(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.

Rocchetti, M., Besana, A., Mostacciuolo, G., Ferrari, P., Micheletti, R., Zaza, A. (2003). Diverse toxicity associated with cardiac Na+/K+ pump inhibition: Evaluation of electrophysiological mechanisms. THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 305(2), 765-771 [10.1124/jpet.102.047696].

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

ROCCHETTI, MARCELLA;MOSTACCIUOLO, GASPARE;ZAZA, ANTONIO
2003

Abstract

(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.
Articolo in rivista - Articolo scientifico
Na/K pump inhibitor, patch clamp, cardiac myocytes
English
mag-2003
305
2
765
771
none
Rocchetti, M., Besana, A., Mostacciuolo, G., Ferrari, P., Micheletti, R., Zaza, A. (2003). Diverse toxicity associated with cardiac Na+/K+ pump inhibition: Evaluation of electrophysiological mechanisms. THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 305(2), 765-771 [10.1124/jpet.102.047696].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/43650
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