Non-β-blocking R-carvedilol enantiomer suppresses Ca2+ waves and stress-induced ventricular tachyarrhythmia without lowering heart rate or blood pressure.

The Biochemical Journal
Jingqun ZhangS R Wayne Chen

Abstract

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 enanti...Continue Reading

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Citations

Apr 27, 2016·The Journal of General Physiology·Josefina Ramos-Franco, Michael Fill
Apr 11, 2020·American Journal of Physiology. Heart and Circulatory Physiology·E Martinez-Hernandez, L A Blatter
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Aug 6, 2021·Journal of Neuroscience Research·Yajing LiuS R Wayne Chen

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