Carvedilol: Molecular and Cellular Basis for Its Multifaceted Therapeutic Potential

Cheng, Jianhua; Kamiya, Kaichiro; Kodama, Itsuo

doi:10.1111/j.1527-3466.2001.tb00061.x

Cited by 115 publications

(62 citation statements)

References 116 publications

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“…Carvedilol, both the beta blocker (β1, β2) and alpha blocker (α1), is indicated in the management of congestive HF. It is used as an adjunct to conventional treatments with its effect probably mediated through the potent antioxidant and anti-apoptotic activities [42] . The Japanese Diastolic Heart Failure Study has recently suggested the beneficial effects of standard dose prescriptions of carvedilol (> 7.5 mg/d) in HF without affecting …”

Section: Of Mitochondria In the Cardiomyocytesmentioning

confidence: 99%

Mitochondria-targeted agents: Future perspectives of mitochondrial pharmaceutics in cardiovascular diseases

Ajith

Jayakumar

2014

WJC

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Mitochondria are one of the major sites for the generation of reactive oxygen species (ROS) as an undesirable side product of oxidative energy metabolism. Damaged mitochondria can augment the generation of ROS. Dysfunction of mitochondria increase the risk for a large number of human diseases, including cardiovascular diseases (CVDs). Heart failure (HF) following ischemic heart disease, infantile cardiomyopathy and cardiac hypertrophy associated with left ventricular dilations are some of the CVDs in which the role of mitochondrial oxidative stress has been reported. Advances in mitochondrial research during the last decade focused on the preservation of its function in the myocardium, which is vital for the cellular energy production. Experimental and clinical trials have been conducted using mitochondria-targeted molecules like: MnSOD mimetics, such as EUK-8, EUK-134 and MitoSOD; choline esters of glutathione and N -acetyl-L-cysteine; triphenylphosphonium ligated vitamin E, lipoic acid, plastoquinone and mitoCoQ10; and Szeto-Schiller (SS)-peptides (SS-02 and SS-31). Although many results are inconclusive, some of the findings, especially on CoQ10, are worthwhile. This review summarizes the role of mitochondria-targeted delivery of agents and their consequences in the control of HF.

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Section: Of Mitochondria In the Cardiomyocytesmentioning

confidence: 99%

Mitochondria-targeted agents: Future perspectives of mitochondrial pharmaceutics in cardiovascular diseases

Ajith

Jayakumar

2014

WJC

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“…It is a non selective blocker of α1 and β-adrenergic receptors, while displaying vasodilating properties has potent antioxidant and antiapoptotic properties [18,19].…”

Section: Introductionmentioning

confidence: 99%

Animal study of Anthracycline-induced Cardiotoxicity and Nephrotoxicity and Evaluation of Protective Agents

Shafik¹,

Khodeir²,

Fadel³

2011

JCST

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Study background: Anticancer chemotherapy Anthracycline (ANT) antibiotics associated with cardiac and renal toxicity which represents serious complication. In this study, the protective effect of the 2 beta-blockers carvedilol and nebivolol were tested in a rat model of ANT induced cardio and renal-toxicity by repeated intraperitoneal doxorubicin (Dox) administration.Methods: Six groups of animals were used, each 8 rats divided as control group-received intraperitoneal saline every other day; control carvedilol: rats received carvedilol dose 30mg/kg/day orally; control nebivolol: rats received nebivolol 1mg/kg/day orally; doxorubicin alone: a dose of 3 mg/kg/day was administered intraperitoneal every other day; doxorubicin + carvedilol: carvedilol started at the same day with Dox; doxorubicin + nebivolol: nebivolol started at the same day with Dox. All substances were administered for 12 days. Detection & quantification of doxorubicin-induced heart and renal damage and therapeutic action of beta-blockers was done using Langendorff's technique, echo-cardiographic function examinations, serum creatinine, total proteins and histopathology.

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“…16,31,32 Carvedilol also has negative inotropic and chronotropic actions, as well as potent vasodilation, antiischemic, antiapoptotic and antioxidant effects. 33 Given that mechanical stressinduced apoptosis does not explain lamin A/C-related DCM, it seems likely that the hemodynamic and antiapoptotic benefits of exercise and carvedilol are relatively less important than other direct myocardial effects. Antioxidant actions of exercise and carvedilol are of particular interest in view of recent data implicating oxidative stress in heart failure and in other laminopathy phenotypes, including lipodystrophy, premature ageing, and amyotrophic quadricipital syndrome with cardiac involvement.…”

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confidence: 99%

Effects of Mechanical Stress and Carvedilol in Lamin A/C–Deficient Dilated Cardiomyopathy

Chandar¹,

Yeo²,

Leimena³

et al. 2010

Circulation Research

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Rationale: Mutations in the LMNA gene, which encodes the nuclear lamina proteins lamin A and lamin C, are the most common cause of familial dilated cardiomyopathy (DCM). Mechanical stress-induced apoptosis has been proposed as the mechanism underpinning DCM in lamin A/C-deficient hearts, but supporting in vivo evidence has been lacking. Objective: Our aim was to study interventions to modify mechanical stress in heterozygous Lmna knockout (Lmna ؉/؊ ) mice. Methods and Results: Cardiac structure and function were evaluated before and after exercise training, thoracic aortic constriction, and carvedilol treatment. Lmna ؉/؊ mice develop adult-onset DCM with relatively more severe disease in males. Lmna ؉/؊ cardiomyocytes show altered nuclear morphology and perinuclear desmin organization, with enhanced responses to hypo-osmotic stress indicative of cytoskeletal instability. Despite these structural defects that provide a template for mechanical stress-induced damage, young Lmna ؉/؊ mice subjected to 6 weeks of moderate or strenuous exercise training did not show induction of apoptosis or accelerated DCM. In contrast, regular moderate exercise attenuated DCM development in male Lmna ؉/؊ mice. Sustained pressure overload generated by thoracic aortic constriction depressed ventricular contraction in young wild-type and Lmna ؉/؊ mice with no sex or genotype differences in the time-course or severity of response. Treatment of male Lmna ؉/؊ mice from 12 to 40 weeks with the ␤-blocker, carvedilol, prevented the dilatation and contractile dysfunction that was observed in placebo-treated mice. Conclusions: These data suggest that factors other than mechanical stress-induced apoptosis contribute to DCM and provide the first demonstration that regular moderate exercise and carvedilol can modify disease progression in lamin A/C-deficient hearts. (Circ Res. 2010;106:573-582.)Key Words: familial dilated cardiomyopathy Ⅲ lamin A/C Ⅲ mechanical stress Ⅲ exercise Ⅲ carvedilol M utations in the LMNA gene that encodes the nuclear lamina proteins lamin A and lamin C are the most common cause of familial dilated cardiomyopathy (DCM) identified to date, 1 accounting for 5% to 10% familial DCM overall and 30% to 45% families with DCM and conduction system disease (CD). [2][3][4][5] Affected individuals frequently have a rapidly progressive downhill clinical course, requiring pacemaker implantation or heart transplantation, with an increased risk of sudden death. [2][3][4][5] Despite the clinical importance of LMNA mutations, very little is known about mechanisms of disease pathogenesis and strategies to prevent DCM have not been investigated.Because one-third of DCM-causing LMNA mutations are stop codons, splice site variants or insertions/deletions that reduce lamin A/C protein levels, 1,5 Lmna knockout mice are a useful and clinically relevant model to study DCM mechanisms. 6 We have previously reported that homozygous Lmna knockout (Lmna Ϫ/Ϫ ) mice exhibit severe DCM by 4 to 6 weeks. 7 Heterozygous Lmna knockout (Lmna ϩ/Ϫ ) mice show ...

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Carvedilol: Molecular and Cellular Basis for Its Multifaceted Therapeutic Potential

Cited by 115 publications

References 116 publications

Mitochondria-targeted agents: Future perspectives of mitochondrial pharmaceutics in cardiovascular diseases

Mitochondria-targeted agents: Future perspectives of mitochondrial pharmaceutics in cardiovascular diseases

Animal study of Anthracycline-induced Cardiotoxicity and Nephrotoxicity and Evaluation of Protective Agents

Effects of Mechanical Stress and Carvedilol in Lamin A/C–Deficient Dilated Cardiomyopathy

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