卡维地洛对充血性心力衰竭患者心功能的影响

目的：探讨卡维地洛对充血性心力衰竭患者心功能的影响。方法：将30例充血性心力衰竭病人随机会为卡维他洛组,安慰剂组。于治疗前后检测左心室射血分数（LVEF）及左心室腔径的变化,15例健康人为正常对照组。结果：结果显示：经卡维地洛治疗后LVEF升高（P＞0．01）,左室舒张末径（LVDED）、左室收缩末径（LVSED）均缩短（P＜0．01）,左室收缩末容量（LVSEV）减少（P＜0．01）。结论：提示卡维地洛能改善左心功能,可使扩大的左心室腔径缩小。     

Effects of carvedilol on serum lipids in hypertensive and normotensive subjects

The effects of carvedilol (an · -blocker) on lipid metabolism were assessed in addition to its hypotensive effect. The subjects were 18 men and 18 women, 20 with hypertension and 16 normotensives with other conditions requiring carvedilol treatment. They were aged from 31 to 79 years and were given a daily dose of 5–20 mg carvedilol (average, 9.7 mg/day) for 12 weeks. Significant falls were seen in blood pressure and heart rate after 12 weeks in the hypertensive subjects (mean ± SE) (systolic: from 164 ± 2 to 141 ± 2 mm Hg,P < 0.001;=" diastolic:=" from=" 98=" ±=" 1=" to=" 85=" ±=" 2=" mm=">P < 0.001;=" heart=" rate:=" from=" 71=" to=" 65=">P < 0.001).=" smaller=" changes=" in=" blood=" pressure=" and=" heart=" rate=" were=" seen=" in=" the=" normotensive=" subjects,=" with=" the=" fall=" in=" systolic=" pressure=" being=" significant=" (from=" 143±3=" to=" 135=" ±=" 2=" mm=">P < 0.01).=" there=" were=" no=" significant=" changes=" in=" the=" overall=" serum=" total=" cholesterol,=" triglycerides,=" high-density=" lipoprotein=" (hdl)=" cholesterol,=" and=" phospholipid=" levels.=" in=" the=" subgroup=" with=" a=" pretreatment=" serum=" triglyceride=" level=" of="> 150 mg/dl, a significant fall of 52.1 mg/dl was seen (P < 0.05).=" lipoprotein=" analysis=" showed=" a=" significant=" fall=" in=">-lipoprotein levels (P < 0.05).=" the=" atherogenic=" index=" did=" not=" change=" significantly,=" and=" it=" was=" concluded=" that=" carvedilol=" was=" an=" effective=" antihypertensive=" agent=" that=" produced=" no=" adverse=" effects=" and=" possibly=" had=" beneficial=" effects=" on=" lipid=">     

The pharmacology of carvedilol

Carvedilol is a potent antihypertensive agent with a dual mechanism of action. At relatively low concentrations it is a competitive -adrenoceptor antagonist and a vasodilator, whereas at higher concentrations it is also a calcium channel antagonist. The antihypertensive activity of carvedilol is characterized by a decrease in peripheral vascular resistance, resulting from the vasodilator activity of the compound, with no reflex tachycardia, as a result of -adrenoceptor blockade. The antihypertensive activity of carvedilol is associated with an apparent renal sparing effect in that the reduction in mean arterial blood pressure does not compromise renal blood flow or urinary sodium excretion. Studies on the mechanism of action of carvedilol indicate that the compound is a potent competitive antagonist of ₁- and ₂-adrenoceptors with a dissociation constant (K_B) of 0.9 nM at both -adrenoceptor subtypes. Carvedilol is also a potent ₁-adrenoceptor antagonist (K_B = 11 nM), which accounts for most, if not all, of the vasodilating response produced by the compound. At concentrations above 1 M, carvedilol is a calcium channel antagonist. This activity can be demonstrated in vivo at doses that represent the higher end of the anti-hypertensive dose-response curve. Although the calcium-channel blocking activity of carvedilol may not contribute to the antihypertensive activity of the compound, it may play a prominent role in certain peripheral vascular beds, such as the cutaneous circulation, where marked increases in blood flow are observed. The data indicate that carvedilol is an antihypertensive agent that is both a -adrenoceptor antagonist and a vasodilator. The vasodilating activity of carvedilol results largely from ₁-adrenoceptor blockade, and its -adrenoceptor blocking activity prevents reflex tachycardia. In some regional vascular beds, such as the cutaneous circulation, the calcium-channel blocking activity of carvedilol may be responsible for increasing the blood flow.     

