Effects Of Carvedilol Research Articles

Comparative effects of nebivolol and carvedilol on left ventricular diastolic function in older heart failure patients with preserved ejection fraction: study protocol for a randomized controlled trial

BackgroundHeart failure (HF) is a common and disabling condition in older people. Randomized clinical trials and meta-analyses have clearly demonstrated that the long-term use of β-Blockers improves the outcome of patients with HF. However, limited data are available on the treatment of older HF patients with preserved ejection fraction (EF). No study has specifically compared the relative effectiveness of carvedilol and nebivolol in treating HF in older patients with preserved EF.Method/designThis trial is a prospective, randomized, open-label, single-centre, active controlled study designed to investigate the effects of nebivolol and carvedilol on diastolic function of the left ventricle (LV) in older HF patients with preserved EF.We will test the hypothesis that nebivolol improves LV diastolic function to a greater extent than carvedilol in patients over 70 years of age. The study population includes 62 older patients newly diagnosed with HF. Patients will be included in the study if they have a LVEF ≥40 %, New York Heart Association (NYHA) functional classes I, II or III status, and have been clinically stable without hospital admission for HF in the preceding 3 months. Eligible patients will be randomly assigned, in a 1:1 ratio, to receive a loading and maintenance dose of either nebivolol or carvedilol. Echocardiographic evaluations will be performed at baseline, 6, and 12 months after therapy. Clinical assessment and laboratory tests are to be performed at fixed times.DiscussionThis trial is a single-center study that aims to evaluate the impact of nebivolol on LV diastolic function. The results of the study will provide information about the optimal choice of a β-Blocker in the management of patients after diagnosis of HF with preserved EF. The results will be available by 2017.Trial registrationClinicalTrials.gov Identifier: NCT02619526, registered on 25 November 2015.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1656-y) contains supplementary material, which is available to authorized users.

The Effects of Carvedilol on Cardiac Function and the AKT/XIAP Signaling Pathway in Diabetic Cardiomyopathy Rats

Objectives: Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction, myocardial inflammation, interstitial fibrosis and cardiomyocytes apoptosis. The present study aimed to investigate the effects of carvedilol on cardiac function and the AKT/XIAP signaling pathway in DCM rats. Methods: Male Wistar rats were randomly divided into 3 groups: the control group, diabetic mellitus (DM) group and DM with carvedilol treatment group. DM rats were induced by streptozotocin accompanied by high energy intake. Carvedilol was orally administered at a dose of 10 mg/kg/day. After 16 weeks, the interrelated blood data were detected by biochemical analysis. Cardiac function was evaluated by echocardiography and the serum NT-proBNP level. The changes of myocardium ultrastructural and fibrosis were determined by electron microscopy and Masson's staining. Apoptotic cells were examined by TUNEL staining and interrelated proteins were measured by immunohistochemical and Western blots. Results: Rats in the DM group showed significant serum elevation of glucose, cholesterol, triglyceride, NT-proBNP, IL-1β and TNF-α, along with decreased cardiac function. Moreover, in the DM group, the levels of myocardial apoptosis and fibrosis were all increased accompanied by upregulation of caspase-3 and downregulation of phos-AKT and phos-XIAP, whereas carvedilol treatment prevented or reversed all the changes without influencing plasma levels of glucose, cholesterol and triglyceride. Conclusions: The AKT/XIAP signaling pathway may be involved in DCM. Carvedilol can improve cardiac function, possibly not only by upregulating the AKT/XIAP antiapoptotic signaling pathway and subsequently attenuating myocardial fibrosis, but also through suppressing the myocardial inflammation response.

Carvedilol suppresses cartilage matrix destruction

Collagen type Ⅱ (col Ⅱ) and aggrecan, the main components of the extracellular matrix (ECM) in human joint cartilage, have been reported to be reduced by chronic production of inflammatory cytokine interleukin (IL)-1β in arthritic joints. Carvedilol, a licensed medicine, has been used for treatment of hypertension, congestive heart failure and coronary disease in clinics. In this study, we investigated the effects of Carvedilol on the expression of col Ⅱ and aggrecan. Our results demonstrate that treatment with Carvedilol didn't change the expression of aggrecan or col Ⅱ at mRNA levels in SW1353 chondrocytes. However, the expression of aggrecan and Col II at protein levels were significantly reduced by IL-1β treatment, which were reversed by Carvedilol in a dose dependent manner, suggesting the inhibitory effects of Carvedilol on the expression of aggrecan and Col II are at post-translational modification levels. In addition, it was shown that IL-1β treatment highly induced MMP-1 and MMP-13 expression in SW1353 chondrocytes at both gene and protein expression levels, which were restored by Carvedilol in a dose dependent manner. Mechanistically, exposure to IL-1β increased phosphorylation of IKK-α/β and degradation of IκB-α in SW1353 chondrocytes, which were suppressed by pretreatment with Carvedilol. Administration of Carvedilol inhibited IL-1β-induced translocation of NF-κB p65 from cytosol to nucleus manner. Notably, a luciferase reporter assay showed that IL-1β severely increased NF-κB luciferase activity, which was markedly suppressed by Carvedilol treatment. Our results suggest that Carvedilol might be a potential therapeutic agent for chondro-protective therapy.

