Local and systemic effects of Na+/K+ATPase inhibition

The positive inotropic and electrophysiological effects of cardiac glycosides on cardiac muscle are mediated through inhibition of Na+/K+ATPase by binding to a specific extracytoplasmic site of the a‐subunit of this enzyme. The inhibition of Na+/K+ATPase affects ionic flux and produces direct local effects on cardiac contractility, electrical excitability and conduction, but also profound systemic effects mainly as a result of haemodynamic changes. These effects are responsible for beneficial therapeutic as well as toxic effects. Inhibition of Na+/K+ATPase results in potentiation of K+loss from cells and Na+entry into cells, so consequently affects action potential generation and propagation. This also underlines the potentiation of certain effects of cardiac glycosides by hypokalemia and hypomagnesaemia, and the effects of changes in calcium homeostasis on the cardiac glycoside pharmacodynamics. Furthermore, inhibition of Na+/Ca++exchange enhances Ca++mobilization and promotes contractility. These effects (locally and systemically) differ greatly, depending on the haemodynamic status and myocardial oxygen supply. Cardiac glycosides have less affinity for Na+/K+ATPases at other sites (e.g. skeletal muscle), but some extracardiac effects (vascular effects, effects on colour vision, CNS and autonomic effects, renal effects) may be related to Na+/K+ATPase inhibition.