Use of Solid SMEDDS in Delivery of Carvedilol

Aim A new solid SMEDDS (self-microemulsifying drug delivery system) capsule has been developed to increase the solubility and dissolution rate. Methods The solubilities of carvedilol in various bases were investigated. Ternary phase diagrams were used to evaluate the self-emulsification and self-microemulsfication domains. The particle size distribution and ζ-potential were determined. The mean diameter of the three formulae decreased with an increase of Lutrol F68. Results The in vitro dissolution rate of ...

Carvedilol对大鼠实验性缺血再灌注心肌细胞凋亡的影响

研究 Carvedilol对缺血再灌注心肌细胞凋亡及 Bcl- 2、Bax蛋白表达的影响 ,探讨 Carvedilol抑制心肌细胞凋亡的可能机制。结扎 Wistar大鼠左冠状动脉前降支 (L AD) ,建立大鼠缺血再灌注动物模型。采用末端标记原位细胞凋亡法检测心肌凋亡细胞 ,并利用光学显微镜进行细胞计数 ;免疫组化法检测 Bcl- 2和 Bax蛋白表达 ,并利用图象分析系统检测二者的平均光密度值 ,进行定量分析。结果显示手术组心肌细胞凋亡数为 37.5 3± 9.2 2个 /视野 ,假手术组 0 .18± 0 .91个 /视野 ,治疗组为 7.6 3± 4.0 5个 /视野。各组间有显著差异 (P<0 .0 5 ) ;手术组 Bcl- 2蛋白平均光密度值为 0 .14± 0 .0 1,假手术组为 0 .0 9± 0 .0 2 ,治疗组为 0 .14± 0 .0 2 ,手术组和治疗组与假手术组相比均有显著差异 (P<0 .0 5 ) ,治疗组与手术组相比无显著差异(P>0 .0 5 ) ;手术组 Bax蛋白平均光密度值为 0 .10± 0 .0 2 ,假手术组为 0 .0 6± 0 .0 1,治疗组为 0 .0 7± 0 .0 1,手术组与治疗组、假手术组相比有显著差异 (P<0 .0 5 ) ,治疗组与假手术组相比无显著差异 (P>0 .0 5 )。结果表明 Carvedilol有显著抗缺血再灌注心肌细胞凋亡作用 ,其作用机制可能与抑制 Bax基因的蛋白表达 ,使 Bcl- 2基因表达的蛋白功能相对增强 ,Bcl-

Carvedilol may attenuate liver cirrhosis by inhibiting angiogenesis through the VEGF-Src-ERK signaling pathway