Carvedilol suppresses circulating and hepatic IL-6 responsible for hepatocarcinogenesis of chronically damaged liver in rats

Carvedilol is an anti-oxidant non-selective β-blocker used for reduction of portal blood pressure, prophylaxis of esophageal varices development and bleeding in chronic liver diseases. Recently, it exhibited potent anti-inflammatory, anti-fibrotic, anti-proliferative and anti-carcinogenic effects. In the present study, we evaluated the possible suppressive effect of carvedilol on circulating and hepatic IL-6 levels responsible for hepatocarcinogenesis in a rat model of hepatic cirrhosis. Besides, its effect on hepatic STAT-3 levels, function tests, oxidative stress markers, and hydroxyproline content, hepatic tissue histopathological changes and immunohistochemical expression of E & N-cadherin. Nine-week-old male Wistar rats injected intraperitoneal by 1ml/kg 10% CCL4 in olive oil three times/week (every other day) for 12weeks to induce hepatic cirrhosis. Carvedilol (10mg/kg/day suspended in 0.5% CMC orally), silymarin (50mg/kg/day suspended in 0.5% CMC orally) or combination of both used to treat hepatic cirrhosis from 15th to 84th day. Our data showed that carvedilol and silymarin co-treatment each alone or in combination efficiently reduced the elevated serum IL-6, ALT, AST, ALP and BIL, hepatic IL-6, STAT-3, MDA levels and hydroxyproline content. In addition, it elevated the reduced serum ALB level, hepatic CAT activity and GSH level. Meanwhile, it apparently restored the normal hepatic architecture, collagen distribution and immunohistochemical E & N-cadherin expression. Furthermore, carvedilol was superior to silymarin in improving MDA level. Moreover, the combination of carvedilol and silymarin showed an upper hand in amelioration of the CCL4 induced hepatotoxicity than each alone. Therefore, carvedilol could be promising in prevention of hepatocarcinogenesis in chronic hepatic injuries.

Suppressive Effect of Carvedilol on Na+/Ca2+ Exchange Current in Isolated Guinea-Pig Cardiac Ventricular Myocytes

Background and Aims: Carvedilol ((+/-)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol), a β-adrenoceptor-blocker, has multi-channel blocking and vasodilator properties. This agent dose-dependently improves left ventricular function and reduces mortality in patients with arrhythmia and chronic heart failure. However, the effect of carvedilol on the cardiac Na⁺/Ca²⁺ exchanger (NCX1) has not been investigated. Methods and Results: We examined the effects of carvedilol and metoprolol, 2 β-blockers, on Na⁺/Ca²⁺ exchange current (I_NCX) in guinea-pig cardiac ventricular cells and fibroblasts expressing dog cardiac NCX1. Carvedilol suppressed I_NCX in a concentration-dependent manner but metoprolol did not. IC₅₀ values for the Ca²⁺ influx (outward) and efflux (inward) components of I_NCX were 69.7 and 61.5 µmol/l, respectively. Carvedilol at 100 μmol/l inhibited I_NCX in CCL39 cells expressing wild type NCX1 similar to mutant NCX1 without the intracellular regulatory loop. Carvedilol at 30 µmol/l abolished ouabain-induced delayed afterdepolarizations. Conclusion: Carvedilol inhibited cardiac NCX in a concentration-dependent manner in isolated cardiac ventricles, but metoprolol did not. We conclude that carvedilol inhibits NCX1 at supratherapeutic concentrations.

Carvedilol alleviates testicular and spermatological damage induced by cisplatin in rats via modulation of oxidative stress and inflammation.

