The Actions of Cardiac Glycosides on Heart Muscle Cells

In experimental heart muscle preparations cardiac glycosides specifically inhibit the active transport of Na ions out of heart muscle cells. By this action they bring about a net cellular accumulation of Na and, secondarily, a net cellular loss of K and uptake of Cl, cell swelling, and a fall in the electrical potential difference across the resting cell membrane. The site of inhibition appears to be the external surface of the cell membrane and to involve a displacement of K ions from a critical site at this surface. Inhibition of active transport by cardiac glycosides in intact cells has a counterpart in cell membrane fragments, in which the drugs inhibit the Na- and K-activated enzymatic splitting of adenosinetriphosphate.The contraction-promoting effect of these drugs is not understood, principally because the sequence of events in cellular contraction and its alterations in heart failure have been only incompletely identified. Cellular contraction has been divided for descriptive purposes into three stages, including depolarization, excitation-contraction coupling, and shortening and relaxation of the myofibrils containing the contractile proteins. Neither the inhibition of active ion transport nor the experimental observations on the three stages of the contractile sequence explain the therapeutic effects of cardiac glycosides. Experimental approaches to the question of cardiac glycoside action at the cellular level and to the related problem of heart muscle cell failure are suggested.