Carvedilol inhibition of lipid peroxidation. A new antioxidative mechanism

To define the molecular mechanism(s) of carvedilol inhibition of lipid peroxidation we have utilized model systems that allow us to study the different reactions involved in this complex process.

Carvedilol inhibits the peroxidation of sonicated phosphatidylcholine liposomes triggered by FeCl₂ addition whereas atenolol, pindolol and labetalol are ineffective. The inhibition proved not to be ascribable (a) to an effect on Fe²⁺ autoxidation and thus on the generation of oxygen derived radical initiators; (b) to the scavenging of the inorganic initiators O^·-₂ and ^·OH; (c) to an effect on the reductive cleavage of organic hydroperoxides by FeCl₂; (d) to the scavenging of organic initiators. The observations that (a) carvedilol effectiveness is inversely proportional to the concentration of FeCl₂ and lipid hydroperoxides in the assay; (b) the drug prevents the onset of lipid peroxidation stimulated by FeCl₃ addition and; (c) it can form a complex with Fe³⁺, suggest a molecular mechanism for carvedilol action. It may inhibit lipid peroxidation by binding the Fe³⁺ generated during the oxidation of Fe²⁺ by lipid hydroperoxides in the substrate. The lag time that carvedilol introduces in the peroxidative process would correspond to the time taken for carvedilol to be titrated by Fe³⁺; when the drug is consumed the Fe³⁺ accumulates to reach the critical parameter that stimulates peroxidation. According to this molecular mechanism the antioxidant potency of carvedilol can be ascribed to its ability to bind a species, Fe³⁺, that is a catalyst of the process and to its lipophilic nature that concentrates it in the membranes where Fe³⁺ is generated by a site specific mechanism.     

卡维地洛对顺铂所致大鼠肾毒性预防作用的形态学研究

目的研究顺铂诱导大鼠肾损伤的组织病理学和超微结构变化以及卡维地洛对大鼠肾损伤的预防作用。方法雄性Wistar大鼠随机分为4组,给药后3～6d处死,取肾组织,常规石蜡切片,HE染色、PAS反应,超薄切片电镜观察。结果卡维地洛组较顺铂肾脏损伤模型组的组织病理学及超微结构变化明显减轻。结论卡维地洛预防性灌胃给与能明显减轻大鼠顺铂所致的肾损伤,其机制可能与其抗氧化和清除自由基活性有关。     

Perturbing effects of carvedilol on a model membrane system: role of lipophilicity and chemical structure

Carvedilol, a beta-adrenergic blocker used to treat cardiovascular diseases, protects cell membranes from lipid peroxidative damage. Previous studies suggested the drug resides in a non-polar environment and partitions into cell membranes, perturbing their fluidity. Here differential scanning calorimetry (DSC) and fluorescence spectroscopy were applied to further investigate interactions of carvedilol with a liposome model. Results indicate the association is relatively unaffected by pH or temperature, but could be sensitive to liposome composition. The drug's carbazole group plays the dominant role in bilayer perturbation. Compared with other beta-blockers examined, carvedilol produced the strongest liposome DSC perturbation. Locations of carbazole and carvedilol in the liposome were determined using depth-dependent fluorescent probes. Both compounds are situated in the middle of the bilayer, consistent with strong hydrophobic interactions. This combination of high lipophilicity and specific chemical structure appear required for carvedilol's novel antioxidant activity, and may enhance cardioprotection.     

卡维地洛对慢性心力衰竭患者神经内分泌及心功能的影响

目的:观察卡维地洛对慢性心力衰竭患者神经内分泌及心功能的影响.方法:60例慢性心力衰竭患者随机分为对照组(n=30)和卡维地洛组(n=30).对照组给予洋地黄、利尿剂、血管紧张素转化酶抑制剂等常规治疗;卡维地洛组在给予常规治疗的基础上加用卡维地洛,从小剂量(3.125mg,1次/天)逐渐加至靶剂量(12.5mg,2次/天或3次/天)治疗6个月.治疗前及治疗6个月后放射免疫法测定血浆血管紧张素Ⅱ(Ang Ⅱ)及内皮素-1(ET-1)水平,超声心动图检测心功能.结果:两组治疗后较治疗前Ang Ⅱ及ET-1水平显著降低,卡维地洛组改善更明显(P＜0.01);两组左房内径、左室舒张末期内径(LVEDD)和左室收缩末期内径(LVESD)明显缩短(P＜0.01),左室射血分数(LVEF)显著增高(P＜0.01).结论:卡维地洛抑制心衰患者的神经内分泌激活,逆转心室重塑,改善心功能.     