The clinical application of the anticancer drug cisplatin is limited by its deleterious side effects, including male reproductive toxicity. In this context, the potential protective effect of carvedilol on testicular and spermatological damage induced by cisplatin in male Sprague-Dawley rats was investigated. Carvedilol was orally administered at a dose of 10mg/kg for 2weeks, and cisplatin was given as a single intraperitoneal injection of 10mg/kg on the 12th day to induce toxicity. Cisplatin significantly reduced reproductive organ weight, sperm count and sperm motility, and increased sperm abnormalities and histopathological damage of testicular tissue. In addition, it resulted in a significant decline in serum testosterone as well as levels of testicular enzymatic and non-enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxides, and reduced glutathione). Moreover, cisplatin remarkably augmented malondialdehyde, nitric oxide, tumor necrosis factor-α, and nuclear factor-kappa B contents in testicular tissue. Conversely, carvedilol administration markedly mitigated cisplatin-induced testicular and spermatological injury as demonstrated by suppression of oxidative/nitrosative and inflammatory burden, amendment of antioxidant defenses, enhancement of steroidogenesis and spermatogenesis, and mitigation of testicular histopathological damage. The current study reveals a promising protective action of carvedilol against cisplatin-induced reproductive toxicity by virtue of its anti-inflammatory and antioxidant properties.

Effects of carvedilol on ventricular remodeling and the expression of β3-adrenergic receptor in a diabetic rat model subjected myocardial infarction

BackgroundThis study was to assess effects of carvedilol on ventricular remodeling and expression of β3-adrenergic receptor (β3-AR) and Gi protein in a rat model of diabetes subjected to myocardial infarction (MI). MethodsRat model of type II diabetes was established by injection of streptozotion. MI was then induced by ligating the left anterior descending coronary artery. Rats were then randomly divided into two groups treated with either placebo (PL) or carvedilol (CA - 10mg·kg−1·d−1). Additional controls consisted of sham-operated rats with diabetes (DS) and rats fed a normal diet subjected to myocardial infarction (NM). Echocardiographic and hemodynamic studies were performed to assess the structural and functional changes. β3-AR and Gi mRNA in the myocardium distal from the infarction region were measured, and β3-AR and Gi protein were measured with western blot. ResultsThere were no significant differences in MI size among the three MI groups. In the PL group, LVEDd, LVWI, E/A and CVF were significantly increased, while LVEF and PW% significantly decreased as compared with the DS and NM groups. Compared with the DS group, the expression of β3-AR and Gi mRNA and protein in the PL group was significantly increased, however, in the CA group, β3-AR and Gi mRNA and protein were decreased. ConclusionsThe expression of β3-AR and Gi mRNA and protein was increased in diabetic rats subjected to MI as compared with rats subject to either condition alone. Carvedilol treatment prevented many of these deleterious effects.

Abstract 2617: Protective effect of the β-blocker carvedilol on UVB-induced skin damage

Abstract The response to ultraviolet (UV) radiation is the primary etiologic factor leading to carcinogenesis of the skin. The effects of UV radiation on the skin is generally transient, but the long term consequences can be carcinogenic. Despite growing public awareness and the use of sunscreen to prevent skin cancer, the incidence continues to rise, and therefore there is a need to develop innovative chemoprevention strategies. Previously, we showed that the receptor subtype nonselective β-adrenergic receptor antagonist (i.e., β-blocker) carvedilol prevented EGF and UVB-mediated neoplastic transformation of the mouse epidermal cell line JB6 P+, indicating its chemopreventive potential against skin cancer. To demonstrate the in vivo effects of carvedilol, in the present study, hairless SKH-1 mice were irradiated for two weeks with 200 mJ/cm2 of UVB and drugs were topically applied immediately after the radiation. Since carvedilol is able to absorb UV, its analogue 4-hydroxycarbazole, which has the same UVB absorption profiling as carvedilol but does not function as a β-blocker, was included as a sunscreen control. Significant skin thickening measured by bi-fold skin thickness on the dorsal skin was observable within a week and over the course of the two-week period. Treatment with carvedilol, but not the analogue, reduced UVB-induced skin hyperplasia, reddening and inflammation. Furthermore, carvedilol, but not the analogue, reduced H2O2 and UVB- induced cytotoxicity and reactive oxygen species production in JB6 P+ cells. To elucidate the molecular mechanism(s) for carvedilol's chemopreventive activity, the signaling profile for JB6 P+ cells treated with EGF and/or carvedilol for 15 min was examined using a Phospho Explorer Antibody Microarray containing 1318 site and phosphor-specific antibodies from over 30 signaling pathways. The antibody array data suggested that the phosphorylation of the intracellular signaling pathways involved in skin carcinogenesis, AP-1 and NF-kB, were increased by EGF but attenuated by carvedilol. These results were validated using luciferase reporter assays. The array data also suggested that carvedilol was able to induce the expression of tumor suppressors p53 and PTEN. In addition, the checkpoint kinases CHK1 and CHK2 and other cell-cycle regulators such as cyclins were also upregulated by carvedilol, suggesting a role in carvedilol's protective effect. Since highly abundant mutations are observable in sun-exposed skin, our current work is to examine the effects of carvedilol on the production of cyclo-pyrimidine dimers (CPDs) induced by UVB. In conclusion, our study has demonstrated novel mechanisms underlying carvedilol's chemopreventive activity against skin cancer. Since carvedilol and other β-blockers are FDA approved drugs and relatively safe, they may offer a new approach of prevention for UVB-induced skin cancer. Citation Format: Kevin M. Huang, Kristan H. Cleveland, Steven Yeung, Bradley T. Andresen, Ying Huang. Protective effect of the β-blocker carvedilol on UVB-induced skin damage. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2617.

