Interdependence of ion transport and the action of quabain in heart muscle.

1 The influence of ouabain (0.4 muM) on contractile force and cellular Na and K concentrations was investigated in isolated left atria of the guinea-pig at rest and at different beat frequencies. Simultaneously the binding of ouabain to the tissue was determined.2 Strict dependence of rates of onset of positive iontropic action and of binding of ouabain on beat frequency are limited to conditions where no alterations of cellular Na and K concentrations occur. A correlation was observed between sodium flux per unit time and the development of positive inotropism and binding to the receptors of ouabain.3 Ouabain exerts its positive inotropic effect without affecting the intracellular Na and K concentrations in spite of the fact that under these conditions even the majority of binding sites, i.e. Na-K-adenosine triphosphatases (Na-K-ATPases), are occupied by the drug. The positive inotropic effect may be explained by a ouabain-induced conformational alteration of the Na-K-ATPase which leads to structural alterations of the plasmalemma connected with an increased availability of coupling calcium.4 Increasing the frequency of stimulation over a critical value, which appears to be determined by an overloading of the Na pump, induces a decrease in contractile force, cellular accumulation of Na and loss of K, and eventually contracture.5 The rate of binding of ouabain appears to depend on the actual concentration of particular conformations of the Na-K-ATPase with high affinity for ouabain. These conformations transiently occur during a pumping cycle and their concentration may therefore be dependent on the frequency of cycling which in turn is determined by the frequency of contraction.6 Ouabain can easily be washed out from the tissue irrespective of the condition of the muscle. If, however, the intracellular Na and K homeostasis is impaired, the inhibition of the pump persists even if ouabain is released from the binding sites upon wash-out. It is suggested that the inhibition of the pump is maintained by an increased intracellular Ca ion concentration and a depletion of ATP.7 A kinetic model is proposed for the interaction between cardiac glycosides and the Na-K-ATPase in intact heart muscle cells.