In unstimulated isolated, rat ventricular muscle, the increase in resting force (DeltaRF) which occurs with an increase in external calcium concentration (Delta[Ca2+]e can be largely abolished by lowering cellular sodium content by removing sodium from the perfusate and can be potentiated by raising cellular sodium content by adding ouabain. We hypothesized that this demonstrated the activity of a membrane Na/Ca exchange. Since this membrane exchange is well known to exhibit graded activity, we sought to extend our observations by demonstrating a graded response between [Na+]i and DeltaRF. External potassium concentration ([K+]e) was set at gradually lowered values for each experiment in the series to give graded inhibition of the Na-K pump and thus graded elevation of [Na+]i. [Ca2+]e was then increased from 0 to 2 mM and the DeltaRF recorded. The results shown that increasing DeltaRF occurs with decreasing [K+]e (and thus increasing [Na+]i. Thus, not only does the Delta RF for a Delta[Ca2+]i depend on [Na+]e, but does so in a graded manner. This is further evidence for the activity of the Na/Ca exchange in controlling DeltaRF in isolated rat muscle. In extending these studies to the intact heart 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. Our 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+ reintroduction, which collectively have been referred to as the """"""""calcium paradox"""""""" in the heart.
