靶剂量比索洛尔治疗慢性心力衰竭对心脏β1和M2受体自身抗体和心功能的影响

目的探讨靶剂量β受体阻滞剂比索洛尔治疗慢性心力衰竭时对血清中抗心脏β1和M2受体自身抗体和心功能的影响.方法 58例慢性心力衰竭患者随机分为常规治疗组(血管紧张素转换酶抑制剂+利尿剂+地高辛)和比索洛尔组(常规治疗组药物+比索洛尔),随访半年,观察二组治疗前后心功能和两种自身抗体的变化.结果 (1)二组治疗后均较治疗前左心室收缩末径、舒张末径及NYHA分级下降,左室射血分数升高(P<0.01),比索洛尔组的上述变化均较常规治疗组明显(P<0.05).(2)常规治疗组治疗后两种自身抗体阳性率和滴度有下降趋势,但无显著性意义(P>0.05);比索洛尔组治疗后β1和M2受体自身抗体阳性率(均为28.95%和31.58%)较治疗前(均为55.26%)明显下降(P<0.05).β1受体自身抗体转阴率为47.62%,M2受体自身抗体转阴率为42.86%;未转阴者,β1和M2受体自身抗体滴度(分别为162.18和171.27)较治疗前明显降低(均为1144.92,P<0.01).结论β1和 M2受体自身抗体在慢性心力衰竭发病中起着重要作用,β受体阻滞剂可通过阻断β1和M2受体自身抗体对心脏的不利作用而进一步阻止心脏扩大,延缓心室重塑,改善心功能.     

卡维地洛对心力衰竭病人肾上腺素能受体自身抗体及Mg2+代谢的影响

摘 要： 目的 探讨卡维地洛对慢性心力衰竭病人肾上腺素能受体?1、?2、α1自身抗体及Mg2+代谢的影响。方法 慢性心功能不全病人60例，分为卡维地洛组36例和常规治疗组24例，正常对照为健康体检者30例。常规治疗组用血管紧张素转换酶抑制药、利尿剂和强心苷。卡维地洛组在常规治疗的基础上加用卡维地洛。随访6个月，用超声心动图测定心功能参数，酶联免疫吸附实验测定血浆?1、?2、α1自身抗体，测外周单核细胞Mg2+含量及24 h尿Mg2+排泄量。结果 治疗后，卡维地洛组左心室舒张末内径和收缩末内径分别为(57±6) mm和(43±6)mm，显著低于常规治疗组的(64±4)mm和(52±5)mm， 差异有统计学意义(P<0.01)；左心室射血分数为0.51±0.08，显著高于常规治疗组的0.42±0.06，P<0.01)。治疗后卡维地洛组3种抗体阳性率及抗体滴度均显著低于治疗前(P<0.01)，且卡维地洛组3种抗体阳性率及抗体滴度均显著低于常规治疗组，差异有统计学意义(P<0.01)。心力衰竭病人尿Mg2+排泄量明显升高(P<0.01)，单核细胞Mg2+含量降低(P<0.01)。结论 ?1、?2、α1受体参与心力衰竭的发生和发展过程，卡维地洛通过阻断?1、?2、α1受体改善心功能，同时减少尿镁排泄，增加细胞内镁水平。     