Enantioselective pharmacokinetic–pharmacodynamic modelling of carvedilol in a NG‐nitro‐l‐arginine methyl ester rat model of secondary hypertension

Objectives The role of vascular sympatholytic activity of carvedilol in its antihypertensive effect in N^G‐nitro‐l ‐arginine methyl ester (L‐NAME) hypertensive rats was assessed by means of enantioselective pharmacokinetic–pharmacodynamic (PK‐PD) modelling. Methods Male Wistar rats were randomly divided into two groups: control rats received tap water to drink for 2 weeks while L‐NAME rats received L‐NAME solution to drink for 2 weeks. The effects of carvedilol (1 and 5 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Enantioselective carvedilol plasma pharmacokinetics were studied by means of traditional blood sampling. The relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by means of PK‐PD modelling. Vascular sympatholytic activity of carvedilol was assessed by the estimation of drug effects on low frequency blood pressure variability by means of spectral analysis. Key findings A dose‐dependent increase in volume of distribution, as well as a greater volume of distribution and clearance of S‐carvedilol as compared with the R‐enantiomer was found in both experimental groups. Although the PK‐PD properties of the S‐carvedilol chronotropic effect were not altered in L‐NAME rats, hypertensive rats showed greater potency and efficacy to the carvedilol hypotensive response. Greater potency of carvedilol for inhibition of sympathetic vascular activity was found in L‐NAME rats. Conclusions Carvedilol showed enantioselective non‐linear pharmacokinetic properties in both groups. An enhanced hypotensive activity of carvedilol was found in L‐NAME hypertensive rats compared with control rats, which may be explained by the greater potency of carvedilol for sympathetic vascular tone inhibition.     

治疗心动过速性心肌病心功能不全中卡维地洛应用

目的:观察卡维地洛在心动过速性心肌病病人心功能的影响。方法:将心动过速性心肌病患者共52例分为治疗组和对照组各26例。对照组行强心、利尿及ACEI治疗。而治疗组在此基础上加用卡维地洛3.125mg,2次/d。口服每2周逐渐加量至最大耐受量,疗程为6个月。结果:作治疗前后NYHA分级心功能均得到改善。结论:卡维地洛治疗6个月后能使心动过速性心肌病心功能得以改善,生活质量得以提高。     

卡维地洛对原发性高血压患者血浆神经肽的影响

目的：为探讨卡维地洛对原发性高血压患者血浆神经肽Y（NPY）与神经降压肽（NT）水平的变化及其与高血压治疗的关系。方法：本文测定了56例原发性高血压患者用药前后血压、血浆NPY、NT的变化,30例健康人做为对照组。结果：原发性高血压组血浆NPY明显高于对照组（P〈0.01）;血浆NT低于对照组（P〈0.01）。卡维地洛治疗后血压明显下降;血浆NPY水平降低;NT水平升高。结论：卡维地洛对原发性高血压体内NPY、NT水平变化的影响,可能与其治疗作用有关。     

After myocardial infarction carvedilol improves insulin resistance compared to metoprolol

Summary Principles Both carvedilol and metoprolol have cardioprotective effects and decrease infarct size in myocardium. We compared effects of carvedilol and metoprolol on insulin resistance and serum lipid levels after myocardial infarction. Methods Fiftynine patients aged between 30 and 70 and BMI = 25–30 kg/m², who were diagnosed with myocardial infarction with ST segment elevation, were considered to be eligible for the study. Patients were randomly allocated to two different therapy protocols. Metoprolol 100 mg bid or carvedilol 25 mg bid was added to their standardized therapy regimen. Baseline to week 4 and 12, fasting blood glucose, serum lipid profile, BMI, C–peptide, insulin and homeostasis model assessment of insulin resistance (HOMA–IR) were measured. Results After 12 weeks of metoprolol therapy HOMA–IR, insulin and C–peptide levels were significantly higher (p<0.05 for all) and total cholesterol and triglyceride levels decreased significantly (p < 0.05 for all) compared to baseline. After 12 weeks of carvedilol therapy HOMA–IR, insulin and C–peptide (p < 0.05 for all), total cholesterol and triglyceride (p = 0.001 for all) decreased significantly compared to baseline. Carvedilol provided more decrease in total cholesterol and LDL levels than metoprolol (p = 0.043 and p = 0.021, respectively). Conclusions In patients after myocardial infarction, carvedilol added to background therapy improved insulin resistance and lipid profile.     