Pharmacological interventions for treating heart failure in patients with Chagas cardiomyopathy.

Chagas disease-related cardiomyopathy is a major cause of morbidity and mortality in Latin America. Despite the substantial burden to the healthcare system, there is uncertainty regarding the efficacy and safety of pharmacological interventions for treating heart failure in people with Chagas disease. This is an update of a Cochrane review published in 2012. To assess the clinical benefits and harms of current pharmacological interventions for treating heart failure in people with Chagas cardiomyopathy. We updated the searches in the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2016, Issue 1), MEDLINE (Ovid; 1946 to to February Week 1 2016), EMBASE (Ovid; 1947 to 2016 Week 07), LILACS (1982 to 15 February 2016), and Web of Science (Thomson Reuters; 1970 to 15 February 2016). We checked the reference lists of included papers. We applied no language restrictions. We included randomised clinical trials (RCTs) that assessed the effects of pharmacological interventions to treat heart failure in adult patients (18 years or older) with symptomatic heart failure (New York Heart Association classes II to IV), regardless of the left ventricular ejection fraction stage (reduced or preserved), with Chagas cardiomyopathy. We did not apply limits to the length of follow-up. Primary outcomes were all-cause mortality, cardiovascular mortality at 30 days, time-to-heart decompensation, disease-free period (at 30, 60, and 90 days), and adverse events. Two authors independently performed study selection, 'Risk of bias' assessment and data extraction. We estimated relative risk (RR) and 95% confidence intervals (CIs) for dichotomous outcomes. We measured statistical heterogeneity using the I² statistic. We used a fixed-effect model to synthesize the findings. We contacted authors for additional data. We developed 'Summary of findings' (SoF) tables and used GRADE methodology to assess the quality of the evidence. In this update, we identified one new trial. Therefore, this version includes three trials (108 participants). Two trials compared carvedilol against placebo and another assessed rosuvastatin versus placebo. All trials had a high risk of bias.Meta-analysis of two trials showed a lower proportion of all-cause mortality in the carvedilol groups compared with the placebo groups (RR 0.69; 95% CI 0.12 to 3.88, I² = 0%; 69 participants; very low-quality evidence). Neither of the trials reported on cardiovascular mortality, time-to-heart decompensation, or disease-free periods.One trial (30 participants) found no difference in hospital readmissions (RR 1.00; 95% CI 0.31 to 3.28; very low-quality of evidence) or reported adverse events (RR 0.92; 95% CI 0.67 to 1.27; very low-quality of evidence) between the carvedilol and placebo groups.There was very low-quality evidence from two trials of inconclusive effects on quality of life (QoL) between the carvedilol and placebo groups. One trial (30 participants) assessed QoL with the Minnesota Living With Heart Failure Questionnaire (21 items; item scores range from 0 to 5; a lower MLHFQ score is better). The MD was -14.74; 95% CI -24.75 to -4.73. The other trial (39 participants) measured QoL with the Medical Outcomes Study 36-item short-form health survey (SF-36; item scores range from 0 to 100; higher SF-36 score is better). Data were not provided.One trial (39 participants) assessed the effect of rosuvastatin versus placebo. The trial did not report on any primary outcomes or adverse events. There was very low-quality evidence of uncertain effects on QoL (no data were provided). This first update of our review found very low-quality evidence for the effects of either carvedilol or rosuvastatin, compared with placebo, for treating heart failure in people with Chagas disease. The three included trials were underpowered and had a high risk of bias. There were no conclusive data to support or reject the use of either carvedilol or rosuvastatin for treating Chagas cardiomyopathy. Unless randomised clinical trials provide evidence of a treatment effect, and the trade-off between potential benefits and harms is established, policy-makers, clinicians, and academics should be cautious when recommending or administering either carvedilol or rosuvastatin to treat heart failure in people with Chagas disease. The efficacy and safety of other pharmacological interventions for treating heart failure in people with Chagas disease remains unknown.

Effects of Carvedilol Compared to Nebivolol on Insulin Resistance and Lipid Profile in Patients With Essential Hypertension.

