title: Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release.
abstract: Carvedilol is one of the most effective beta blockers for preventing ventricular tachyarrhythmias in heart failure, but the mechanisms underlying its favorable antiarrhythmic benefits remain unclear. Spontaneous Ca(2+) waves, also called store overload-induced Ca(2+) release (SOICR), evoke ventricular tachyarrhythmias in individuals with heart failure. Here we show that carvedilol is the only beta blocker tested that effectively suppresses SOICR by directly reducing the open duration of the cardiac ryanodine receptor (RyR2). This unique anti-SOICR activity of carvedilol, combined with its beta-blocking activity, probably contributes to its favorable antiarrhythmic effect. To enable optimal titration of carvedilol's actions as a beta blocker and as a suppressor of SOICR separately, we developed a new SOICR-inhibiting, minimally beta-blocking carvedilol analog, VK-II-86. VK-II-86 prevented stress-induced ventricular tachyarrhythmias in RyR2-mutant mice and did so more effectively when combined with either of the selective beta blockers metoprolol or bisoprolol. Combining SOICR inhibition with optimal beta blockade has the potential to provide antiarrhythmic therapy that can be tailored to individual patients.
authors: Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
authors: Qiang
authors: Q
authors: Zhou
authors: Jianmin
authors: J
authors: Xiao
authors: Dawei
authors: D
authors: Jiang
authors: Ruiwu
authors: R
authors: Wang
authors: Kannan
authors: K
authors: Vembaiyan
authors: Aixia
authors: A
authors: Wang
authors: Chris D
authors: CD
authors: Smith
authors: Cuihong
authors: C
authors: Xie
authors: Wenqian
authors: W
authors: Chen
authors: Jingqun
authors: J
authors: Zhang
authors: Xixi
authors: X
authors: Tian
authors: Peter P
authors: PP
authors: Jones
authors: Xiaowei
authors: X
authors: Zhong
authors: Ang
authors: A
authors: Guo
authors: Haiyan
authors: H
authors: Chen
authors: Lin
authors: L
authors: Zhang
authors: Weizhong
authors: W
authors: Zhu
authors: Dongmei
authors: D
authors: Yang
authors: Xiaodong
authors: X
authors: Li
authors: Ju
authors: J
authors: Chen
authors: Anne M
authors: AM
authors: Gillis
authors: Henry J
authors: HJ
authors: Duff
authors: Heping
authors: H
authors: Cheng
authors: Arthur M
authors: AM
authors: Feldman
authors: Long-Sheng
authors: LS
authors: Song
authors: Michael
authors: M
authors: Fill
authors: Thomas G
authors: TG
authors: Back
authors: S R Wayne
authors: SR
authors: Chen
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D017298:Bisoprolol; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D002227:Carbazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000077261:Carvedilol; D002460:Cell Line; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D055879:Gene Knock-In Techniques; D006801:Humans; D008790:Metoprolol; D051379:Mice; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D020125:Mutation, Missense / Q000235:genetics; D011412:Propanolamines / Q000494:pharmacology* / Q000627:therapeutic use; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*
chemical_list: D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D002227:Carbazoles; D011412:Propanolamines; D019837:Ryanodine Receptor Calcium Release Channel; D000077261:Carvedilol; D008790:Metoprolol; D002118:Calcium; D017298:Bisoprolol