AIM: To investigate the effect of carvedilol on angiogenesis and the underlying signaling pathways.METHODS: The effect of carvedilol on angiogenesis was examined using a human umbilical vascular endothelial cell(HUVEC) model. The effect of carvedilol on cell viability was measured by CCK8 assay. Flow cytometry was used to assess the effect of carvedilol on cell cycle progression. Cell migration, transwell migration and tube formation assays were performed to analyze the effect of carvedilol on HUVEC function. Vascular endothelial growth factor(VEGF) induced activation of HUVECs, which were pretreated with different carvedilol concentrations or none. Western blot analysis detected the phosphorylation levels of three cell signaling pathway proteins, VEGFR-2, Src, and extracellular signal-regulated kinase(ERK). The specific Src inhibitor PP2 was used to assess the role of Src in the VEGF-induced angiogenic pathway.RESULTS: Carvedilol inhibited HUVEC proliferation in a dose-dependent manner(IC50 = 38.5 mmol/L). The distribution of cells in the S phase decreased from 43.6% to 37.2%, 35.6% and 17.8% by 1, 5 and 10 μmol/L carvedilol for 24 h, respectively. Carvedilol(10 μmol/L) reduced VEGF-induced HUVEC migration from 67.54 ± 7.83 to 37.11 ± 3.533(P < 0.001). Carvedilol concentrations of 5 μmol/L and 10 μmol/L reduced cell invasion from 196.3% ± 18.76% to 114.0% ± 12.20% and 51.68% ± 8.28%, respectively. VEGFinduced tube formation was also reduced significantly by 5 μmol/L and 10 μmol/L carvedilol from 286.0 ± 36.72 to 135.7 ± 18.13(P < 0.05) and 80.27 ± 11.16(P < 0.01) respectively. We investigated several intracellular protein levels to determine the reason for these reductions. Treatment with 10 μmol/L carvedilol reduced VEGF-induced tyrosine phosphorylation of VEGFR-2 from 175.5% ± 8.54% to 52.67% ± 5.33%(P < 0.01). Additionally, 10 μmol/L carvedilol reduced VEGF-induced ERK 1/2 phosphorylation from 181.9% ± 18.61% to 56.45% ± 7.64%(P < 0.01). The VEGFinduced increase in Src kinase activity was alleviated by carvedilol [decreased from 141.8% ± 15.37% to 53.57 ± 7.18%(P < 0.01) and 47.04% ± 9.74%(P < 0.01) at concentrations of 5 and 10 μmol/L, respectively]. Pretreatment of HUVECs with Src kinase inhibitor almost completely prevented the VEGF-induced ERK upregulation [decreased from 213.2% ± 27.68% to 90.96% ± 17.16%(P < 0.01)].CONCLUSION: Carvedilol has an anti-angiogenic effect on HUVECs. This inhibitory effect is mediated by VEGF-induced Src-ERK signaling pathways.

Is it time to replace propranolol with carvedilol for portal hypertension?

Beta-adrenergic receptor antagonists(β-blockers) have been well established for use in portal hypertension for more than three decades. Different Non-selective β-blockers like propranolol, nadolol, timolol, atenolol, metoprolol and carvedilol have been in clinical practice in patients with cirrhosis. Carvedilol has proven 2-4 times more potent than propranolol as a beta-receptor blocker in trials conducted testing its efficacy for heart failure. Whether the same effect extends to its potency in the reduction of portal venous pressures is a topic of on-going debate. The aim of this review is to compare the hemodynamic and clinical effects of carvedilol with propranolol, and attempt assess whether carvedilol can be used instead of propranolol in patients with cirrhosis. Carvedilol is a promising agent among the beta blockers of recent time that has shown significant effects in portal hypertension hemodynamics. It has also demonstrated an effective profile in its clinical application specifically for the prevention of variceal bleeding. Carvedilol has more potent desired physiological effects when compared to Propranolol. However, it is uncertain at the present juncture whether the improvement in hemodynamics also translates into a decreased rate of disease progression and complications when compared to propranolol. Currently Carvedilol shows promise as a therapy for portal hypertension but more clinical trials need to be carried out before we can consider it as a superior option and a replacement for propranolol.

Carvedilol vs endoscopic variceal ligation for primary and secondary prevention of variceal bleeding: Systematic review and metaanalysis