Beta-blockers have unfavorable effects on metabolic parameters in hypertensive treatment. New generation beta-blockers with vasodilatory capabilities are superior to traditional beta-blockers, but studies examining their effects on metabolic parameters are still lacking. This study aimed to compare the effects of 2 new generation beta-blockers, carvedilol and nebivolol, on insulin resistance (IR) and lipid profiles in patients with essential hypertension. This was a prospective, randomized, open-label, single-center clinical trial. A total of 80 patients were randomized into 2 groups: the carvedilol group (n = 40, 25 mg of carvedilol daily) and the nebivolol group (n = 40, 5 mg of nebivolol daily). Follow-up was performed for 4 months. Fasting plasma glucose, insulin levels, and the lipid profile (high-density lipoprotein [HDL], low-density lipoprotein [LDL], total cholesterol, triglyceride, apolipoprotein AI, and apolipoprotein B levels) were measured and IR was calculated by the homeostasis model assessment (HOMA) index. These variables were compared before and 4 months after treatment. Blood pressure and heart rate were significantly and similarly reduced in the carvedilol and nebivolol groups after treatment compared to those before treatment (both P < .001). Serum glucose ( P < .001), insulin ( P < .01), HOMA-IR (P < .01), HDL ( P < .001), LDL ( P < .001), total cholesterol ( P < .001), and apolipoprotein B ( P < .05) levels decreased in a similar manner in the carvedilol and nebivolol groups after treatment compared to those before treatment. Serum triglyceride and apolipoprotein AI levels did not change after treatment with both drugs. New generation beta-blockers, carvedilol and nebivolol, efficiently and similarly decrease blood pressure. They have similar favorable effects on glucose, insulin, IR, and the lipid profile.

Carvedilol-responsive microRNAs, miR-199a-3p and -214 protect cardiomyocytes from simulated ischemia-reperfusion injury.

The nonselective β-adrenergic receptor antagonist (β-blocker) carvedilol has been shown to protect against myocardial injury, but the detailed underlying mechanisms are unclear. We recently reported that carvedilol stimulates the processing of microRNA (miR)-199a-3p and miR-214 in the heart via β-arrestin1-biased β1-adrenergic receptor (β1AR) cardioprotective signaling. Here, we investigate whether these β-arrestin1/β1AR-responsive miRs mediate the beneficial effects of carvedilol against simulated ischemia/reperfusion (sI/R). Using cultured cardiomyocyte cell lines and primary cardiomyocytes, we demonstrate that carvedilol upregulates miR-199a-3p and miR-214 in both ventricular and atrial cardiomyocytes subjected to sI/R. Overexpression of the two miRs in cardiomyocytes mimics the effects of carvedilol to activate p-AKT survival signaling and the expression of a downstream pluripotency marker Sox2 in response to sI/R. Moreover, carvedilol-mediated p-AKT activation is abolished by knockdown of either miR-199a-3p or miR-214. Along with previous studies to directly link the cardioprotective actions of carvedilol to upregulation of p-AKT/stem cell markers, our findings suggest that the protective roles of carvedilol during ischemic injury are in part attributed to activation of these two protective miRs. Loss of function of miR-199a-3p and miR-214 also increases cardiomyocyte apoptosis after sI/R. Mechanistically, we demonstrate that miR-199a-3p and miR-214 repress the predictive or known apoptotic target genes ddit4 and ing4, respectively, in cardiomyocytes. These findings suggest pivotal roles for miR-199a-3p and miR-214 as regulators of cardiomyocyte survival and contributors to the functional benefits of carvedilol therapy.

Clinical effects of carvedilol and trimetazidine for the treatmentof alcoholic myocardiopathy.

The aim of the study was to compare the clinical effects of carvedilol and trimetazidine for the treatment of alcoholic cardiomyopathy. A total of 60 patients diagnosed with alcoholic cardiomyopathy were enrolled in the study. The patients were randomly divided into the carvedilol (n=20), trimetazidine (n=20) and control (n=20) groups. The patients in the control, carvedilol and trimetazidine groups were treated with conventional drugs, conventional drugs + carvedil and conventional drugs + trimetazidine respectively, for 12 weeks. The patients were compared for their heart functions [left ventricular ejection fraction (LVEF), C-reactive protein (CRP) and 6 min walking], heart rate, blood pressure and heart enlargement (cardiothoracic proportion and left ventricular diameter) before and after treatment. The parameters studied for heart functions, heart rate, blood pressure, heart enlargement, clinical effects before and after treatment were statistically insignificant (p>0.05). After treatment, the carvedilol and trimetazidine groups showed higher LVEF and CRP, longer walking distance in 6 min, as well as lower heart rate and blood pressure (both systolic and diastolic) compared to the control group. Similarly, the cardiothoracic proportion and left ventricular internal diameter for the carvedilol and trimetazidine groups was lower than those of the control group, with better clinical effects (p<0.05). In conclusion, the curative effects of the carvedilol and trimetazidine groups of alcoholic myocardiopathy similar. Both are safe agents that may improve the cardiac function and heart expansion of patients.