心力衰竭患者抗β3 肾上腺素能受体自身抗体的分布及特性

目的探讨心力衰竭(心衰)患者血清中的抗β3肾上腺素能受体(β3-AR)自身抗体的生物学效应,为临床治疗心衰提供新的思路和线索.方法 (1)以人β3-AR细胞外第二环的合成肽段作为抗原,采用ELISA筛选正常人和心衰患者血清中抗β3-AR自身抗体.(2)提纯该抗体阳性的患者血清中的IgG.(3)设立各组对照观察该抗体对成年大鼠心肌细胞收缩效应的影响.(4)设立各组对照观察该抗体对乳鼠心肌细胞跳动频率的影响.结果 (1)正常人抗β3-AR自身抗体的阳性率为11.0%,平均滴度为1∶ 14.59±1.61;心衰患者抗β3-AR自身抗体的阳性率为26.7%,平均滴度为1∶ 43.27±2.71;与正常人相比,P＜0.05.(2)与空白对照组相比,该抗体可降低成年大鼠心肌细胞收缩幅度/初长度(3.84%±0.33%)、收缩速率(-0.47 μm/s±0.07 μm/s)和舒张速率(0.17 μm/s±0.02 μm/s),P＜0.05.该作用不能被纳多洛尔(nadolol,β1-AR和β2-AR受体拮抗剂)阻断,但可被布拉洛尔(bupranolol,非特异性β受体拮抗剂)或β3抗原阻断.(3)与空白对照组(94.3次/min±10.7次/min)相比,该抗体可降低乳鼠心肌细胞跳动频率(47.1次/min±8.11次/min),P＜0.05.同样该作用不能被纳多洛尔阻断,但可被布拉洛尔或β3抗原阻断.此外,该抗体的负性变时效应在观察时间内(6 h)无衰减.结论心衰患者血清中含有较高滴度的抗β3-AR自身抗体并具有负性变力和变时效应,提示该抗体可能参与心衰的病理生理机制.     

卡维地洛对心功能不全患者神经激素系统的影响

目的探讨卡维地洛对慢性心功能不全患者神经激素及肾上腺素受体β1、β2、α1自身抗体的影响。方法60例慢性心功能不全患者随机分为卡维地洛组（36例）和常规治疗组（24例）。常规治疗组应用血管紧张素转换酶抑制剂、利尿剂和洋地黄制剂。卡维地洛组在此基础上加用卡维地洛。随访半年,超声心动图测定心功能参数,检测血浆去甲肾上腺素（NE）、肾素（PRA）、血管紧张素II（AngII）、醛固酮（ALD）、及对抗心脏β1、β2、α1自身抗体。结果治疗后,卡维地洛组左室舒张末内径和收缩末内径分别为（57±6）mm和（43±6）mm显著低于常规治疗组的（64±5）mm和（52±5）mm（均P<0.01）;左室射血分数为（51±8）%,显著高于常规治疗组的（42±6）%（P<0.01）。治疗后卡维地洛组血浆NE、PRA、AngII、ALD、3种抗体滴度均显著降低（均P<0.01）,且卡维地洛组血浆NE、PRA、AngII、ALD水平、3种抗体滴度也显著低于常规治疗组,差异有统计学意义（P<0.05）。结论卡维地洛通过阻断神经激素激活及降低心衰患者心脏自身β1、β2、α1受体抗体水平而改善心功能。     

卡维地洛对心力衰竭病人肾上腺素能受体自身抗体及镁代谢的影响

目的 探讨卡维地洛对慢性心力衰竭病人肾上腺素能受体β1、β2、α1自身抗体及Mg2＋代谢的影响.方法 慢性心功能不全病人60例,分为卡维地洛组36例和常规治疗组24例,正常对照为健康体检者30例.常规治疗组用血管紧张素转化酶抑制药、利尿剂和强心苷.卡维地洛组在常规治疗的基础上加用卡维地洛.随访6个月,用超声心动图测定心功能参数,酶联免疫吸附实验测定血浆β1、β2、α1自身抗体,测外周单核细胞Mg2＋含量及24 h尿Mg2＋排泄量.结果 治疗后,卡维地洛组左心室舒张末内径和收缩末内径分别为（57±6）mm和（43±6）mm,显著低于常规治疗组的（64±4）mm和（52±5）mm,差异有统计学意义（P＜0.01）;左心室射血分数为0.51±0.08,显著高于常规治疗组的0.42±0.06（P＜0.01）.治疗后卡维地洛组3种抗体阳性率及抗体滴度均显著低于治疗前（P＜0.01）,且卡维地洛组3种抗体阳性率及抗体滴度均显著低于常规治疗组,差异有统计学意义（P＜0.01）.心力衰竭病人尿Mg2＋排泄量明显升高（P＜0.01）,单核细胞Mg2＋含量降低（P＜0.01）.结论 β1、β2、α1受体参与心力衰竭的发生和发展过程,卡维地洛通过阻断β1、β2、α1受体改善心功能,同时减少尿镁排泄,增加细胞内镁水平.     