BACKGROUND Variceal hemorrhage is associated with high mortality and is the cause of death for 20–30%of patients with cirrhosis.Nonselectiveβblockers(NSBBs)or endoscopic variceal ligation(EVL)are recommended for primary prevention of variceal bleeding in patients with medium to large esophageal varices.Meanwhile,combination of EVL and NSBBs is the recommended approach for the secondary prevention.Carvedilol has greater efficacy than other NSBBs as it decreases intrahepatic resistance.We hypothesized that there was no difference between carvedilol and EVL intervention for primary and secondary prevention of variceal bleeding in cirrhosis patients.AIM To evaluate the efficacy of carvedilol compared to EVL for primary and secondary prevention of variceal bleeding in cirrhotic patients METHODS We searched relevant literatures in major journal databases(CENTRAL,MEDLINE,and EMBASE)from March to August 2018.Patients with cirrhosis and portal hypertension,regardless of aetiology and severity,with or without a history of variceal bleeding,and aged≥18 years old were included in this review.Only randomized controlled trials(RCTs)that compared the efficacy of carvedilol and that of EVL for primary and secondary prevention of variceal bleeding and mortality in patients with cirrhosis and portal hypertension were considered,irrespective of publication status,year of publication,and language.RESULTS Seven RCTs were included.In four trials assessing the primary prevention,no significant difference was found on the events of variceal bleeding(RR:0.74,95%CI:0.37-1.49),all-cause mortality(RR:1.10,95%CI:0.76-1.58),and bleedingrelated mortality(RR:1.02,95%CI:0.34-3.10)in patients who were treated with carvedilol compared to EVL.In three trials assessing secondary prevention,there was no difference between two interventions for the incidence of rebleeding(RR:1.10,95%CI:0.75-1.61).The fixed-effect model showed that,compared to EVL,carvedilol decreased all-cause mortality by 49%(RR:0.51,95%CI:0.33-0.79),with little or no evidence of heterogeneity.CONCLUSION Carvedilol had similar efficacy to EVL in preventing the first variceal bleeding in cirrhosis patients with esophageal varices.It was superior to EVL alone for secondary prevention of variceal bleeding in regard to all-cause mortality reduction.

Effect of matrine and carvedilol on collagen and MMPs activity of hypertrophy myocardium induced by pressure overload

Objective： To explore the effect and mechanism of matrine （Mt.） on myocardial interstitial fibrosis induced by pressure overload. Methods： Pressure overloaded myocardial hypertrophy was produced by banding of aorta abdominalis in 67 male Sprague-Dawley rats weighing （200±15） g. The rats were assigned into one of the following groups： sham-operation control, operation control, operation group treated with matrine （15 mg/（kg·d）） and treated with carvedilol （Car.） （3.6 mg/（kg·d）） group. The rats were given drugs one day after operation. Five weeks after treatment, the left ventricular weight （LVW） was measured and the volume of myocardial cells was detected with Hematoxylin-Eosin （H-E） stain and Masson stain was used to assess the level of fibrosis of the myocardial matrix. Myocardial metalloproteinase activity was quantified with zymography, and survival rate was calculated. Results： Survival rate significantly decreased （P〈0.05）, LVW/BW （body weight）, MMP-2 （matrix metalloproteinase-2） activity （P〈0.05）, size of cardiomyocytes and interstitial fibrosis obviously increased in the operation group compared with sham control group. Mr. and Car. treatment can significantly increase survival rate （P〈0.05）, decrease LVW/BW （P〈0.05） and MMP-2 activity （P〈0.05）, decrease size of cardiomyocytes and interstitial fibrosis compared with operation group. But there was difference compared with sham group. Conclusion： Matrine was shown to be able to prevent cardiac remodelling of bypertrophy cardium induced by pressure overload including myocardial hypertrophy and fibrosis which may be associated with the decrease in MMP-2 activity of heart.

Addition of simvastatin to carvedilol non responders: A new pharmacological therapy for treatment of portal hypertension

AIMTo determine whether addition of simvastatin could be an important pharmacological rescue therapy for carvedilol non-responders. METHODSOne hundred and two consecutive patients of cirrhosis of liver with significant portal hypertension were included. Hepatic venous pressure gradient (HVPG) was measured at the base line and after proper optimization of dose; chronic response was assessed at 3 mo. Carvedilol non-responders were given simvastatin 20 mg per day (increased to 40 mg per day at day 15). Carvedilol plus simvastatin was continued for 1 mo and hemodynamic response was again measured at 1 mo. RESULTSA total of 102 patients with mean age of 58.3 ± 6.6 years were included. Mean baseline HVPG was 16.75 ± 2.12 mmHg and after optimization of dose and reassessment of HVPG at 3 mo, mean reduction of HVPG from baseline was 5.5 ± 1.7 mmHg and 2.8 ± 1.6 mmHg among responders and non-responders respectively (P CONCLUSIONAddition of simvastatin to carvedilol non-responders may prove to be an excellent rescue therapy in patients with portal hypertension.