Effects of carvedilol on an ischemia/reperfusion model: Biochemical, histopathological and immunohistochemical evaluation.

The aim of this study was to investigate the effects of carvedilol (CVD) on experimentally induced ovarian ischemia/reperfusion (I/R) injury in rats. An ovarian I/R model was applied to rats, classified into three groups: 1 (n = 7), sham operated (control); 2 (n = 7), 3 h ischemia + 3 h reperfusion (I/R); 3 (n = 7), 3 h ischemia + CVD + 3 h reperfusion (I/R + CVD). Malondialdehyde (MDA) levels and glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities in ovarian tissues and serum were measured. Tissue damage was examined histopathologically; Bax and caspase-3 expression was determined immunhistochemically. Terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL) assay was performed to show apoptotic cell death. MDA levels in ovarian tissues were significantly increased in the I/R group compared with the control. CVD administration significantly decreased tissue MDA levels in the I/R + CVD in comparison with the I/R group. GSH-Px activities in serum were higher in the I/R + CVD than in the I/R group. SOD activities in tissue and serum were significantly decreased in the I/R compared with the control group. Histological examination showed a significant improvement in ovarian morphology in the I/R + CVD compared with the I/R group. Bax and caspase-3 protein was more strongly expressed in the I/R group compared with the control and I/R + CVD groups. Apoptotic index detected by TUNEL assay was significantly increased in the I/R and decreased in the I/R + CVD group. Our results suggest that CVD reduces the deleterious effects of oxidative damage on ovaries in a rat I/R model.

Carvedilol for portal hypertension in cirrhosis: systematic review with meta-analysis

ObjectiveTo assess the clinical and haemodynamic effects of carvedilol for patients with cirrhosis and portal hypertension.DesignA systematic review and meta-analysis.Data sourcesWe searched PubMed, Cochrane library databases, EMBASE and the Science...

Blocking effect of carvedilol, a beta‐blocker on Na+/Ca2+ exchange current in isolated cardiac ventricular cells of guinea pig

BackgroundCarvedilol has a1, b1, and b2‐adrenergic blocking effects together with the effects such as vasodilating, anti‐ischemic, anti‐oxidant, anti‐apoptotic, anti‐proliferate and anti‐inflammatory activities. Carvedilol inhibited IKr, IKs, ICa‐L and Ito in rabbit cardiac ventricular myocytes. On the other hand, metoprolol, a nonselective b‐blocker also has blocking several channels, including IK1, ICa and Ito in hearts. Murayama et al. (2013) reported that carvedilol and its analogues inhibit delayed after depolarizations (DADs) in Langendorff‐perfused rabbit hearts. It is well known that DADs are caused by the Na+/Ca2+ exchange current (INCX).MethodsWe examined the effects of carvedilol and metoprolol, two b‐blockers, on INCX by using the whole‐cell voltage‐clamp method in isolated guinea pig ventricles and CCL39 fibroblast cells expressing dog cardiac Na+/Ca2+ exchanger (NCX1).ResultsCarvedilol suppressed INCX in a concentration‐dependent manner but metoprolol did not in isolated guinea pig cardiac ventricular myocytes. IC50 values for the Ca2+ influx (outward) and efflux (inward) components of INCX were 69.7 μM and 61.5 μM, respectively. Carvedilol at 100 μM inhibited INCX in CCL39 cells expressing wild type NCX1 similarly to mutant NCX1 without the intracellular regulatory loop. Carvedilol at 30 μM abolished ouabain‐induced DADs in isolated cardiac ventricular myocytes.ConclusionsCarvedilol suppressed bi‐directional INCX in a concentration‐dependent manner with the IC50 value of approximately 65 μM. We conclude that carvedilol inhibits NCX1 at supratherapeutic concentrations.

