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CARDIOVASCULAR

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]

Dipartimento di Biotecnologie e Bioscienze (M.R., A.B., G.M., A.Z.), Università Milano-Bicocca, Prassis Sigma-Tau Research Institute (R.M., P.F.), Settimo Milanese, Italy; and Department of Physiology, University of Debrecen, Hungary (S.S., C.S., I.J.)

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.

Address correspondence to: Dr. Antonio Zaza, Dipartimento di Biotecnologie e Bioscienze, Università degli Studi Milano-Bicocca, P.zza della Scienza 2, 20126 Milano, Italy. E-mail: antonio.zaza{at}unimib.it

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