Separation of carvedilol enantiomers in very small volumes of human plasma by capillary electrophoresis with laser-induced fluorescence

A sensitive capillary electrophoretic method for the determination of carvedilol enantiomers in 100 μl of human plasma has been developed and validated. Carvedilol and the internal standard carazolol are isolated from plasma samples by liquid–liquid extraction using diethylether. A sensitive and selective detection is provided by helium–cadmium laser-induced fluorescence. The total analysis time is 17.5 min, about 30 min are needed for the sample preparation. The linearity of the assay ranges from 1.56 to 50 ng/ml per carvedilol enantiomer. The limits of quantification (LOQ) for the carvedilol enantiomers in 100 μl of human plasma are 1.56 ng/ml. The inter-day accuracy for R-carvedilol is between 95.8 and 103% (104% at LOQ) and for S-carvedilol between 97.1 and 103% (107% at LOQ); the inter-day precision values are between 3.81 and 8.64% (10.9% at LOQ) and between 5.47 and 7.86% (7.91% at LOQ) for R- and S-carvedilol, respectively. The small sample volume needed is especially advantageous for the application in clinical studies in pediatric patients. As an application of the assay concentration/time profiles of the carvedilol enantiomers in a 5-year-old patient receiving a test dose of 0.09 mg/kg carvedilol are reported.     

卡维地洛对老年慢性心肾综合征患者血浆IL-6、IL-10水平的影响

目的:观察卡维地洛对慢性心衰合并肾功能不全(CRS)患者血浆IL-6、IL-10水平的影响。方法:将2011~2012年我院收治的60例CRS患者采用数字表分组法随机分为对照组和治疗组两组,对照组仅给予常规心力衰竭治疗,治疗组在接受常规心力衰竭治疗的基础上加用卡维地洛直至目标剂量。治疗6个月后比较两组患者的心功能、肾功能和血浆IL-6、IL-10的水平。结果:治疗6个月后,治疗组LVEDD、LVESD较治疗前明显缩小(P0.05),且明显小于对照组(P0.05),而LVEF比治疗前明显升高(P0.05),也明显高于对照组(P0.05);治疗组的血浆BUN、Cr和IL-6水平均较治疗前显著降低(P0.05),且均明显低于对照组(P0.05),血浆IL-10有上升趋势,但差异无统计学意义(P0.05)。治疗前后,对照组以上指标比较差别均无统计学意义(均P0.05)。结论:卡维地洛辅助治疗可显著降低CRS患者血浆IL-6水平,对血浆IL-10的影响不明显。     

Therapeutic effect of antihypertensive drug on diabetic nephropathy: Functional and structural kidney investigation

Due to the growth of diabetic mellitus (DM) and diabetic nephropathy as a significant complication for diabetic patients, study on effective treatment with fewer side effects has been fascinated. In this study for the first time carvedilol effects on both function and structure of kidney in diabetic nephropathy treatment were evaluated. Diabetes was induced by injection of streptozotocin (STZ) intravenously in rats and three groups including control, diabetic, and treatment with carvedilol were considered. Biochemical parameters such as, blood glucose level, BUN, creatinine, uric acid, Na⁺, K⁺ was determined. Results showed that glucose (516 to 291 mg/dl), BUN (42 to 21.67 mg/dl), creatinine (0.75 to 0.6 mg/dl), uric acid (4.45 to 1.36 mg/dl), and K⁺ (7.433 to 5.433 mEq/l) level reduced. Decrease in glucose, BUN, creatinine, uric acid, and K⁺ and increase in Na⁺ level (138 to 146.33 mEq/l) confirmed therapeutic effect of carvedilol. Furthermore, the histopathological study was done for each group. Histopathological results confirmed the data obtained by biochemical parameters. For further investigation, SPECT imaging with ^99mTc-DMSA, which is a gold standard in diabetic nephropathy detection, was done. SPECT imaging showed that accumulation of ^99mTc-DMSA was increased in treated group (5 to 25 kcpm) which means the improvement in renal structure in the treated group compare to the diabetic group (5 kcpm). Finally, obtained results confirmed our hypothesis that carvedilol had a therapeutic effect on diabetic nephropathy.     

