Nuttall S L, Routledge H C, Kendall M J
Division of Medical Sciences, Queen Elizabeth Hospital, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
J Clin Pharm Ther. 2003 Jun;28(3):179-86. doi: 10.1046/j.1365-2710.2003.00477.x.
To determine the relative beta1-selectivity of three beta-blockers (nebivolol, bisoprolol and atenolol), administered orally at normal therapeutic doses, by assessing their impact on the beta2-mediated, haemodynamic and biochemical responses to a terbutaline infusion, which decreases serum potassium and increases serum glucose and insulin.
Twenty-four healthy volunteers (14 men, 10 women), with no history of respiratory disease, attended on five separate occasions; beta-blockers (nebivolol 5 mg, bisoprolol 10 mg, atenolol 50 and 100 mg) or placebo were supplied in random order. Three baseline blood samples were collected at 65-85 min post-beta-blocker. A 60-min terbutaline infusion was started 90 min after taking the beta-blocker. Blood samples were taken and blood pressure and heart rate recorded at 15 min intervals up to 30-min post-infusion. Blood samples were analysed for serum potassium, glucose and insulin concentrations.
Terbutaline increased heart rate. Pretreatment with nebivolol caused a modest and non-significant reduction in terbutaline-induced tachycardia whilst bisoprolol produced a more marked effect. Atenolol at both 50 and 100 mg doses caused a highly significant reduction in terbutaline-induced tachycardia. All active preparations had a comparable impact on the terbutaline-induced increase in systolic blood pressure, but the drugs had no impact on the changes produced in diastolic blood pressure. After pretreatment with placebo, the terbutaline infusion caused a significant decrease in serum potassium and increases in serum glucose and insulin. Pretreatment with nebivolol had no discernible effect on potassium compared with placebo. In contrast, when compared with either placebo or nebivolol, bisoprolol (P < 0.01) and both doses of atenolol (P < 0.001) significantly attenuated the hypokalaemic effect of terbutaline. Treatment with nebivolol and bisoprolol modestly but significantly reduced the terbutaline-induced increases in glucose (P < 0.05). The blocking effects of both doses of atenolol were highly significant (P < 0.001) when compared with placebo and also significant (P < 0.05 and P < 0.01, respectively) when compared with nebivolol and bisoprolol. A similar pattern of responses with the different beta-blocker treatments was observed for the effects on insulin concentrations during the terbutaline infusion.
The beta1-selectivity of three different beta1-blockers has been demonstrated in healthy volunteers using the blocking of biochemical and haemodynamic responses to a beta2 stimulus. Terbutaline alone caused an increase in heart rate, a rise in systolic blood pressure, a fall in serum potassium and a rise in both serum glucose and insulin. In this study, for both haemodynamic and biochemical responses, atenolol 100 mg had the greatest beta2-blocking effect, nebivolol 5 mg the least. Bisoprolol 10 mg and atenolol 50 mg had intermediate effects; bisoprolol was the more beta1-selective of these two.
通过评估三种β受体阻滞剂（奈必洛尔、比索洛尔和阿替洛尔）在正常治疗剂量口服时，对特布他林输注所介导的β2血流动力学和生化反应的影响，来确定它们的相对β1选择性。特布他林输注会降低血清钾水平，并升高血清葡萄糖和胰岛素水平。
24名无呼吸系统疾病史的健康志愿者（14名男性，10名女性）分五次前来；β受体阻滞剂（奈必洛尔5毫克、比索洛尔10毫克、阿替洛尔50毫克和100毫克）或安慰剂按随机顺序给药。在服用β受体阻滞剂后65 - 85分钟采集三份基线血样。服用β受体阻滞剂90分钟后开始60分钟的特布他林输注。在输注后30分钟内，每隔15分钟采集血样，并记录血压和心率。对血样进行血清钾、葡萄糖和胰岛素浓度分析。
特布他林使心率增加。奈必洛尔预处理使特布他林诱发的心动过速有适度且无显著意义的降低，而比索洛尔产生的作用更明显。50毫克和100毫克剂量的阿替洛尔均使特布他林诱发的心动过速显著降低。所有活性制剂对特布他林诱发的收缩压升高有类似影响，但这些药物对舒张压的变化无影响。安慰剂预处理后，特布他林输注使血清钾显著降低，血清葡萄糖和胰岛素升高。与安慰剂相比，奈必洛尔预处理对钾无明显影响。相比之下，与安慰剂或奈必洛尔相比，比索洛尔（P < 0.01）和两种剂量的阿替洛尔（P < 0.001）均显著减弱了特布他林的低钾血症作用。奈必洛尔和比索洛尔治疗适度但显著降低了特布他林诱发的葡萄糖升高（P < 0.05）。与安慰剂相比，两种剂量的阿替洛尔的阻断作用均高度显著（P < 0.001），与奈必洛尔和比索洛尔相比也显著（分别为P < 0.05和P < 0.01）。在特布他林输注期间，不同β受体阻滞剂治疗对胰岛素浓度的影响观察到类似的反应模式。
在健康志愿者中，通过阻断对β2刺激的生化和血流动力学反应，证实了三种不同β1受体阻滞剂的β1选择性。单独使用特布他林会使心率增加、收缩压升高、血清钾降低以及血清葡萄糖和胰岛素升高。在本研究中，对于血流动力学和生化反应，100毫克阿替洛尔的β2阻断作用最大，5毫克奈必洛尔最小。10毫克比索洛尔和50毫克阿替洛尔有中等作用；比索洛尔在这两者中β1选择性更强。
