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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 20, 2003; DOI: 10.1124/jpet.102.047696

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Vol. 305, Issue 2, 765-771, May 2003

Diverse Toxicity Associated with Cardiac Na+/K+ Pump Inhibition: Evaluation of Electrophysiological Mechanisms

M. Rocchetti, A. Besana, G. Mostacciuolo, P. Ferrari, R. Micheletti and A. Zaza

Dipartimento di Biotecnologie e Bioscienze, Università Milano-Bicocca (M.R., A.B., G.M., A.Z.), and Prassis Istituto Ricerche Sigma Tau (P.F., R.M.), Milan, Italy

(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 current IKs (<= -21%); delayed rectifier current IKr 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 ITI, 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.

0022-3565/03/3052-0765$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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