比索洛尔对抗β1-肾上腺素能受体自身抗体阳性心衰大鼠心功能的影响

目的 探讨比索洛尔对抗β1-肾上腺素能受体（β1-AR）自身抗体阳性心衰大鼠心功能的影响。方法 采用缩窄腹主动脉的方法,建立慢性心力衰竭的大鼠模型。将心衰组大鼠（90只最终入组65只）随机分为心衰治疗组（40只）和心衰非治疗组（25只）。心衰治疗组接受比索洛尔4周的治疗。心衰非治疗组接受同剂量的蒸馏水同样时间的治疗。应用ELISA法检测大鼠血清β1-AR自身抗体的阳性率和滴度;应用BL-420E生物机能实验系统于治疗前及治疗后4周检测心功能。结果 ①治疗组组内抗β1-AR自身抗体阳性者较阴性者左室舒张末压低,左室变化的最大速率升高,但无统计学意义;非治疗组组内抗β1-AR自身抗体阳性者较阴性大鼠的心功能进一步恶化,左室舒张末压明显升高（P<0.01）,左室变化的最大速率下降（P<0.05）。②治疗组中抗β1-AR自身抗体阳性者与非治疗组中抗β1-AR自身抗体阳性者比较,前者较后者左室舒张末压明显下降（P<0.01）;左室变化的最大速率均显著升高（P<0.05）。结论 比索洛尔治疗后,心衰大鼠抗β1-AR自身抗体阳性者的心功能较非治疗组中抗β1-AR自身抗体阳性者的心功能明显改善。同为治疗组的抗β1-AR自身抗体阳性者的心功能较阴性者的左室舒张末压低,左室变化的最大速率升高。     

心力衰竭患者与心脏β2、α1肾上腺素能受体和血管紧张素Ⅱ1型受体的自身抗体

目的　本研究检测不同心脏病所致的慢性心力衰竭 (心衰 )患者 β2 、α1 肾上腺素能受体和血管紧张素Ⅱ 1型 (AT1 )受体的自身抗体 ,探讨心功能发生病理变化时 ,上述三种自身抗体的产生与疾病的相关性。方法　以细胞外第二环表位肽段的合成肽作为抗原 ,应用酶联免疫吸附测定(ELISA)技术 ,随机检测 2 67例受试者血清中 β2 、α1 和AT1 受体的自身抗体。心衰组为 2 0 6例不同心脏病的心衰患者 ,其中缺血性心肌病 63例、扩张型心肌病 86例、高血压病 57例。正常组为 61例正常人作对照。结果　 (1 )心衰组 β2 、α1 和AT1 受体的自身抗体阳性分别为 46 1 % (95/ 2 0 6)、48 5 % (1 0 0 /2 0 6)和 46 6 % (96/ 2 0 6) ,明显高于正常组的 8 2 % (5/ 61 )、9 8% (6/ 61 )和 1 3 1 % (8/ 61 ) ,P <0 0 1 ;(2 )心衰组自身抗体阳性患者的抗体滴度分别为 1∶89、1∶98和 1∶96 ,明显高于正常组的 1∶35、1∶32和 1∶31 ,P <0 0 1 ;(3)心衰组 β2 受体自身抗体阳性者 95例中 ,有 60例 (63 2 % )患者同时具有α1 受体的自身抗体 ,有 64例 (67 4% )患者同时具有AT1 受体的自身抗体 ,有 51例 (53 7% )的患者同时具有上述三种受体的自身抗体阳性。结论　β2 、α1 和AT1 受体的自身抗体不仅存在于多种心脏病心衰患者     