Carvedilol protected diabetic rat hearts via reducing oxidative stress

Oxidative stress plays a dominant role in the pathogenesis of diabetes mellitus. Bcl-2 gene has close connection with antioxidant stress destruction in many diseases including diabetes. Carvedilol, an adrenoceptor blocker, also has antioxidant properties. To study the effect of carvedilol on the antioxidant status in diabetic hearts, we investigated carvedilol-administrated healthy and streptozotocin-induced diabetic rats. After small and large dosage carvedilol-administered for 5 weeks, hemodynamic parameters, the levels of malondialdehyde, activities of antioxidant enzymes and expression of Bcl-2 mRNA in the cardiac tissues were measured. The diabetic rats not only had cardiac disfunction, weaker activities of antioxidant enzymes, but also showed lower expression of Bcl-2. Carvedilol treatment increased activities of antioxidant enzymes and expression of Bcl-2 in healthy rats as well as diabetic rats. These results indicated that carvedilol partly improves cardiac function via its antioxidant properties in diabetic rats.

Effects of Carvedilol on Cardiomyocyte Apoptosis and Gene Expression In Vivo after Ischemia-Reperfusion in Rats

The effects of carvedilol on cardiomyocyte apoptosis and expression of bcl-2. bax genes following ischemia (0. 5 h) and reperfusion (48 h) in vivo and the possible biological mechanism of carvedilol inhibiting cardiomyocyte apoptosis were studied. The left anterior descending artery in Wistar rats were ligated to establish ischemia-reperfusion (I/R) models. The model animals were divided into two groups: I/R group, the model rats not subject to other treatments except ischemia-reperfusion (n= 8); carvedilol-treated group (n= 8), I/R model rats treated with carvedilol. Eight rats in the sham-operated group were subjected to only experimental open operation. The number of apoptotic cardiomyocyte was determined by TUNEL staining. Immunohistochemistry and in situ hybridization histochemistry (ISHH) were used to detect the expression of bcl-2 and bax genes. Image processing system was used to quantitatively dispose the positive metric substances of both immuno-histochemistry and ISHH through the average optical density (OD) value. The results showed that the number of the apoptotic cells were 36. 18±9 (I/R group) . 0-1 (sham-operated group) and 9. 5± 3 (carvedilol-treated group) in each visual field respectively with the difference being very significant among the groups (P<0. 001). The OD values of bcl-2 protein in sham-operated group, I/R group and carvedilol-treated group were 0. 14±0. 01, 0. 08±0. 02 and 0. 15±0. 03, respectively. The OD values of bcl-2 mRNA in sham-operated group, I/R group and carvedilol-treated group were 0. 08± 0. 01, 0. 06±0. 01 and 0. 09±0. 01, respectively. There was no significant difference between carvedilol-treated group and I/R group (P>0. 05). The OD values of bax protein in I/R group, sham-operated and carvedilol-treated-treated group were 0. 13±0. 02, 0. 07±0. 01, 0. 06±0. 01, respectively. There was very significant difference between carvedilol-treated group and I/R group (P <0. 01). Bcl-2/bax ratio was 1. 07±0. 14 (I/R group), 1. 28±0. 16 (sham-operated group), 2. 5 ±0. 26 (carvedilol-treated group) respectively with the difference being very significant between carvedilol-treated group and I/R group (P<0. 05). It was indicated that carvedilol could inhibit cardiomyocyte apoptosis following ischemia and reperfusion, which was related to the increased bcl-2/ bax ratio due to inhibition of bax gene expression.

