Non-β-blocking R-carvedilol enantiomer suppresses Ca2+ waves and stress-induced ventricular tachyarrhythmia without lowering heart rate or blood pressure.
Carvedilol is the current β-blocker of choice for suppressing ventricular tachyarrhythmia (VT). However, carvedilol's benefits are dose-limited, attributable to its potent β-blocking activity that can lead to bradycardia and hypotension. The clinically used carvedilol is a racemic mixture of β-blocking S-carvedilol and non-β-blocking R-carvedilol. We recently reported that novel non-β-blocking carvedilol analogues are effective in suppressing arrhythmogenic Ca(2+) waves and stress-induced VT without causing bradycardia. Thus, the non-β-blocking R-carvedilol enantiomer may also possess this favourable anti-arrhythmic property. To test this possibility, we synthesized R-carvedilol and assessed its effect on Ca(2+) release and VT. Like racemic carvedilol, R-carvedilol directly reduces the open duration of the cardiac ryanodine receptor (RyR2), suppresses spontaneous Ca(2+) oscillations in human embryonic kidney (HEK) 293 cells, Ca(2+) waves in cardiomyocytes in intact hearts and stress-induced VT in mice harbouring a catecholaminergic polymorphic ventricular tachycardia (CPVT)-causing RyR2 mutation. Importantly, R-carvedilol did not significantly alter heart rate or blood pressure. Therefore, the non-β-blocking R-carvedilol enantiomer represents a very promising prophylactic treatment for Ca(2+)- triggered arrhythmia without the bradycardia and hypotension often associated with racemic carvedilol. Systematic clinical assessments of R-carvedilol as a new anti-arrhythmic agent may be warranted.
['Zhang|Jingqun|J|', 'Zhou|Qiang|Q|', 'Smith|Chris D|CD|', 'Chen|Haiyan|H|', 'Tan|Zhen|Z|', 'Chen|Biyi|B|', 'Nani|Alma|A|', 'Wu|Guogen|G|', 'Song|Long-Sheng|LS|', 'Fill|Michael|M|', 'Back|Thomas G|TG|', 'Chen|S R Wayne|SR|']
D000818:Animals D000889:Anti-Arrhythmia Agents D001794:Blood Pressure D002118:Calcium D002227:Carbazoles D000077261:Carvedilol D057809:HEK293 Cells D006339:Heart Rate D006801:Humans D015640:Ion Channel Gating D051379:Mice D008817:Mice, Mutant Strains D009154:Mutation D009206:Myocardium D011412:Propanolamines D019837:Ryanodine Receptor Calcium Release Channel D013237:Stereoisomerism D017180:Tachycardia, Ventricular
Ca2+ waves β-blockers ryanodine receptor Ca2+-triggered arrhythmias carvedilol enantiomers sarcoplasmic reticulum