Role and mechanism of subcellular Ca2+ distribution in the action of two inotropic agents with different toxicity
| Autor: | Daniele Re, Antonio Zaza, Marcella Rocchetti, Matteo Alemanni |
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| Přispěvatelé: | Alemanni, M, Rocchetti, M, Re, D, Zaza, A |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Inotrope
medicine.medical_specialty Digoxin Cardiotonic Agents chemistry.chemical_element Stimulation Calcium Pharmacology Mice Internal medicine Etiocholanolone medicine Animals Cardiotonic Agent Molecular Biology Cells Cultured Calcium metabolism Ryanodine receptor Animal Mice Inbred C57BL Electrophysiology Sarcoplasmic Reticulum Endocrinology Istaroxime chemistry Toxicity Female Sodium-Potassium-Exchanging ATPase Cardiology and Cardiovascular Medicine medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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