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(+)/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 Ca(2+) current (I(CaL)), without affecting its peak amplitude; 4) the transient inward current (I(TI)) induced by a Ca(2+) transient in the presence of complete Na(+)/K(+) pump blockade was inhibited (-43%) by PST2744 but not by digoxin; 5) the conductance of Na(+)/Ca(2+) exchanger current (I(NaCa)), 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 I(Ks) (<or=-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(+)/Ca(2+) exchanger.
Rocchetti
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Dipartimento di Biotecnologie e Bioscienze, Università Milano-Bicocca, Piazza della Scienza 2, Room U3-3013 20126 Milan, Italy.
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Micheletti
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Zaza
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D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002316:Cardiotonic Agents / Q000633:toxicity*; D002469:Cell Separation; D004077:Digoxin / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000633:toxicity*; D005043:Etiocholanolone / Q000031:analogs & derivatives / Q000633:toxicity*; D005260:Female; D006168:Guinea Pigs; D006331:Heart Diseases / Q000139:chemically induced* / Q000201:enzymology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
D015220:Calcium Channels; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D024661:Potassium Channels, Inwardly Rectifying; D004077:Digoxin; D005043:Etiocholanolone; D000254:Sodium-Potassium-Exchanging ATPase; C468128:Istaroxime