Clinical value of detecting autoantibodies against β1-, β2-, and α1-adrenergic receptors in carvedilol treatment of patients with heart failure

Objective To determine the possible association of anti-β1-adrenergic receptors(anti-β1-AR), anti-β2-AR and anti-α1-AR with carvedilol treatment in patients with heart failure(HF). Methods A total of 267 HF patients were prospectively enrolled. Blood samples were measured by an enzyme-linked immunosorbent assay. All of the patients received carvedilol for their HF. Each patient was followed up for six months and their cardiac function was measured. Results The final analysis encompassed 137 patients comprising 65 patients with three autoantibodies(positive group) and 72 patients without all three autoantibodies but with one or two autoantibodies(negative group). The frequency and geometric mean titer of anti-β1-AR, anti-β2-AR, and anti-α1-AR were significantly lower in the group without all three autoantibodies after six months of carvedilol treatment(all P < 0.01;from 100% to 57%, 50%, and 49%, respectively;and from 1: 118, 1: 138, and 1: 130 to 1: 72, 1: 61, and 1: 67, respectively). Furthermore, 28 patients in the positive group demonstrated complete ablation of autoantibodies. In addition, left ventricular remodelling and function was significantly improved by the use of carvedilol combined with the standard treatment regime for six months in the positive group(P < 0.01) when compared to the negative group(P < 0.05). Conclusions Carvedilol treatment significantly decreases frequency and geometric mean titer in patients with all three autoantibodies, even up to complete ablation, and significantly improved cardiac function and remodelling. The effect of carvedilol is probably correlated to the presence of all three autoantibodies.

Temperature and eluent composition effects on enantiomer separation of carvedilol by high-performance liquid chromatography on immobilized amylose-based chiral stationary phases

Carvedilol is a chiral drug with potent antihypertensive and antianginal activities. Although it is clinically used as a racemic mixture, its enantiomers show different pharmacokinetic and pharmacodynamic profiles. Here, the direct chiral separation of racemic drug by high performance liquid chromatography using two immobilized-type amylose-based chiral stationary phases is presented. Some chromatographic parameters, such as retention and selectivity, were determined under multimodal eluent conditions and different temperatures. A temperature-dependent inversion of the elution order of enantiomers was observed in the operative temperature range of chiral chromatographic support. Finally, an effective direct enantioselective method was successfully applied to the separation of the enantiomers of carvedilol on a semipreparative scale.

Molecular mechanism of carvedilol in attenuating the reversion to fetal energy metabolism during cardiac hypertrophy development

Objective: To explore the molecular regulation mechanism of carvedilol in attenuating the reversion back towards fetal energy metabolism during the development of cardiac hypertrophy induced by coarctation of abdominal aorta (CAA) in male Wistar rats. Methods: Hemodynamic and ventricular remodeling parameters, free fatty acid content in the serum were measured in the experimental animals at 16 weeks after the surgical CAA, the rats receiving carvedilol intervention (CAR) after CAA, and those with sham operation (SH). The expressions of muscle carnitine palmitoyltransferaseⅠ (M-CPTⅠ) and medium chain acyl-CoA dehydrogenase (MCAD) mRNA in the cardiac myocytes from every group were studied with RT-PCR. Results: Significant left ventricular hypertrophy were observed in the rats 16 weeks after coarctation operation (P<0.05), together with significant free fatty acids accumulation and downregulation of M-CPTⅠ and MCAD mRNA (P<0.05) in CAA group. Carvedilol at a dose of 30 mg/kg/d for 12 weeks inhibited the left ventricular hypertrophy induced by pressure overload and enhanced the gene expressions of rate-limiting enzyme (M-CPTⅠ) and key enzyme of fatty acid (MCAD) in the CAR group compared with CAA group (P<0.05). Conclusion: Pressure overload-induced hypertrophy in CAA rats causes the reversion back towards fetal enery metabolism, that is, downregulates the expressions of rate-limiting enzyme and key enzyme of fatty acid oxidation. The intervention therapy with carvedilol, a vasodilating alpha- and beta-adrenoreceptor antagonist, attenuates the reversion of the metabolic gene expression to fetal type through upregulating M-CPTⅠ and MCAD mRNA expressions. Thus, carvedilol may exert cardioprotective effects on heart failure by the mechanism of preserving the adult metabolic gene regulation.