卡维地洛对老年慢性心力衰竭合并室性心律失常患者血清肾上腺素受体自身抗体的影响

目的 研究卡维地洛对老年慢性心力衰竭(心衰)合并室性心律失常(室律失常)患者血清抗β1、β2和α1肾上腺素受体自身抗体的影响.方法 将68例老年冠心病心衰合并有室律失常的患者随机分为两组,在常规强心利尿治疗的同时,一组给予美托洛尔、另一组给予卡维地洛治疗,检测两组治疗前和治疗后6个月心脏超声、B型利钠肽(BNP)、动态心电图和抗β1、β2和α1受体自身抗体阳性率的改变,同时检测治疗前后血压、心率、肝和肾功能的变化.结果 与治疗前相比,两组均使心衰患者的基础心率和BNP下降,左室射血分数(LVEF值)升高,心脏功能得到改善;与美托洛尔组相比,卡维地洛治疗后收缩压和BNP下降更明显,差异有统计学意义(P<0.01).美托洛尔治疗后,可使患者血清中抗β1受体自身抗体的阳性率下降(P<0.05),而对抗β2和α1 受体自身抗体的阳性率没有影响(P>0.05).卡维地洛治疗后,血清中抗β1、β2和α1受体自身抗体的阳性率均明显下降(P<0.01),室律失常的发生率也比美托洛尔治疗组明显下降(P<0.01).结论 对老年冠心病慢性心衰合并室律失常患者,应用卡维地洛比美托洛尔能更有效地降低室律失常的发生.     

慢性心力衰竭患者心脏β1受体自身抗体与心功能的相关性及临床意义

目的 通过对慢性心力衰竭（心衰）患者血清中β1肾上腺素能受体自身抗体水平的监测,预测心功能情况,并指导β受体阻滞剂卡维地洛的临床应用。方法 65例心衰患者采用酶联免疫法测定患者血清中β1受体自身抗体水平,据此分为β1受体自身抗体阳性组（β1阳性组）30例和β1受体自身抗体阴性组（β1阴性组）35例,在血管紧张素转换酶抑制剂、利尿剂和洋地黄制剂治疗基础上加用β受体阻滞剂卡维地洛。随访半年,治疗前后采用超声心动图测量左室舒张末径（LVEDD）,左室收缩末径（LVESD）和左室射血分数（LVEF）进行比较。结果 （1）β1阳性组卡维地洛靶剂量明显高于β1阴性组[（36．25±14．31）mg／d与（25．97±8．83）mg／d],P〈0．01。（2）治疗前,p1阳性组心率显著高于p1阴性组[（94．19±14．46）次／min与（86．56±15．88）次／min],P〈0．05。治疗后,两组心率、血压均较治疗前显著减低（P〈0．01）,β1阳性组心率与β阴性组差异无统计学意义（P〉0．05）。（3）治疗前,β1阳性组LVEDD显著大于β1阴性组[（66．01±5．47）mm与（63．07±5．64）min],P〈0．05;LVESD大于β1阴性组[（54．24±8．43）mm与（50．72±6．12）min],P=0．052;LVEF显著低于β1阴性组[（32．16±9．00）％与（36．64±8．20）％],P〈0．05。治疗后,两组LVEDD、LVESD均较治疗前显著减小（P〈0．01）,LVEF较治疗前提高（P〈0．01）。β1阳性组LVEDD、LVESD和LYEF与β1阴性组差异无统计学意义（P〉0．05）。（4）β1阳性组治疗后血清中抗心脏β1受体自身抗体滴度较治疗前显著降低（1：119．35与1：72．21）,P〈0．01。结论 β1受体自身抗体参与心衰的病理生理过程,通过对β1受体自身抗体的检测可以预测患者的临床过程,提示对β1受体抗体阳性患者尽早使用β受体阻滞剂对于抑制心肌重构、改善心功能受益更大。     