Liver functional state parameters in patients with nonalcoholic fatty disease associated with liver cardiovascular pathology in the dynamic of treatment

Aim. The liver functional state disorders at liver nonalcoholic fatty disease (LNAFD) were described in numerous researches carried out earlier but the data about the intensity degree of these disorders at LNAFD clinical course associated with hypertonic disease (HD) and ischemic heart disease (IHD) are absent or contradictory. The aim of this research was the study of liver functional state in patients with LNAFD at its isolated clinical course and also in combination with HD and IHD with following determination of influence of the offered differentiated complex therapy on studied parameters.Methods. There were examined 140 patients with LNAFD divided into 3 groups: I – patients with LNAFD, II – patients with LNAFD associated with HD, III patients with LNAFD associated with HD and IHD. Parameters of the liver function state (general blood bilirubin level, transaminases, gammaglutalyltranspeptidase, thymol test and alkaline phosphatase) were studied in patients of all groups before and after 12 month differentiated complex therapy. Basis therapy of LNAFD that received patients of all groups included metformin (2000 mg/day) and ursodeoxycholic acid (750 mg/day) in combination with recommendations about the way of life modification. In addition to basis therapy patients of the II group received lisinopril (2,5 mg/day with dose titration) and patients of III group – combination of lisinopril (2,5 mg/day with dose titration) and carvedilol (3,125 mg/day with dose titration). Statistic processing of the results was carried out using the common methods of parametric and nonparametric statistics.Results. Analysis of the received results demonstrated that patients with LNAFD had intense disorders of liver functional state and its intensity increased with addition of HD to LNAFD and especially of combination of HD and IHD. On the background of complex therapy in patients of all groups was formed the reliable tendency to normalization of liver functional state parameters especially intense in patients of III group that is probably explained by the mutual potentiation of lisinopril and carvedilol effects.Conclusions. In patients with LNAFD there are intense disorders of liver functional state that are aggravated at addition of HD and especially of combination of HD and IHD to the main disease. Addition of lisinopril to the basis therapy of LNAFD in patients of II group and especially of combination of lisinopril and carvedilol in patients of III group allow attain the reliable tendency to normalization of the liver functional state parameters

Effects of carvedilol reduce conjunctivitis through changes in inflammation, NGF and VEGF levels in a rat model.

Carvedilol is a novel third generation β-blocker that acts as an antagonist of β and α adrenergic receptors, and is able to regulate various cell factors. In addition, it possesses antioxidant activity, is capable of reversing cardiac remodeling effects and has anti-arrhythmic effects. The present study aimed to investigate whether the effects of carvedilol were able to reduce conjunctivitis clinical scores. Initially, 24 Sprague Dawley (SD) rats were randomly divided into three equal groups as follows: Control group, model group and carvedilol group. The model and carvedilol group adult SD rats were injected with lipopolysaccharide (LPS) to induce conjunctivitis. In the carvedilol group, the eight SD rats with LPS-induced conjunctivitis also received 50 mg/kg/day of carvedilol for 4 weeks. Next, the effects carvedilol were assessed utilizing a system of clinical sign scores, and an enzyme-linked immunosorbent assay was used to determine the expression levels of interleukin-1β (IL-1β), IL-6, IL-8 and tumor necrosis factor-α (TNF-α). Finally, nuclear factor-κB (NF-κB), nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) were analyzed by western blotting. Carvedilol was observed to significantly reduce clinical sign scores in a dose-dependent manner (P<0.01), and reduce IL-1β, IL-6, IL-8 and TNF-α expression levels (P<0.01) in the LPS-induced rat model of conjunctivitis. Carvedilol was also able to significantly reduce the protein expression levels of NF-κB, and induce the protein expression levels of NGF and VEGF in the LPS-induced rat model of conjunctivitis (P<0.01). In conclusion, the effects of carvedilol may reduce conjunctivitis clinical scores through inflammation, NGF and VEGF in LPS-induced rat models.

EFFICACY OF CARVEDILOL COMBINED WITH ENDOSCOPIC VARICEAL LIGATION IN THE PREVENTION OF RECURRENT VARICEAL BLEEDING IN PATIENTS OF CIRRHOSIS

Background: The recurrent variceal bleeding is still very high with a very poor prognosis. The combination of a non-selective beta-blocker and endoscopic variceal ligation (EVL) is still a standard therapy for the prevention, but many patients showed no response to propranolol. Carvedilol is a new, non-selective beta-blocker having intrinsic alpha-blocker activity, but the data about the efficacy and safety of carvedilol is still very limited. This study is aimed at assessing the efficacy and safety of carvedilol combined with EVL in the prevention of recurrent variceal bleeding. Patients and methods: 33 patients having variceal bleeding were enrolled. All patients received carvedilol and were performed the EVL until variceal eradication. All the patients were followed after 9 months. Results: rate of variceal eradication of oesophageal varices was 87.88%; the recurrence rate of variceal bleeding was 12.12% after 9 months. The side effects of carvedilol were rare and not severe, including vertiges, headache, and orthostatic hypertension. Conclusion: Carvedilol combined with EVL appeared as a relatively safe and effective in the prevention of recurrent variceal bleeding in patients of cirrhosis. Key words: carvedilol, variceal bleeding, EVL

Carvedilol Improves Inflammatory Response, Oxidative Stress and Fibrosis in the Alcohol-Induced Liver Injury in Rats by Regulating Kuppfer Cells and Hepatic Stellate Cells.

