Non-beta-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain

GONANO LA, SEPÚLVEDA M, MORELL M, TOTEFF T, RACIOPPI MF, LASCANO E, NEGRONI J, FERNÁNDEZ RUOCCO MJ, MEDEI E, NEIMAN G, MIRIUKA SG, BACK TG, CHEN SRW, MATTIAZZI A, VILA PETROFF M.

CIRCULATION JOURNAL

JAPANESE CIRCULATION SOC

Año: 2018 vol. 83 p. 41 - 51

1346-9843

BACKGROUND:It has been shown that carvedilol and its non β-blocking analog, VK-II-86, inhibit spontaneous Ca2+ release from the sarcoplasmic reticulum (SR). The aim of this study is to determine whether carvedilol and VK-II-86 suppress ouabain-induced arrhythmogenic Ca2+ waves and apoptosis in cardiac myocytes. Methods and Results: Rat cardiac myocytes were exposed to toxic doses of ouabain (50 µmol/L). Cell length (contraction) was monitored in electrically stimulated and non-stimulated conditions. Ouabain treatment increased contractility, frequency of spontaneous contractions and apoptosis compared to control cells. Carvedilol (1 µmol/L) or VK-II-86 (1 µmol/L) did not affect ouabain-induced inotropy, but significantly reduced the frequency of Ca2+ waves, spontaneous contractions and cell death evoked by ouabain treatment. This antiarrhythmic effect was not associated with a reduction in Ca2+ calmodulin-dependent protein kinase II (CaMKII) activity, phospholamban and ryanodine receptor phosphorylation or SR Ca2+ load. Similar results could be replicated in human cardiomyocytes derived from stem cells and in a mathematical model of human myocytes.CONCLUSIONS:Carvedilol and VK-II-86 are effective to prevent ouabain-induced apoptosis and spontaneous contractions indicative of arrhythmogenic activity without affecting inotropy and demonstrated to be effective in human models, thus emerging as a therapeutic tool for the prevention of digitalis-induced arrhythmias and cardiac toxicity.