比索洛尔对β_1肾上腺素受体自身抗体阳性心力衰竭大鼠Bcl-2/Bax的影响

目的探讨比索洛尔在降低β1肾上腺素受体(β1-AR)自身抗体阳性率和抗体滴度的同时,是否可以抑制细胞凋亡。方法将90只SD大鼠中80只采用缩窄腹主动脉方法,建立心力衰竭的大鼠模型,15只死亡,入组65只,将大鼠随机分为治疗组(40只)和非治疗组(25只)。治疗组接受比索洛尔4周治疗后,应用ELISA技术检测两组大鼠血清β1-AR自身抗体阳性率和滴度。应用免疫组织化学测两组大鼠血清β1-AR自身抗体阳性的Bax/Bcl-2。结果治疗组较治疗前β1-AR自身抗体阳性率降低27.5%(P<0.05);非治疗组无统计学差异(P>0.05);治疗组较治疗前β1-AR自身抗体滴度降低(P<0.01);非治疗组β1-AR自身抗体阳性滴度无显著差异(P>0.05);治疗组中Bcl-2的表达在β1-AR自身抗体阳性大鼠比阴性大鼠、非治疗组β1-AR阳性大鼠明显增高(P<0.01);Bax的表达比非治疗组阳性大鼠降低(P<0.01);且比同组阴性略有降低。结论比索洛尔治疗降低心力衰竭大鼠β1-AR自身抗体阳性率及抗体滴度,升高了β1-AR自身抗体阳性心力衰竭大鼠Bcl-2/Bax的比值。     

Lung function with carvedilol and bisoprolol in chronic heart failure: Is β selectivity relevant?

BACKGROUND: Carvedilol is a beta-blocker with similar affinity for beta1- and beta2 receptors, while bisoprolol has higher beta1 affinity. The respiratory system is characterized by beta2-receptor prevalence. Airway beta receptors regulate bronchial tone and alveolar beta receptors regulate alveolar fluid re-absorption which influences gas diffusion. AIMS: To compare the effects of carvedilol and bisoprolol on lung function in patients with chronic heart failure (CHF). METHODS AND RESULTS: We performed a double-blind, cross-over study in 53 CHF patients. After 2 months of full dose treatment with either carvedilol or bisoprolol, we assessed lung function by salbutamol challenge, carbon monoxide lung diffusion (DLCO), including membrane conductance (DM), and gas exchange during exercise. FEV1 and FVC were similar; after salbutamol FEV1 was higher with bisoprolol (p<0.04). DLco was 82+/-21% of predicted with carvedilol and 90+/-20% with bisoprolol (p<0.01) due to DM changes. Peak VO2 was 17.8+/-4.5 mL/min/kg on bisoprolol and 17.0+/-4.6 on carvedilol, (p<0.05) with no differences in bronchial tone (same expiratory time) throughout exercise. Differences were greater in the 22 subjects with DLCO<80%. CONCLUSION: Carvedilol and bisoprolol have different effects on DLCO and response to salbutamol. DLCO differences, being DM related, are due to changes in active membrane transport which is under alveolar beta2-receptor control. Peak VO2 was slightly higher with bisoprolol particularly in CHF patients with reduced DLCO.     

Lack of evidence for peripheral alpha(1)- adrenoceptor blockade during long-term treatment of heart failure with carvedilol.

OBJECTIVES: The purpose of this study was to determine whether carvedilol's alpha(1)-adrenoceptor antagonism persists during long-term therapy of patients with congestive heart failure (CHF). BACKGROUND: Carvedilol and metoprolol differ in that carvedilol also antagonizes beta(2)- and alpha(1)-adrenoceptors. We hypothesized that in contrast to metoprolol, carvedilol would increase calf vascular conductance (CVC), blunt neurally mediated vasoconstriction and attenuate neuroeffector transfer function gain. METHODS: We randomized 36 patients with CHF (age 55 +/- 1 years, ejection fraction 19 +/- 1%, means +/- SE) to either drug. Blood pressure (BP), heart rate, muscle sympathetic nerve activity (MSNA) and CVC were assessed before and after four months of treatment. The variability of BP and MSNA was determined using fast Fourier transformation. RESULTS: Paired data were obtained in 23 (carvedilol, 13; metoprolol, 10) subjects. Both beta-blockers decreased heart rate, but neither affected mean BP or CVC (carvedilol: 0.016 +/- 0.002 to 0.018 +/- 0.003 U; metoprolol: 0.020 +/- 0.002 to 0.020 +/- 0.004 U). Isometric handgrip exercise (30% of maximum) increased heart rate, mean BP and MSNA. The calf vasoconstrictor response to handgrip exercise was not affected by carvedilol (from 16 +/- 6 resistance U to 25 +/- 10 resistance U, NS). The gain of the transfer of oscillations in MSNA into BP under resting conditions was not attenuated by carvedilol. CONCLUSIONS: Carvedilol did not increase CVC, blunt the calf vasoconstrictor response to handgrip or attenuate the gain of the neuroeffector transfer function, indicating the absence of functionally important peripheral alpha(1)-adrenoceptor antagonism during long-term treatment of CHF.     