AimTo evaluate the anti-inflammatory, anti-oxidant and antifibrotic effects of carvedilol (CARV) in rats with ethanol-induced liver injury.MethodsLiver injury was induced by gavage administration of alcohol (7 g/kg) for 28 consecutive days. Eighty Wistar rats were pretreated with oral CARV at 1, 3, or 5 mg/kg or with saline 1 h before exposure to alcohol. Liver homogenates were assayed for interleukin (IL)-1β, IL-10, and tumor necrosis factor (TNF)-α level as well as for myeloperoxidase (MPO) activity and malonyldialdehyde (MDA) and glutathione (GSH) levels. Serum aspartate aminotransferase (AST) activity and liver triglyceride (TG) levels were also assayed. Immunohistochemical analyses of cyclooxygenase 2 (COX-2), receptor activator of nuclear factor kappa-B/ligand (RANK/RANKL), suppressor of cytokine signalling (SOCS1), the Kupffer cell marker IBA-1 (ionized calcium-binding adaptor molecule 1), intercellular adhesion molecule 1 (ICAM-1), superoxide dismutase (SOD-1), and glutathione peroxidase (GPx-1) expression were performed. Confocal microscopy analysis of IL-1β and NF-κB expression and real-time quantitative PCR analysis for TNFα, PCI, PCIII, and NF-κB were performed.ResultsCARV treatment (5 mg/kg) during the alcohol exposure protocol was associated with reduced steatosis, hepatic cord degeneration, fibrosis and necrosis, as well as reduced levels of AST (p < 0.01), ALT (p < 0.01), TG (p < 0.001), MPO (p < 0.001), MDA (p < 0.05), and proinflammatory cytokines (IL-1β and TNF-α, both p < 0.05), and increased levels of the anti-inflammatory cytokine IL-10 (p < 0.001) and GSH (p < 0.05), compared to the alcohol-only group. Treatment with CARV 5 mg/kg also reduced expression levels of COX-2, RANK, RANKL, IBA-1, and ICAM-1 (all p < 0.05), while increasing expression of SOCS1, SOD-1, and GPx-1 (all p < 0.05) and decreasing expression of IL-1β and NF-κB (both, p < 0.05). Real-time quantitative PCR analysis showed that mRNA production of TNF-α, procollagen type I (PCI), procollagen type III (PCIII), and NF-κB were decreased in the alcohol-CARV 5 mg/kg group relative to the alcohol-only group.ConclusionsCARV can reduce the stress oxidative, inflammatory response and fibrosis in ethanol-induced liver injury in a rat model by downregulating signalling of Kuppfer cells and hepatic stellate cells (HSCs) through suppression of inflammatory cytokines.

Effect of aliskiren and carvedilol on expression of Ca2+/calmodulin-dependent protein kinase II δ-subunit isoforms in cardiac hypertrophy rat model

Context: The critical role of CaMKIIδ isoforms in cardiac hypertrophy is well documented.Objective: This study was aimed to investigate the possible inhibitory effects of aliskiren (ALS) and/or carvedilol (CAV) on CaMKIIδ isoforms expression in experimental cardiac hypertrophy.Materials and methods: Male Wistar albino rats were subcutaneously injected with isoproterenol (ISO) (5 mg/kg/day) for 4 weeks to induce cardiac hypertrophy. Hypertrophied rats were daily treated with either ALS (10 mg/kg) and/or CAV (10 mg/kg). At the end of the treatment, rats were killed; blood and hearts were collected for assessing different biochemical parameters.Results: ISO treatment significantly increased heart weight to body weight (HW/BW) ratio, serum creatine kinase MB (CK-MB) and troponin T (Tn-T) levels, and plasma renin activity (PRA) as compared to control rats. Additionally, ISO treatment produced a significant increase in the expression of myocardial CaMKIIδ2 and CaMKIIδ3 that were associated with significant elevation in myocardial caspase-3 protein expression. Histopathological examination of rats exposed to ISO treatment showed severe myocardial cell degeneration. ALS and/or CAV treatment significantly reduced the altered HW/BW ratio, serum CK-MB and Tn-T levels, PRA, and caspase-3 protein expression in hypertrophied rats, with maximal improvement in the combination group. These biochemical findings were supported by the histopathological examination of the heart tissue. Additionally, treatment with ALS and CAV significantly inhibited ISO-induced increase in CaMKIIδ2 and CaMKIIδ3 expression levels.Discussion and conclusion: The present study indicated that ALS and CAV treatment ameliorated ISO-induced hypertrophy via inhibiting the expression and the activity of CaMKIIδ isoforms and the associated myocardial apoptosis.