'Calcium paradox' in the heart is modulated by cell sodium during the calcium-free period

We hypothesized that after a Ca²⁺-free period the magnitude of the Na⁺ gradient at the onset of Ca²⁺ reperfusion would grade the ensuing cell Ca²⁺ gain. Rabbit interventricular septa perfused with Hepes buffered solution (pH 7.4, [Ca²⁺]=1.0 mm) and stimulated to contract isometrically at 60 min^-1 at 30°C were exposed to a 30-min Ca²⁺-free period followed by 30-min of Ca²⁺ re-introduction. Cell Na without Ca²⁺-free perfusion was 137±5 μmol/g dry wt. During the Ca²⁺-free period, the perfusate was manipulated to resultin three groups of septa in which cell Na just prior to Ca²⁺ re-introduction was 64±9 (perfusate [Na⁺ reduced to 47 mm), 170±12 (perfusate unaltered), and 293±16 μmol/g dry wt (addition of 5×10^-5m ouabain). Following Ca²⁺ re-introduction, cell Ca²⁺ content was 3.4±0.5, 6.5±1.0, and 10.6±0.7 μmol/g dry wt in the low, intermediate, and high cell Na⁺ groups, respectively. Similar marked and highly significant gradations among the three groups were observed in the extent of cell K⁺ loss and recovery of contractile function during Ca²⁺ re-introduction. These results indicate that (1) myocardial cell Na⁺ increases during Ca²⁺ free perfusion and (2) the magnitude of the Na⁺ gradient at the end of the Ca²⁺ free period is an important determinant of the extent of cell Ca²⁺ gain, cell K⁺ loss, and reduction of contractile function with Ca²⁺ re-introduction, which collectively have been referred to as the 'calcium paradox' in the heart.