title: Role and mechanism of subcellular Ca2+ distribution in the action of two inotropic agents with different toxicity.
abstract: Pro-arrhythmic risk strongly limits the therapeutic value of current inotropic interventions. Istaroxime (previously PST2744) is a novel inotropic agent, significantly less pro-arrhythmic than digoxin that, in addition to block Na(+)/K(+) pump, stimulates sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2). Here we compare istaroxime and digoxin effects to further address the role of SR modulation in reducing the toxicity associated with Na(+)/K(+) pump blockade. In murine ventricular myocytes both compounds increased cell twitch (inotropy) in a concentration-dependent fashion. At high concentrations digoxin, but not istaroxime, induced unstimulated contractions, a sign of pro-arrhythmic toxicity. To evaluate the mechanism of this difference, we compared the two drugs at concentrations exerting equal inotropy but different toxicity. At these concentrations: (1) the two drugs equally inhibited the Na(+)/K(+) pump; (2) digoxin induced larger increases in resting Ca(2+) and in diastolic Ca(2+) during pacing; (3) neither drug affected the relationship between RyR-mediated SR Ca(2+) leak and Ca(2+) content; (4) istaroxime, but not digoxin, enhanced SR Ca(2+) reuptake rate. In conclusion, digoxin toxicity was associated to larger accumulation of cytosolic Ca(2+), which did not result from RyR facilitation, but which might ultimately induce it to promote unstimulated Ca(2+) release. The lower toxicity of Na(+)/K(+) pump blockade by istaroxime may thus reflect improved Ca(2+) confinement within the SR, likely to result from concomitant SERCA2 stimulation.
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano–Bicocca, P.za della Scienza 2, 20126 Milano, Italy
authors.forename: Matteo
authors.initials: M
authors.lastname: Alemanni
authors.forename: Marcella
authors.initials: M
authors.lastname: Rocchetti
authors.forename: Daniele
authors.initials: D
authors.lastname: Re
authors.forename: Antonio
authors.initials: A
authors.lastname: Zaza
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004077:Digoxin / Q000494:pharmacology*; D004594:Electrophysiology; D005043:Etiocholanolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D004077:Digoxin; D005043:Etiocholanolone; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium; C468128:Istaroxime