Diverse toxicity associated with cardiac Na+/K+ pump inhibition: Evaluation of electrophysiological mechanisms

(E, Z)-3-((2-Aminoethoxy) imino) androstane-6,17-dione hydrochloride (PST2744) is a novel Na? pump inhibitor with positive inotropic effects. Compared with digoxin in various experimental models, PST2744 was consistently found to be less arrhythmogenic, thus resulting in a significantly higher therapeutic index. The present work compares the electrophysiological effects of PST2744 and digoxin in guinea pig ventricular myocytes, with the aim to identify a mechanism for their different toxicity. The work showed that 1) the action potential was transiently prolonged and then similarly shortened by both agents; 2) the ratio between Na? pump inhibition and inotropy was somewhat larger for PST2744 than for digoxin; 3) both agents accelerated inactivation of high-threshold Ca2 current (I-CaL), without affecting its peak amplitude; 4) the transient inward current (I-TI) induced by a Ca2 transient in the presence of complete Na? pump blockade was inhibited (-43%) by PST2744 but not by digoxin; 5) the conductance of Na? exchanger current (I-NaCa), recorded under Na? pump blockade, was only slightly inhibited by PST2744 (-14%) and unaffected by digoxin; and 6) both agents inhibited delayed rectifier current I-Ks (less than or equal to-21%); delayed rectifier current I-Kr was inhibited by PST2744 only, but the effect was marginal (-6%). Thus, 1) the higher therapeutic index of PST2744 may be accounted for by inhibition of I-TI, a current directly involved in digitalis-induced arrhythmias. Indeed, the other differences observed concern quantitatively small effects; and 2) I-TI suppression by PST2744 may be only partly accounted for by inhibition of the Na? exchanger.