Carvedilol vs. metoprolol: A comparison of effects on endothelial function and oxidative stress in response to acute hyperglycemia in patients with type 2 diabetes and hypertension

Introduction: The GEMINI trial compared the effects of treatment with metoprolol versus carvedilol in patients with type 2 diabetes. Carvedilol demonstrated a more favorable effect on factors associated with the metabolic syndrome than metoprolol. We hypothesize that carvedilol will have additional beneficial effects on markers of inflammation, oxidative stress, and endothelial function than metoprolol. Methods: Twenty subjects were randomized to either carvedilol or metoprolol. Study procedures including assessment of metabolic parameters and endothelial function, while fasting and after a 75 g oral glucose tolerance were conducted at baseline and following 5 months of treatment. Results: Following 5 months of treatment, PAI-1 increased significantly from baseline in the metoprolol group. There were no changes in PAI-1 in the carvedilol group. While not reaching statistical significance, there was a trend toward worsening insulin resistance with metoprolol treatment compared to carvedilol treatment. Flow mediated vasodilation increased in both groups following the 2-hr OGGT during the baseline study. After five months of treatment, there was a non-significant increase in flow-mediated vasodilation under both fasting and post OGTT conditions in the carvedilol group compared to baseline. Conversely, there was no change in fasting flow mediated vasodilation in the metoprolol group. Additionally, metoprolol treatment blunted the increase in flow mediated vasodilation following OGGT compared to baseline (p < 0.05). Conclusion: Treatment with metoprolol was associated with adverse metabolic effects including increases in PAI-1 and trends toward worsening insulin resistance and endothelial function compared to treatment with carvedilol.

Carvedilol suppresses ventricular arrhythmia in a pressure over-load rabbit model through relieving transmural dispersion of repolarization with long-term administration

Objective： To investigate the effects of carvedilol （CVD） on transmural dispersion of repolarization（TDR） and arrhythmia in pressure over-load rabbits. Methods： Left ventricular hypertrophied（LVH） rabbit models were established by pressure over-load; All animal models were assigned into CVD group or LVH group randomly. The action potentials of endocardium, cpicardium and transmural ECG of arterially perfused left ventricular preparations were recorded concurrently. Action potential duration （APD）, TDR, ventricular arrhythmia and ultrasonic parameters, ratio of LVM to body weight （LVMI） were compared correspondingly. The stable plasma concentration of carvedilol in CVD group was detected by HPLC. APD, TDR and arrhythmia of LVH models were compared just preor post-perfusion with stable concentration of CVD. Results： In Contrast with values in LVH group, LVEFof CVD group were significantly elevated while the LVMI was remarkably reduced, TDRs were significantly shortened, and ratio of ventricular arrhythmia was lowered remarkably. No significant difference of APD, TDR and ratio of arrhythmia was found preor post-perfusion at stable plasma concentration of CVD. Conclusion： CVD can ameliorate the structure and function of pressure over-load ventricles; CVD contributes to the improvement of ventricular arrhythmia associated with its long-term effect on APD,TDR shortening ,whereas has nothing to do with its transient function on ionic channel blockade

HPLC Method Development and Validation of S(-)-Carvedilol from API and Formulations

A simple chiral HPLC method was developed and validated for quantification of S(-)-Carvedilol in Active Pharmaceutical Ingredient (API) and marketed tablet formulation of racemic Carvedilol. Chiral resolution of enantiomers of Carvedilol was achieved on Phenomenex Lux-cellulose–4 (250 mm × 4.6 mm;5 μ particle size) chiral column by using a mobile phase, Isopropanol and n-Heptane (60:40 v/v), at a flow rate of 1.0 ml/min and by employing UV detection at 254 nm wavelength. The method was validated according to the ICH guidelines and was proved to be specific, linear, precise and accurate for the analysis of S(-)-Carvedilol.

