PubMed1984
A broad survey of the experimental literature suggests that the only unifying concept of digitalis action is that these drugs, at pharmacologically relevant doses, bind with high affinity and specificity to sites on the NaK-ATPase complex that face the outer surface of nearly all eukaryotic cells. Alternative receptors, if they exist, have not been defined. As might be expected, a broad range of biologic effects results from this basic interaction. The clinical therapeutic effects of digitalis include enhancement of myocardial contractility and changes in the properties of the cardiac conduction system; the latter, in turn, result from both direct and autonomically mediated effects [44]. Autonomic effects involve alterations in both parasympathetic and sympathetic activity, and these are attributable to both central and peripheral neural mechanisms [44]. As we have reviewed, there is compelling evidence that one mechanism leading to sustained positive inotropic effects of digitalis glycosides in heart muscle is partial inhibition of sodium transport. Earlier evidence [16, 17] is now supported by electrophysiologic studies [29, 30, 45, 46], intracellular ion-sensitive microelectrode methods [47, 48], and ion flux measurements using radioisotope tracers [14, 15, 49]. Inhibition of myocardial monovalent cation transport has been documented in intact glycoside-sensitive animal models at doses and plasma and myocardial levels causing a positive inotropic effect without overt toxicity [12]. However, these findings do not preclude other mechanisms that may be operative in addition to, or in some circumstances instead of, myocardial Na-K pump inhibition. In the context of much seemingly conflicting evidence [35, 36, 37, 50, 51], the hypothesis advanced by Akera and Brody is of interest [17]. These authors suggest that interaction of subtoxic digitalis concentrations with myocardial NaK-ATPase reduces maximum sodium transport capacity, resulting in an enhanced transient increase in [Na]i during the early phase of the cardiac cycle. Such an increase in subsarcolemmal [Na+] could cause increased Ca++ influx via Na+-Ca++ exchange, with a consequent positive inotropic effect. If the Na+ increase were cyclic and not cumulative, cell Na+ content could return to normal by the end of a cycle due to enhanced turnover of unblocked Na-K pump sites. This hypothesis suggests a mechanism by which Na-K pump inhibition could cause a positive inotropic effect without any measurable increase in steady-state [Na+]i or decrease in [K+]i.(ABSTRACT TRUNCATED AT 400 WORDS)