DISSOCIATION OF ELECTROPHYSIOLOGICAL AND INOTROPIC ACTIONS OF STROPHANTHIDIN-3-BROMOACETATE: POSSIBLE ROLE OF ADENOSINE TRIPHOSPHATASE IN THE MAINTENANCE OF THE MYOCARDIAL TRANSMEMBRANE Na⁺ AND K⁺ GRADIENTS

¹ Departments of Pharmacology, Northwestern University Medical School, Chicago, Illinois and College of Physicians and Surgeons, Columbia University, New York, New York

The alkylating cardiac glycoside, strophanthidin-3-bromoacetate has been shown to increase the force of contraction, reduce the transmembrane resting potential (E_r) and inhibit the membrane Na, K-dependent adenosine triphosphatase activity (Na,K-ATPase) of atrial and ventricular myocardium. The onset of these effects in isolated and in vivo heart preparations is nearly simultaneous during exposure to strophanthidin-3-bromoacetate (3-9x10^-7 M). The coincidence of onset of the inotropic, electrophysiological and enzymatic effects of other glycosides such as digoxin, ouabain and acetylstrophanthidin has led to the postulation that either or both the inotropic and electrophysiological effects of the glycosides may be causally related to the glycoside-induced inhibition of Na, K-ATPase. A possible causal relationship between the inotropic and electrophysiological actions has also been postulated. In this study, by utilizing a drug washout technique and isolated, Tyrode's solution perfused canine and lapine ventricular muscle preparations, it has been possible to show that the inotropic effect of strophanthidin-3-bromoacetate can be clearly temporally dissociated from both the electrophysiological (as evidenced by a sustained loss in E_r while contractile force returned to control values) and the inhibitory effect of the glycoside on the Na, K-ATPase. Furthermore, the time course of recovery of E_r closely parelleled the previously determined time course of recovery of the Na, K-ATPase activity. Because, under the experimental conditions employed, the membrane of ventricular myocardium closely approximates a K⁺electrode, the loss of E_r can be best interpreted as being due to a reduction in the intracellular K+ activity. The most reasonable mechanism of such a loss of intracellular K+ is a glycoside-induced reduction in the transport capacity of the membrane active transport mechanism for Na+ and K+. Therefore, the temporal correlation between the loss of E_r and the inhibition of Na,K-ATPase activity suggests that the myocardial tmansmembrane transport is in some way linked to, and regulated by, the level of Na, K-ATPase activity.

This article has been cited by other articles:

				J. A. Wasserstrom and G. L. Aistrup Digitalis: new actions for an old drug Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1781 - H1793. [Abstract] [Full Text] [PDF]

				M. Nishio, S. W. Ruch, and J. A. Wasserstrom Positive inotropic effects of ouabain in isolated cat ventricular myocytes in sodium-free conditions Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H2045 - H2053. [Abstract] [Full Text] [PDF]

				T. Sagawa, K. Sagawa, J. E. Kelly, R. G. Tsushima, and J. A. Wasserstrom Activation of cardiac ryanodine receptors by cardiac glycosides Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H1118 - H1126. [Abstract] [Full Text] [PDF]