The Na^+-Ca^<2+> exchange expressed in the plasma membrane of all animal cells regulates cytosolic Ca^<2+> which plays a key role in intracellular signaling. This is important in cardiac muscle cells that need to extrude a lot of Ca^<2+> rapidly (resting free Ca^<2+> is 0.1×10^<-6> M and not less). The Na^+-Ca^<2+> exchange current was investigated in single ventricular cells from guinea-pig hearts by combining the techniques of whole-cell voltage clamp and intracellular perfusion (12). The stoichiometry of 3Na^+:1Ca^<2+> determined from the reversal potential was consistent with the Hill coefficient for Na^+ of 2.9 (n=6) and for Ca^<2+> of 0.9 (n=5). Subsequently, the stoichiometry of cardiac Na^+-Ca^<2+> exchange has generally been accepted as 3:1 (18). In 2000, Fujioka et al. showed that the reversal potential of the Na^+-Ca^<2+> exchange current measured from the inside-out macropatch excised from intact sarcolemma of guinea-pig ventricular myocytes is, for the most part, close to the equilibrium potential of the 4Na^+:1Ca^<2+> exchange. On the other hand, Hinata et al. concluded that the 4:1 stoichiometry could be explained by Ca^<2+> accumulation on the cytoplasmic side of the membrane, and that the stoichiometry of cardiac Na^+-Ca^<2+> exchange is 3:1. Bers and Weber carefully measured both internal Ca^<2+> and Na^+ during Na^+-Ca^<2+> exchange current measurements, because Fujioka et al. did not measure internal Ca^<2+> or Na^+ during their measurements of reversal potential, and found that both internal Ca^<2+> and Na^+ change via Na^+-Ca^<2+> exchange at the holding potential (even with 6 mM BAPTA+Br_2BAPTA in the pipette). They showed some data that strongly favor the 3:1 stoichiometry under physiological conditions. Furthermore, Kang et al. simultaneously measured extracellular Ca^<2+> transients in a giant cardiac patch using a Ca^<2+>-selective electrode placed into the pipette tip at a distance of about 0.01mm from the membrane and inward Na^+-Ca^<2+> exchange currents. They have not obtained clear evidence for deviations from 3-to-1 stoichiometry. These studies indicate that the Na^+-Ca^<2+> exchanger in cardiac myocytes likely has a fixed coupling ratio of 3Na^+:1Ca^<2+>.