Sigmund M, Jakob H, Becker H, Hanrath P, Schumacher C, Eschenhagen T, Schmitz W, Scholz H, Steinfath M
Medical Clinic I, Rheinisch-Westfälische Technische Hochschule Aachen, Germany.
Eur J Clin Pharmacol. 1996;51(2):127-32. doi: 10.1007/s002280050172.
In human heart failure downregulation of beta-adrenoceptors and upregulation of Gi-protein alpha-subunits (Gi alpha) results desensitization of the myocardial beta-adrenergic signal transduction pathway and reduced positive inotropic effects of catecholamines. Metoprolol treatment has been shown to restore the reduced beta-adrenoceptor density in dilated cardiomyopathy. The main objective of the present study was to investigate whether metoprolol also decreases the elevated inhibitory Gi alpha levels in patients suffering from congestive heart failure.
Total Gi alpha was determined by pertussis toxin-catalysed ADP ribosylation and beta 1- and beta 2-adrenoceptor densities by radioligand binding in right ventricular myocardial biopsies of 18 patients with dilated or ischaemic cardiomyopathy (NYHA II-IV) before and after 3 months of therapy. Nine controls were treated with conventional therapy only [diuretics, digitalis, nitrates, angiotensin-converting enzyme (ACE) inhibitors], and nine received the beta 1-selective blocker metoprolol in addition (mean 98 +/- 12 mg daily).
In biopsies from patients treated with metoprolol, Gi alpha significantly decreased to 74% of predrug value and total beta-adrenoceptor increased by a selective increase in beta 1-adrenoceptors (44.7 vs 34.0 fmol mg-1 protein). These effects were accompanied by significantly increased oxygen uptake at the anaerobic threshold (8.65 vs 6.95 ml . kg-1 . min-1). In the control group no significant changes in biochemical and clinical parameters occurred.
Metoprolol partly reverses Gi alpha-upregulation and beta-adrenoceptor downregulation in heart failure, which might contribute to the clinical improvement of patients treated with beta-blockers.
在人类心力衰竭中，β-肾上腺素能受体下调以及Gi蛋白α亚基（Giα）上调导致心肌β-肾上腺素能信号转导通路脱敏，儿茶酚胺的正性肌力作用减弱。美托洛尔治疗已被证明可恢复扩张型心肌病中降低的β-肾上腺素能受体密度。本研究的主要目的是调查美托洛尔是否也能降低充血性心力衰竭患者升高的抑制性Giα水平。
通过百日咳毒素催化的ADP核糖基化测定总Giα，并通过放射性配体结合法测定18例扩张型或缺血性心肌病（纽约心脏协会II-IV级）患者在治疗3个月前后右心室心肌活检中的β1和β2肾上腺素能受体密度。9名对照组患者仅接受常规治疗（利尿剂、洋地黄、硝酸盐、血管紧张素转换酶抑制剂），另外9名患者还接受β1选择性阻滞剂美托洛尔（平均每日98±12毫克）。
在接受美托洛尔治疗的患者活检中，Giα显著降低至用药前值的74%，总β-肾上腺素能受体通过β1肾上腺素能受体的选择性增加而增加（44.7对34.0 fmol mg-1蛋白）。这些作用伴随着无氧阈值时氧摄取的显著增加（8.65对6.95 ml·kg-1·min-1）。对照组的生化和临床参数无显著变化。
美托洛尔可部分逆转心力衰竭中Giα上调和β-肾上腺素能受体下调，这可能有助于β受体阻滞剂治疗患者的临床改善。
