RT Journal Article
SR Electronic
T1 Modulation of Sarcoplasmic Reticulum Function by Na+/K+ Pump Inhibitors with Different Toxicity: Digoxin and PST2744 [(E,Z)-3-((2-Aminoethoxy)imino)androstane-6,17-dione Hydrochloride]
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 207
OP 215
DO 10.1124/jpet.104.077933
VO 313
IS 1
A1 Marcella Rocchetti
A1 Alessandra Besana
A1 Gaspare Mostacciuolo
A1 Rosella Micheletti
A1 Patrizia Ferrari
A1 Sandor Sarkozi
A1 Csaba Szegedi
A1 Istvan Jona
A1 Antonio Zaza
YR 2005
UL http://jpet.aspetjournals.org/content/313/1/207.abstract
AB Objective: To gain some insight on the lesser arrhythmogenic properties of PST2744 [(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride] compared with digoxin, we compared modulation of intracellular Ca2+ dynamics by the two agents. Methods: SERCA (sarcoplasmic reticulum Ca2+-ATPase) activity and Ca2+ leak rate were measured in sarcoplasmic reticulum (SR) vesicles from guinea pig ventricles. Membrane current, intracellular Ca2+, and twitch amplitude were evaluated in guinea pig ventricular myocytes with or without blockade of the Na+/Ca2+ exchanger. Results: In SR vesicles, PST2744 (30–300 nM), but not digoxin, increased SERCA activity; digoxin only (≥0.1 nM) increased SR Ca2+ leak. In myocytes with blocked Na+/Ca2+ exchanger, Ca2+ reloading of caffeine-depleted SR was enhanced by PST2744 and slightly inhibited by digoxin. In myocytes with functioning Na+/Ca2+ exchanger, both agents increased diastolic Ca2+, SR Ca2+ content, the gain of Ca2+-induced Ca2+ release, the rate of cytosolic Ca2+ decay, twitch amplitude, and relaxation rate. Consistent with the observations in SR vesicles, the effects on SR Ca2+ content and Ca2+ decay rate were significantly larger for PST2744 than for digoxin. Conclusions: In isolated SR vesicles, PST2744 and digoxin directly affected SR function in opposite ways; this could be reproduced in myocytes during Na+/Ca2+ exchanger blockade. Under physiological conditions (functioning Na+/Ca2+ exchanger), the two agents affected Ca2+ dynamics in the same direction, as expected by their Na+/K+ pump inhibition; however, differential SR modulation was still expressed by quantitative differences. Thus, the more favorable inotropy-to-toxicity ratio previously described for PST2744 appears to be associated with direct SERCA stimulation and/or lack of enhancement of Ca2+ leak. The American Society for Pharmacology and Experimental Therapeutics