Stereoselective glucuronidation of carvedilol by Chinese liver microsomes

Objective: To study the stereoselective glucuronidation of carvedilol (CARV) by three Chinese liver microsomes. Methods: The metabolites of CARV were identified by a hydrolysis reaction with β-glucuronidase and HPLC-MS/MS. The enzyme kinetics for CARV enantiomers glucuronidation was determined by a reversed phase-high pressure liquid chromatogra-phy (RP-HPLC) assay using (S)-propafenone as internal standard after precolumn derivatization with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylisothiocyanate. Results: Two CARV glucuronides were found in three Chinese liver microsomes incubated with CARV. The non-linear regression analysis showed that the values of Km and Vmax for (S)-CARV and (R)-CARV enantiomers were (118±44) μmol/L, (2 500±833) pmol/(min·mg protein) and (24±7) μmol/L, (953±399) pmol/(min·mg protein), respectively. Conclusion: These results suggested that there was a significant (P<0.05) stereoselective glucuronidation of CARV enantiomers in three Chinese liver microsomes, which might partly explain the enantioselective pharmacokinetics of CARV.

Protective Effect of Carvedilol on Abnormality of L-type Calcium Current Induced by Oxygen Free Radical in Cardiomyocytes

The protective effect of carvedilol on abnormality of L-type calcium current induced by oxygen free radical in single guinea pig ventricular myocytes was studied. Whole-cell patch clamp technique was used to study the effect of H 2O 2 (0.5 mmol/L) on L-type calcium current in single guinea pig ventricular myocytes and the action of pretreatment with carvedilol (0.5 μmol/L). 0.5 μmol/L carvedilol had no significant effect on I Ca,L and its channel dynamics. In the presence of 0.5 mmol/L H 2O 2, peak current of I Ca,L was reduced significantly (P<0.001), the I-V curve of I Ca,L was shifted upward, steady-state activation curve and steady-state deactivation curve of I Ca,L were shifted left and recovery time of I Ca,L was delayed significantly (P<0.001). 0.5 μmol/L carvedilol significantly alleviated the inhibitory effect of H 2O 2 on I Ca,L as compared with that in H 2O 2 group (P<0.01). In addition, carvedilol reversed the changes of dynamics of I Ca,L induced by H 2O 2. It was concluded that carvedilol could alleviate the abnormality of L-type calcium current induced by oxygen free radical in cardiomyocytes. It shows partly the possible mechanism of the special availability of carvedilol in chronic heart failure.

Molecular mechanism of carvedilol on attenuating the reversion back towards fetal energy metabolism during the development of cardiac hypertrophy

Objective to explore the molecular mechanism of carvedilol effect on fetal energy metabolism during the development of cardiac hypertrophy. Methods Male Wistar rats were divided into the coarctation of abdominal aorta group (CAA), sham operation group (SH), and carvedilol intervention group (CAR+CAA, carvedilol 30mg·kg -1 ·day -1 orally) and carvedilol control group (CAR+SH). Hemodynamics, ventricular remodeling parameters, free fatty acid in blood serum and cardiac myocyte, RT PCR analysis of the expressions of Muscle Carnitine Palmitoyltransferase I (M CPT I) and Medium Chain Acyl CoA Dehydrogenase (MCAD) mRNA were measured in all rats at 16 week after operation. Results Left ventricular hypertrophy occurrd after operation 16 weeks in group of CAA, accompanying with plasma free fatty acids accumulation, and both the levels of M CPT I and MCADmRNA were decreased significantly ( P <0.05). Carvedilol can reduce the left ventricular hypertrophy induced by pressure overload. The gene expressions of rate limiting enzyme(M CPT I) and key enzyme of fatty acid (MCAD) were upregulated in the CAR+CAA group, comparing with CAA group ( P <0.05). There was no statistically significant difference between SH group and CAR + SH group. Pressure overload in CAA rats downregulates the gene expression of rate limiting enzyme and key enzyme of fatty acid oxidation. Conclusions The intervention with carvedilol may attenuates the reversion of the metabolic gene expression back towards fetal type through up regulating the expression of M CPT I and MCADmRNA. Thus, carvedilol may confer cardioprotective effects in heart failure partly by preserving of the normal metabolic gene regulation.