Comparison of pharmacodynamics between carvedilol and metoprolol in rats with isoproterenol-induced cardiac hypertrophy: Effects of carvedilol enantiomers

Hanada, Kazuhiko; Asari, Kazuhiko; Saitō, Masako; Kawana, Junichi; Mita, Mitsuo; Ogata, Hiroyasu

doi:10.1016/j.ejphar.2008.04.055

Cited by 15 publications

(17 citation statements)

References 28 publications

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“…Pre-treating mice with racemic carvedilol (1.6 mg/kg/day) for 5 days significantly reduced the systolic, diastolic and mean blood pressure, whereas pre-treatment with R -carvedilol (1.6 mg/kg/day) for 5 days had no significant effect on any of these blood pressure measurements (only mean blood pressure shown; R -carvedilol: from 98.6 ± 4.5 mmHg to 96.4 ± 3.6 mmHg; compared with DMSO: from 98.4 ± 3.1 mmHg to 95.6 ± 3.0 mmHg; compared with racemic carvedilol: from 100.1 ± 2.6 mmHg to 83.3 ± 2.5 mmHg; Figure 6C). This is consistent with previous reports [35–38]. Taken together, our data indicate that, unlike racemic carvedilol, the non- β -blocking R -carvedilol enantiomer suppresses stress-induced VT without lowering heart rate or blood pressure.…”

Section: Resultssupporting

confidence: 93%

“…Racemic carvedilol is a potent β -blocker that lowers both heart rate and blood pressure [35–38]. Since R -carvedilol has little β -blocking activity, R -carvedilol would be expected to have minimal impact on heart rate or blood pressure.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, unlike S-carvedilol, the R -carvedilol enantiomer does not have β -blocking activity [35–38]. This raises the exciting possibility that, like our novel non- β -blocking carvedilol analogues, the R -carvedilol enantiomer may provide carvedilol’s favourable RyR2-targeted anti-arrhythmic action without the adverse effects of excessive β -blockade.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Zhou

Smith

et al. 2015

Biochemical Journal

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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 Ca2+ 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 Ca2+ release and VT. Like racemic carvedilol, R-carvedilol directly reduces the open duration of the cardiac ryanodine receptor (RyR2), suppresses spontaneous Ca2+ oscillations in human embryonic kidney (HEK) 293 cells, Ca2+ 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 Ca2+-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.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhang

Zhou

Smith

et al. 2015

Biochemical Journal

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“…In rodents with isoproterenol-induced cardiac hypertrophy and heart failure, carvedilol resulted in a greater reduction of heart weight and increase in cAMP than with metoprolol, despite similar reductions in heart rate [26].…”

Section: Sympathetic Activationmentioning

confidence: 88%

Which Beta-Blocker is Most Effective in Heart Failure?

Remme¹

2010

Cardiovasc Drugs Ther

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“…The underlying mechanisms associated with βAR overstimulation have been studied in vivo in heart tissue using isoproterenol (ISO)-treated models and in vitro in cultured cardiomyocytes. This βAR overstimulation represents an important hallmark of pathologic cardiac hypertrophy 15, 20, 21, 22, 23, 24…”

Section: Effect Of Prolonged βAr Stimulation On the Heartmentioning

confidence: 99%

Different effects of prolonged β-adrenergic stimulation on heart and cerebral artery

Shin

Rhee

et al. 2014

Integrative Medicine Research

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The aim of this review was to understand the effects of β-adrenergic stimulation on oxidative stress, structural remodeling, and functional alterations in the heart and cerebral artery. Diverse stimuli activate the sympathetic nervous system, leading to increased levels of catecholamines. Long-term overstimulation of the β-adrenergic receptor (βAR) in response to catecholamines causes cardiovascular diseases, including cardiac hypertrophy, stroke, coronary artery disease, and heart failure. Although catecholamines have identical sites of action in the heart and cerebral artery, the structural and functional modifications differentially activate intracellular signaling cascades. βAR-stimulation can increase oxidative stress in the heart and cerebral artery, but has also been shown to induce different cytoskeletal and functional modifications by modulating various components of the βAR signal transduction pathways. Stimulation of βAR leads to cardiac dysfunction due to an overload of intracellular Ca2+ in cardiomyocytes. However, this stimulation induces vascular dysfunction through disruption of actin cytoskeleton in vascular smooth muscle cells. Many studies have shown that excessive concentrations of catecholamines during stressful conditions can produce coronary spasms or arrhythmias by inducing Ca2+-handling abnormalities and impairing energy production in mitochondria, In this article, we highlight the different fates caused by excessive oxidative stress and disruptions in the cytoskeletal proteome network in the heart and the cerebral artery in responsed to prolonged βAR-stimulation.

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Comparison of pharmacodynamics between carvedilol and metoprolol in rats with isoproterenol-induced cardiac hypertrophy: Effects of carvedilol enantiomers

Cited by 15 publications

References 28 publications

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

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

Which Beta-Blocker is Most Effective in Heart Failure?

Different effects of prolonged β-adrenergic stimulation on heart and cerebral artery

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