Dataset Information

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

ABSTRACT: Carvedilol is the current ?-blocker of choice for suppressing ventricular tachyarrhythmia (VT). However, carvedilol's benefits are dose-limited, attributable to its potent ?-blocking activity that can lead to bradycardia and hypotension. The clinically used carvedilol is a racemic mixture of ?-blocking S-carvedilol and non-?-blocking R-carvedilol. We recently reported that novel non-?-blocking carvedilol analogues are effective in suppressing arrhythmogenic Ca(2+) waves and stress-induced VT without causing bradycardia. Thus, the non-?-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-?-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.

SUBMITTER: Zhang J

PROVIDER: S-EPMC4902270 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

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

The Biochemical journal 20150708 2

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 wit ...[more]

PMID: 26348911

Similar Datasets

Project description:Skin cancer is the most common malignancy worldwide and is rapidly rising in incidence, representing a significant public health challenge. The β-blocker, carvedilol, has shown promising effects in preventing skin cancer. However, as a potent β-blocker, repurposing carvedilol to an anticancer agent is limited by cardiovascular effects. Carvedilol is a racemic mixture consisting of equimolar S- and R-carvedilol, whereas the R-carvedilol enantiomer does not possess β-blocking activity. Because previous studies suggest that carvedilol's cancer preventive activity is independent of β-blockade, we examined the skin cancer preventive activity of R-carvedilol compared with S-carvedilol and the racemic carvedilol. R- and S-carvedilol were equally effective in preventing EGF-induced neoplastic transformation of the mouse epidermal JB6 Cl 41-5a (JB6 P+) cells and displayed similar attenuation of EGF-induced ELK-1 activity. R-carvedilol appeared slightly better than S-carvedilol against UV-induced intracellular oxidative stress and release of prostaglandin E2 from the JB6 P+ cells. In an acute UV-induced skin damage and inflammation mouse model using a single irradiation of 300 mJ/cm2 UV, topical treatment with R-carvedilol dose dependently attenuated skin edema and reduced epidermal thickening, Ki-67 staining, COX-2 protein, and IL6 and IL1β mRNA levels similar to carvedilol. In a chronic UV (50-150 mJ/cm2) induced skin carcinogenesis model in mice with pretreatment of test agents, topical treatment with R-carvedilol, but not racemic carvedilol, significantly delayed and reduced skin squamous cell carcinoma development. Therefore, as an enantiomer present in an FDA-approved agent, R-carvedilol may be a better option for developing a safer and more effective preventive agent for skin carcinogenesis. PREVENTION RELEVANCE: In this study, we demonstrated the skin cancer preventive activity of R-carvedilol, the non-β-blocking enantiomer present in the racemic β-blocker, carvedilol. As R-carvedilol does not have β-blocking activity, such a preventive treatment would not lead to common cardiovascular side effects of β-blockers.

Project description:The study investigates the prognostic role of treatment with carvedilol as compared to metoprolol in patients with ventricular tachyarrhythmias. A large retrospective registry was used including consecutive patients on beta-blocker (BB) treatment with episodes of ventricular tachycardia (VT) or fibrillation (VF) from 2002 to 2015. Patients treated with carvedilol were compared to patients with metoprolol. The primary prognostic outcome was all-cause mortality at three years. Secondary endpoints comprised a composite arrhythmic endpoint (i.e., recurrences of ventricular tachyarrhythmias, appropriate implantable cardioverter defibrillator (ICD) therapies) and cardiac rehospitalization. Kaplan-Meier survival curves, multivariable Cox regression analyses, and propensity score matching were applied for statistics. There were 1098 patients included, 80% treated with metoprolol and 20% with carvedilol. Patients with carvedilol were older, more often presenting with VT (78% vs. 62%; p = 0.001) and with more advanced stages of heart failure. Treatment with carvedilol was associated with comparable all-cause mortality compared to metoprolol (20% vs. 16%, log rank p = 0.234; HR = 1.229; 95% CI 0.874-1.728; p = 0.235). However, secondary endpoints (i.e., composite arrhythmic endpoint: 32% vs. 17%; p = 0.001 and cardiac rehospitalization: 25% vs. 14%; p = 0.001) were more frequently observed in patients with carvedilol, which was still evident after multivariable adjustment. After propensity score matching (n = 194 patients with carvedilol and metoprolol), no further differences regarding the distribution of baseline characteristics were observed. Within the propensity-score-matched cohort, higher rates of the composite arrhythmic endpoint were still observed in patients treated with carvedilol, whereas the risk of cardiac rehospitalization was not affected by the type of beta-blocker treatment. In conclusion, carvedilol and metoprolol are associated with comparable all-cause mortality in patients with ventricular tachyarrhythmias, whereas the risk of the composite arrhythmic endpoint was increased in patients with carvedilol therapy.

Project description:Phospholamban (PLN) is an inhibitor of cardiac sarco(endo)plasmic reticulum Ca²? ATPase. PLN knockout (PLN-KO) enhances sarcoplasmic reticulum Ca²? load and Ca²? leak. Conversely, PLN-KO accelerates Ca²? sequestration and aborts arrhythmogenic spontaneous Ca²? waves (SCWs). An important question is whether these seemingly paradoxical effects of PLN-KO exacerbate or protect against Ca²?-triggered arrhythmias.We investigate the impact of PLN-KO on SCWs, triggered activities, and stress-induced ventricular tachyarrhythmias (VTs) in a mouse model of cardiac ryanodine-receptor (RyR2)-linked catecholaminergic polymorphic VT.We generated a PLN-deficient, RyR2-mutant mouse model (PLN-/-/RyR2-R4496C+/-) by crossbreeding PLN-KO mice with catecholaminergic polymorphic VT-associated RyR2-R4496C mutant mice. Ca²? imaging and patch-clamp recording revealed cell-wide propagating SCWs and triggered activities in RyR2-R4496C+/- ventricular myocytes during sarcoplasmic reticulum Ca²? overload. PLN-KO fragmented these cell-wide SCWs into mini-waves and Ca²? sparks and suppressed the triggered activities evoked by sarcoplasmic reticulum Ca²? overload. Importantly, these effects of PLN-KO were reverted by partially inhibiting sarco(endo)plasmic reticulum Ca²? ATPase with 2,5-di-tert-butylhydroquinone. However, Bay K, caffeine, or Li? failed to convert mini-waves to cell-wide SCWs in PLN-/-/RyR2-R4496C+/- ventricular myocytes. Furthermore, ECG analysis showed that PLN-KO mice are not susceptible to stress-induced VTs. On the contrary, PLN-KO protected RyR2-R4496C mutant mice from stress-induced VTs.Our results demonstrate that despite severe sarcoplasmic reticulum Ca²? leak, PLN-KO suppresses triggered activities and stress-induced VTs in a mouse model of catecholaminergic polymorphic VT. These data suggest that breaking up cell-wide propagating SCWs by enhancing Ca²? sequestration represents an effective approach for suppressing Ca²?-triggered arrhythmias.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets