Importance of antioxidant and antiapoptotic effects of β-receptor blockers in heart failure therapy

Kawai, Keisuke; Qin, Fuzhong; Shite, Junya; Mao, Weike; Fukuoka, Shuji; Liang, Chang‐seng

doi:10.1152/ajpheart.00797.2003

Cited by 63 publications

(44 citation statements)

References 49 publications

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“…Ventricular tachypacing has been shown to increase proinflammatory cytokines, including TNF-␣ and IL-1␣, which leads to the generation of reactive oxygen species (ROS) in mitochondria and early impairment in mitochondrial function (25,34). In addition to free radical-induced damage in myocardium of paced animals, as evidenced by markedly increased levels of left ventricular tissue aldehyde levels (21), a decreased GSH/GSSG ratio and increased level of oxidation products of mitochondrial DNA (19), ROS could act as molecular intermediates in the translation of electrical/mechanical stimuli to a cellular response. These effects could be mediated by activation of different ROS-sensitive signal transduction pathways, including MAPK, JAK-STAT, and TGF-␤ signaling pathways (13,16), all of which were found to have an increased transcriptional activity in the present study (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The activation of these signaling pathways early in the course of the disease provides a rationale for early pharmacological interventions aimed at blocking these cell signaling cascades. It is tempting to speculate that the im- proved clinical outcomes, observed after early treatment with beta-blockers or ACE inhibitors might not only be related to modulation of neurohumoral blockade but also to significant antioxidant and antiapoptotic effects of these drugs (19).…”

Section: Discussionmentioning

confidence: 99%

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Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling

Zhong

Barth

DiSilvestre

et al. 2008

Physiological Genomics

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Gao Z, Barth AS, DiSilvestre D, Akar FG, Tian Y, Tanskanen A, Kass DA, Winslow RL, Tomaselli GF. Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling. Physiol Genomics 35: 222-230, 2008. First published September 9, 2008 doi:10.1152/physiolgenomics.00100.2007.-Heart failure (HF) is the leading cause of morbidity and mortality in the industrialized world. While the transcriptomic changes in end-stage failing myocardium have received much attention, no information is available on the gene expression patterns associated with the development of HF in large mammals. Therefore, we used a well-controlled canine model of tachycardia-induced HF to examine global gene expression in left ventricular myocardium with Affymetrix canine oligonucleotide arrays at various stages after initiation of rapid ventricular pacing (days 3, 7, 14, and 21). The gene expression data were complemented with measurements of action potential duration, conduction velocity, and left ventricular end diastolic pressure, and dP/dt(max) over the time course of rapid ventricular pacing. As a result, we present a phenotypecentered gene association network, defining molecular systems that correspond temporally to hemodynamic and electrical remodeling processes. Gene Ontology analysis revealed an orchestrated regulation of oxidative phosphorylation, ATP synthesis, cell signaling pathways, and extracellular matrix components, which occurred as early as 3 days after the initiation of ventricular pacing, coinciding with the early decline in left ventricular pump function and prolongation of action potential duration. The development of clinically overt left ventricular dysfunction was associated with few additional changes in the myocardial transcriptome. We conclude that the majority of tachypacing-induced transcriptional changes occur early after initiation of rapid ventricular pacing. As the transition to overt HF is characterized by few additional transcriptional changes, posttranscriptional modifications may be more critical in regulating myocardial structure and function during later stages of HF. transcriptional remodeling; microarray; oxidative phosphorylation; action potential HEART FAILURE (HF) is the leading cause of morbidity and mortality in the industrialized world, with an estimated 5 million HF patients in the United States alone (5). Virtually any form of cardiovascular disease may culminate in HF, a final common pathway to mortality, through maladaptive left ventricular remodeling, which may begin before clinical symptoms become apparent (14, 29). Hence, early diagnosis of asymptomatic left ventricular dysfunction and timely intervention are critical to slowing or arresting the development of HF. While the clinical symptoms of decompensated HF are well described, it is difficult, if not impossible, for a physician to make a diagnosis when left ventricular dysfunction is in its earliest stages. Limited understanding of the molecular systems underlying ventricular dysfunction an...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling

Zhong

Barth

DiSilvestre

et al. 2008

Physiological Genomics

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“…35) Further studies are needed to clarify whether the optimal dose of carvedilol in Japanese patients with the CYP2D6*10 allele is different from that in Japanese and/or Caucasian extensive metabolizers.…”

Section: Discussionmentioning

confidence: 99%

Multiple Regression Analysis of Pharmacogenetic Variability of Carvedilol Disposition in 54 Healthy Japanese Volunteers

Honda

Ogura

Toyoda

et al. 2006

Biological & Pharmaceutical Bulletin

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Carvedilol is a b-adrenoceptor antagonist used clinically to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias.1-4) Carvedilol is highly lipophilic and eliminated predominantly by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose.5) The drug is absorbed rapidly from the gastrointestinal tract after oral administration; however, the amount of unchanged drug excreted in the feces was 23% of the administered dose probably because of incomplete intestinal absorption.6) In addition, orally administered carvedilol undergoes stereoselective first-pass metabolism, and the maximal plasma concentration of R-enantiomer with low bblocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity.6) The mean absolute bioavailability of R-and S-enantiomer in humans is 31% and 15%, respectively. 7)In the previous study, we investigated the effect of genetic polymorphisms of cytochrome P450 (CYP) 2D6 on the pharmacokinetics of R-and S-carvedilol in 23 healthy Japanese volunteers.8) The large interindividual variability was observed in the pharmacokinetics of carvedilol, and the coefficient of variation of the weight (WT)-corrected oral clearance ((CL/F)/ WT) value among the subjects was 36.1%. In addition, the (CL/F)/WT value was highly correlated with the apparent distribution volume ((V/F)/WT) value among the subjects, suggesting that the interindividual difference in bioavailability (F) was at least partly responsible for the pharmacokinetic variability of carvedilol. The (CL/F)/WT and (V/F)/WT values of R-and S-carvedilol were significantly lower in healthy volunteers with at least one CYP2D6*10 allele than those with the CYP2D6*1/*1 and *1/*2 genotype. The result suggested that the systemic and/or pre-systemic metabolism of R-and S-carvedilol in the liver is significantly decreased in Japanese subjects with the CYP2D6*10 allele.Carvedilol is metabolized extensively via aliphatic sidechain oxidation and conjugation pathways, as well as the aromatic ring oxidation pathway which is mediated mainly by CYP2D6. 6) Oldham et al. reported that considerable metabolic activity for carvedilol is observed in CYP1A2, 2C9, 2D6, and 3A4. 9) On the other hand, it is still unclear whether the other P450s are involved in the metabolism of carvedilol. However, a substrate of CYP2C9, such as phenytoin, is partly catalyzed by another CYP2C subfamily, CYP2C19. 10)CYP3A5 is another important CYP3A protein in the liver, the substrate specificity of which largely overlaps with that of CYP3A4.11) In addition, Ohno et al. reported that UDP-glucuronosyltransferase (UGT) 1A1, 2B4, and 2B7 as well as human hepatic microsomes are capable of catalyzing the glucuronidation of carvedilol.12) Moreover, carvedilol has high affinity for the multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp). Giessmann et al. reported that the intestinal expression of P-gp is a major variable in the disposition of carvedilol. 13)In the presen...

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“…Adriamycin (1 mg/kg, twice weekly) was intravenously administered via a marginal ear vein for 8 weeks. In the CHF group treated with carvedilol, the rabbits received low-dose carvedilol (0.25 mg/kg, twice daily) orally for 8 weeks at the same time [11] . In both of the groups, the last administration of adriamycin or carvedilol was given 48 h before the experiment.…”

Section: Methodsmentioning

confidence: 99%

Low-dose carvedilol reduces transmural heterogeneity of ventricular repolarization in congestive heart failure

Zhong

Chen

Meiling

et al. 2007

Acta Pharmacologica Sinica

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Aim: To study the effects of carvedilol on the transmural heterogeneity of ventricular repolarization in rabbits with congestive heart failure (CHF). Methods: Rabbits were randomly divided into 3 groups: control, CHF and carvedilol treated CHF group. Monophasic action potential duration (MAPD) in the 3 myocardial layers was simultaneously recorded. Results: All the rabbits in the CHF group had signs of severe CHF. Compared with the control group, the mean blood pressure and cardiac output were significantly decreased, while peripheral resistance was significantly increased in the CHF group. This proved that the CHF model was successful created with adriamycin in this study. Compared to the control group, the ventricular fibrillation threshold (VFT) was remarkably decreased and all MAPD of the 3 myocardial layers were extended in rabbits with CHF. However, the extension of MAPD in the midmyocardium was more obvious. The transmural dispersion of repolarization (TDR) was significantly increased in CHF. Low-dose carvedilol (0.25 mg/kg, twice daily) had no effects on ventricular remodeling. Treatment with low-dose carvedilol significantly increased VFT. Although the MAPD of the 3 myocardial layers were further prolonged in the carvedilol treated CHF group, the prolongation of MAPD in the midmyocardium was shorter than those in the epicardium and endocardium. Treatment with low-dose carvedilol significantly decreased TDR in CHF. Conclusion: In the present study, the transmural heterogeneity of ventricular repolarization increased in the rabbits with CHF. Low-dose carvedilol decreased the transmural heterogeneity of ventricular repolarization in CHF, which may be related to its direct electrophysiological property rather than its effect on ventricular remodeling.

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Importance of antioxidant and antiapoptotic effects of β-receptor blockers in heart failure therapy

Cited by 63 publications

References 49 publications

Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling

Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling

Multiple Regression Analysis of Pharmacogenetic Variability of Carvedilol Disposition in 54 Healthy Japanese Volunteers

Low-dose carvedilol reduces transmural heterogeneity of ventricular repolarization in congestive heart failure

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