major classes of ion channels, Na⁺/Ca²⁺ exchange (NCX) and the distributions of Na⁺/K⁺-ATPase 1 and 2 isoforms in the plasma membrane. Ca²⁺ release from SR stores is assumed to occur via ryanodine (RyR) and inositol tris phosphate (IP₃R) receptors. The model shows that requisite existence of a significant Na⁺ concentration difference between the cytosol ([Na]_cyt) and microdomains ([Na]_md) necessitates restriction of intercompartmental diffusion. Accepting the latter, the model predicts resting ion concentrations that are compatible with experimental measurements and temporal changes in [Ca]_cyt similar to those observed upon NCX inhibition. An important role for NCX in the regulation of Ca⁺ signaling is verified. In the resting state, NCX operates in "forward mode", with Na⁺ entry and Ca²⁺ extrusion from the cell. Inhibition of NCX respectively raises and reduces [Ca]_cyt and [Na]_cyt by 40% and 30%. NCX translates variations in Na⁺/K⁺-ATPase activity into changes in [Ca]_md, [Ca]_sr and [Ca]_cyt. Taken together, the model simulations verify the feasibility of the central hypothesis that modulation of [Na]_md can influence both the loading of Ca²⁺ into SR stores and [Ca²⁺]_cyt variation.