TY - JOUR T1 - Diverse Toxicity Associated with Cardiac Na<sup>+</sup>/K<sup>+</sup> Pump Inhibition: Evaluation of Electrophysiological Mechanisms JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 765 LP - 771 DO - 10.1124/jpet.102.047696 VL - 305 IS - 2 AU - M. Rocchetti AU - A. Besana AU - G. Mostacciuolo AU - P. Ferrari AU - R. Micheletti AU - A. Zaza Y1 - 2003/05/01 UR - http://jpet.aspetjournals.org/content/305/2/765.abstract N2 - (E,Z)-3-((2-Aminoethoxy)imino)androstane-6,17-dione hydrochloride (PST2744) is a novel Na+/K+ 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+/K+ pump inhibition and inotropy was somewhat larger for PST2744 than for digoxin; 3) both agents accelerated inactivation of high-threshold Ca2+ current (ICaL), without affecting its peak amplitude; 4) the transient inward current (ITI) induced by a Ca2+transient in the presence of complete Na+/K+pump blockade was inhibited (−43%) by PST2744 but not by digoxin; 5) the conductance of Na+/Ca2+ exchanger current (INaCa), recorded under Na+/K+ pump blockade, was only slightly inhibited by PST2744 (−14%) and unaffected by digoxin; and 6) both agents inhibited delayed rectifier currentIKs (≤−21%); delayed rectifier currentIKr 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 ofITI, a current directly involved in digitalis-induced arrhythmias. Indeed, the other differences observed concern quantitatively small effects; and 2)ITI suppression by PST2744 may be only partly accounted for by inhibition of the Na+/Ca2+ exchanger. The American Society for Pharmacology and Experimental Therapeutics ER -