卡维地洛及TNF-α对内皮细胞释放t-PA和PAI-1的影响

目的　研究卡维地洛及肿瘤坏死因子α(TNF α)对内皮细胞分泌组织纤溶酶原激活物 (t PA)和纤溶酶原激活物抑制剂 1(PAI 1)的影响。方法　培养内皮细胞株 (ECV3 0 4) ,分为TNF α刺激组 ,培养基中TNF α加至终浓度为 5、10、2 5、5 0、10 0ng/ml;卡维地洛干预组 ,培养基中加TNF α (5 0ng/ml)后加入卡维地洛 ,终浓度为 2 0、5 0、10 0、2 0 0nmol/L ,2 4h后测定上清中的组织纤溶酶原激活物 (t PA)和纤溶酶原激活物抑制剂 1(PAI 1)的含量。结果　内皮细胞在TNF α刺激 2 4h后 ,其分泌的PAI 1抗原含量与对照组比有明显升高 ,有显著性差异 (P <0 0 5 ) ,而两组间t PA含量无明显差异 (P >0 0 5 )。而卡维地洛干预组却显著降低PAI 1(P <0 0 5 ) ,对t PA含量无明显作用 (P >0 0 5 )。结论　TNF α对内皮细胞株分泌的PAI 1有显著的升高作用 ,而对t PA无显著影响 ;用卡维地洛干预后 ,PAI 1显著降低 ,t PA含量无明显改变。     

Effects of carvedilol on left ventricular remodeling and systolic function in elderly patients with heart failure

BACKGROUND: Recent studies have shown that carvedilol therapy in patients with heart failure improves clinical outcome and survival, however, the effects of such treatment on left cardiac morphology and function in elderly patients with severe heart failure has not been widely studied. AIM: The purpose of this study was to establish the effect of carvedilol at short- and long-term on left ventricular size and performance with mono- and two-dimensional echocardiography, in subjects with dilated cardiomyopathy, NYHA III functional class, low LV ejection fraction (EF < 35%) and mean age of > 70 years. METHODS: We studied 48 patients, previously randomized to treatment with either carvedilol or placebo, and we performed echocardiographic evaluation at the start, and after 3 and 12 months. Left ventricular diameters, LV mass and fractional shortening were calculated by Deveraux formula; left ventricular volumes and ejection fraction were measured by area-length formula; pulmonary pressure was calculated by tricuspid reflow. RESULTS: After 3 months, only LV end-diastolic diameter was lower in the carvedilol group compared to the placebo group. Nevertheless, after 12 months, patients on carvedilol treatment showed a LV geometric and functional improvement compared to placebo. We found significant differences in: diastolic (P < 0.01) and systolic diameters (P < 0.001); on LV mass (P < 0.002); on LV systolic volume (P < 0.03); and on LV ejection fraction (P<0.01). Pulmonary pressure was also reduced in beta-blocker subjects (P < 0.001). CONCLUSIONS: Carvedilol therapy for 12 months reduced LV diameters and volumes. Thus, improving cardiac remodeling and LV systolic function in elderly patients with severe heart failure. Several months of therapy are required for these favorable effects to occur, as these changes do not occur in the short term.     

卡维地洛、美托洛尔对心衰大鼠心功能及体液因子的影响

目的探讨β受体阻滞剂卡维地洛、美托洛尔对心衰大鼠体液因子及心功能的影响。方法建立心衰大鼠模型,随机分为三组,B组为安慰剂组;C组给予卡维地洛,D组给予美托洛尔;同时设假手术组(A组)。观察6周后行心脏超声、血流动力学检查,以及血清尿钠素(ANP)、血管紧张素(Ang)、肿瘤坏死因子α(TNF-α)、白介素6(IL-6)及去甲基肾上腺素(NE)测定。结果β受体阻滞剂能显著降低心衰大鼠的左室舒张末压,增加左室短轴缩短率、左室压力最大上升及下降速率,以及ANP、TNF-α、IL-6、NE(均P<0.05),减小室间隔厚度及左室质量指数(LVWI)(P<0.05);其中卡维地洛降低Ang、减小左室舒张末期直径、降低LVWI的作用明显优于美托洛尔(P<0.05)。结论β受体阻滞剂能较全面地降低神经内分泌、细胞因子,这可能是其改善心脏功能,抑制左室重塑的机制之一。卡维地洛降低神经内分泌、细胞因子,减轻心肌重塑的作用优于美托洛尔。