卡维地洛对慢性心力衰竭患者心功能和脑钠素的影响

目的观察卡维地洛对慢性心力衰竭(CHF)患者心功能和脑钠素(BNP)的影响。方法50例CHF患者随机分为常规治疗组和卡维地洛治疗组,观察治疗前、后BNP以及左室射血分数(LVEF)、左室短轴缩短率(FS)、每搏出量(SV)、心输出量(CO)、心脏指数(CI)等指标变化。结果两组治疗后BNP浓度均比治疗前有显著降低(P<0.05或P<0.01);与常规治疗组相比较,卡维地洛治疗组治疗后的BNP浓度降低差异有统计学意义(P<0.01),临床症状改善的总有效率显著增加(P<0.05),心功能各项指标(LVEF、FS、SV、CO、CI)得到明显改善(P<0.05或P<0.01)。结论卡维地洛能显著降低CHF患者的血浆BNP水平,改善其心功能状态。     

心脏β1和M2受体自身抗体与心力衰竭的研究

目的：探讨心力衰竭（心衰）患者心脏β1和M2受体自身抗体的产生与疾病发生、发展的相关性。方法：以细胞外第二环表位肽段的合成肽作为抗原,应用酶联免疫吸附测定技术,检测265例受试者血清中心脏β1和M2受体的自身抗体。结果：心衰组β1受体自身抗体的阳性率为45．7％（86／188）,明显高于单纯高血压组和对照组的10．4％（8／77）,P＜0．01;心衰组M2受体自身抗体的阳性率为52．7％（99／188）,明显高于单纯高血压组和对照组的11．7％（9／77）,P＜0．01;心功能Ⅱ-Ⅲ级的阳性率及抗体滴度明显高于Ⅳ级;心衰组β1受体自身抗体阳性血清中高达56．1％的患者同时具有M2受体的自身抗体。结论：心脏β1和M2受体自身抗体存在于多种心脏病心衰患者的血清中,可能与心衰时心肌结构变化和功能下降有关,与原发心脏病无明显因果关系;心脏β1和M2受体的双抗体阳性可能是自身免疫反应的多重性表现,提示免疫学机制参与心衰和（或）心肌重构的病理生理过程,参与的程度与疾病的早、中期大于晚期。     

The effects of chronic carvedilol therapy on QT dispersion in patients with congestive heart failure.

BACKGROUND: Carvedilol therapy reduces mortality from sudden cardiac death and progressive pump failure in congestive heart failure (CHF). However, the effect(s) of carvedilol on ventricular repolarization characteristics is unclear. AIM: The aim of the study was to investigate the effects of chronic carvedilol therapy on ventricular repolarization characteristics as assessed by QT dispersion (QTd) in patients with CHF. METHOD: Nineteen patients (age 53+/-12 years; 16 male, three female) with CHF (eight ischemic, 11 non-ischemic dilated cardiomyopathy) were prospectively included in the study. Carvedilol was administered in addition to standard therapy for CHF at a dose of 3.125 mg bid and uptitrated biweekly to the maximum tolerated dose. From standard 12-lead electrocardiograms the maximum and minimum QT intervals (QTmax, QTmin), QTd, corrected QT intervals (QTcmax, QTcmin) and corrected QTd (QTcd) values were calculated at baseline, after the 2nd and the 16th month of carvedilol therapy. RESULTS: A significant reduction was noted in the QTd and QTcd values with carvedilol therapy after the 16th month (QTd: 81+/-22 ms vs. 40+/-4.3 ms P<0.001; QTcd: 91+/-25 ms vs. 51+/-7 ms P<0.001), but not after the 2nd month (P>0.05). The resting heart rate was also significantly reduced after a 16-month course of carvedilol therapy (78+/-13 bpm vs. 66+/-15 bpm, P<0.05). Carvedilol therapy did not alter QTmax and QTcmax intervals (P>0.05), however, QT min and QTcmin significantly increased with carvedilol at the 16th month (P<0.001 and P<0.01, respectively). CONCLUSION: Long-term carvedilol therapy was associated with a reduction in QTd, an effect that might contribute to the favorable effects of carvedilol in reducing sudden cardiac death in CHF.     

