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Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity.
- Source :
-
Circulation journal : official journal of the Japanese Circulation Society [Circ J] 2018 Dec 25; Vol. 83 (1), pp. 41-51. Date of Electronic Publication: 2018 Oct 23. - Publication Year :
- 2018
-
Abstract
- Background: It has been shown that carvedilol and its non β-blocking analog, VK-II-86, inhibit spontaneous Ca <superscript>2+</superscript> release from the sarcoplasmic reticulum (SR). The aim of this study is to determine whether carvedilol and VK-II-86 suppress ouabain-induced arrhythmogenic Ca <superscript>2+</superscript> 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 Ca <superscript>2+</superscript> waves, spontaneous contractions and cell death evoked by ouabain treatment. This antiarrhythmic effect was not associated with a reduction in Ca <superscript>2+</superscript> calmodulin-dependent protein kinase II (CaMKII) activity, phospholamban and ryanodine receptor phosphorylation or SR Ca <superscript>2+</superscript> load. Similar results could be replicated in human cardiomyocytes derived from stem cells and in a mathematical model of human myocytes.<br />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.
- Subjects :
- Animals
Apoptosis drug effects
Calcium Signaling drug effects
Cardiotoxicity metabolism
Cardiotoxicity pathology
Disease Models, Animal
Humans
Male
Myocardial Contraction drug effects
Myocytes, Cardiac metabolism
Myocytes, Cardiac pathology
Ouabain pharmacology
Rats
Rats, Wistar
Cardiotoxicity prevention & control
Carvedilol analogs & derivatives
Carvedilol pharmacology
Models, Cardiovascular
Ouabain adverse effects
Subjects
Details
- Language :
- English
- ISSN :
- 1347-4820
- Volume :
- 83
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Circulation journal : official journal of the Japanese Circulation Society
- Publication Type :
- Academic Journal
- Accession number :
- 30369562
- Full Text :
- https://doi.org/10.1253/circj.CJ-18-0247