肾上腺素能受体阻断剂预防慢性压力超负荷左心室的电重构

研究长期使用肾上腺素能受体阻断剂治疗对慢性压力超负荷左心室电重构的影响。新西兰兔通过肾上腹主动脉次全结扎诱发慢性压力超负荷,10周后行心脏超声检查,并采用全细胞膜片钳技术分别记录腹主动脉结扎组(简称结扎组)、腹主动脉结扎 Carvedilol 干预组(简称Carvedilol组)及正常对照组(简称对照组)动物左室肌中层细胞的动作电位(action potential,AP)、内向整流钾电流(inward rectifier potassium current,IKi)、延迟整流钾电流(delayed rectifier potassium current,IK)及Na /Ca2 交换体电流。结果表明,结扎组的左室质量指数较对照组明显升高,Carvedilol组较结扎组明显降低(P<0.01)。在2 s的基础周长下,动作电位持续时间(以90％的复极时间表示,简称APD90)在对照组、结扎组及Carvedilol组分别为522.0±19.5 ms(n=6)、664.7± 46.2 ms(n=7)、567.8±14.3 ms(n=8),结扎组同对照组相比,P<0.01,Carvedilol组同结扎组相比,P<0.05。在测试电位为-100mV时,IKi电流密度(pA/pF)在对照组、结扎组及Carvedilol组分别为-11.8±0.50(n=8),-8.07±0.28 (n=8),-10.69±0.35(n=8),结扎组与对照组及Carvedilol组相比,P<0.01。在测试电位为 50 mV时,IK尾电流密度(pA/pF)在对照组、结扎组及Carvedilol组分别为0.59±0.40(n=     

Carvedilol,a third-generation β-blocker prevents oxidative stress-induced neuronal death and activates Nrf2/ARE pathway in HT22 cells

Carvedilol, a nonselective β-adrenoreceptor blocker with pleiotropic activities has been shown to exert neuroprotective effect due to its antioxidant property. However, the neuroprotective mechanism of carvedilol is still not fully uncovered. Nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cellular stress response pathway involved in neuroprotection. Here we investigated the effect of carvedilol on oxidative stress-induced cell death (glutamate 2 mM and H₂O₂ 600 μM) and the activity of Nrf2/ARE pathway in HT22 hippocampal cells. Carvedilol significantly increased cell viability and decreased ROS in HT22 cells exposed to glutamate or H₂O₂. Furthermore, carvedilol activated the Nrf2/ARE pathway in a concentration-dependent manner, and increased the protein levels of heme oxygenase-1(HO-1) and NAD(P)H quinone oxidoreductase-1(NQO-1), two downstream factors of the Nrf2/ARE pathway. Collectively, our results indicate that carvedilol protects neuronal cell against glutamate- and H₂O₂-induced neurotoxicity possibly through activating the Nrf2/ARE signaling pathway.     

Carvedilol modifies antioxidant status of patients with stable angina

The aim of this study was to evaluate the effect of carvedilol on the enzymatic antioxidative defence and plasma antioxidative activity in patients with stable angina. The study comprised 30 patients, aged 37–49 years with stable angina. Patients received carvedilol in escalating doses of 12.5 mg/24 h, 25 mg/24 h, and 50 mg/24 h for 4 weeks each. The control group was matched for age and gender, and consisted of 12 healthy volunteers, aged 39-49 years. Blood samples were collected from the cubital vein before and 4, 8 and 12 weeks after the therapy from the patients and once from the control group. For all the subjects, the superoxide dismutase (SOD-1), glutathione peroxidase (GSH-Px), catalase (CAT) activities in the erythrocytes and the antioxidant activity of the blood plasma were determined. The enzymatic antioxidative defence was significantly decreased in patients with stable angina in comparison to the healthy subjects. During the carvedilol therapy, an increase in the SOD-1, GSH-Px and CAT activities was observed. Moreover, 8 and 12 weeks after carvedilol therapy, the GSH-Px activity did not differ significantly from that observed in the group of healthy subjects. Carvedilol also increased the plasma antioxidative activity in patients with stable angina, but its level remained significantly lower than in the control group. In conclusion, carvedilol enhances antioxidant defense mechanisms in patients with chronic stable angina pectoris.