Carvedilol blocks beta2- more than beta1-adrenoceptors in human heart

OBJECTIVE: To understand the basis of the effectiveness of carvedilol in heart failure by determining its specific properties at human heart beta1- and beta2-adrenoceptors. METHODS: The positive inotropic effects of noradrenaline (in the presence of the beta2-selective antagonist ICI118551) and adrenaline (in the presence of the beta1-selective antagonist CGP20712), mediated through beta1- and beta2-adrenoceptors, respectively, were investigated in atrial and ventricular trabeculae. The patch-clamp technique was used to investigate effects of noradrenaline and adrenaline on L-type Ca2+ current in human atrial myocytes. RESULTS: Carvedilol was a 13-fold more potent competitive antagonist of the effects of adrenaline at beta2-adrenoceptors (-logKB=10.13+/-0.08) than of noradrenaline at beta1-adrenoceptors (-logKB=9.02+/-0.07) in human right atrium. Chronic carvedilol treatment of patients with non-terminal heart failure reduced the inotropic sensitivity of atrial trabeculae to noradrenaline and adrenaline 5.6-fold and 91.2-fold, respectively, compared to beta1-blocker-treated patients, consistent with persistent preferential blockade of beta2-adrenoceptors. In terminal heart failure carvedilol treatment reduced 1.8-fold and 25.1-fold the sensitivity of right ventricular trabeculae to noradrenaline and adrenaline, respectively, but metoprolol treatment did not reduce the sensitivity to the catecholamines. Increases of current (ICa,L) produced by noradrenaline and adrenaline were not different in atrial myocytes obtained from non-terminal heart failure patients treated with metoprolol or carvedilol, consistent with dissociation of both beta-blockers from the receptors. CONCLUSIONS: Carvedilol blocks human cardiac beta2-adrenoceptors more than beta1-adrenoceptors, thereby conceivably contributing to the beneficial effects in heart failure. The persistent blockade of beta-adrenoceptors is attributed to accumulation of carvedilol in cardiac tissue.     

Beneficial effects of carvedilol on angiotensin-converting enzyme activity and renin plasma levels in patients with chronic heart failure

OBJECTIVE: To assess the effects of carvedilol treatment on the renin-angiotensin system in patients with chronic heart failure (CHF). Background: Carvedilol improves survival of patients suffering from CHF but the effects of the drug on angiotensin-converting enzyme (ACE) activity, renin and aldosterone are not well characterized in patients receiving an ACE inhibitor. METHODS: A randomized, multicenter, double-blind, 6-month, placebo-controlled study of carvedilol vs. placebo was conducted in 64 CHF patients. Circulating levels of ACE activity, active renin and aldosterone as well as left ventricular diameters and ejection fraction by echography were assessed. RESULTS: During the study, left ventricular ejection fraction increased from 25+/-11% to 31+/-12% with carvedilol and from 27+/-12% to 28+/-12% with placebo (P=0.03). This beneficial effect was associated with marked blunting of active renin secretion (-53% in the carvedilol group vs.-13% in the placebo group, P=0.04). ACE activity was reduced by 30% in the carvedilol group (P=0.07 vs. placebo). Aldosterone was not changed. CONCLUSION: Carvedilol markedly reduced the increase in active renin observed with time despite ACE-inhibitors and tended to decrease ACE activity. These findings may in part explain the beneficial actions of carvedilol and highlights the profound effect of betablockade on renin in patients already receiving ACE-inibitors.