Anderson R, Ramafi G, Theron A J
Department of Immunology, University of Pretoria, South Africa.
Biochem Pharmacol. 1996 Jul 26;52(2):341-9. doi: 10.1016/0006-2952(96)00212-2.
We have investigated the effects of the beta-adrenoreceptor-blocking agent, propranolol (9-300 microM) on several pro-inflammatory activities of human neutrophils in vitro. Superoxide production by calcium ionophore (A23187)-activated neutrophils was particularly sensitive to inhibition by low concentrations (9-18.7 microM) of this drug. However, inhibition of superoxide generation by neutrophils activated with phorbol myristate acetate (PMA), opsonized zymosan (OZ), and arachidonate (AA) only occurred with higher concentrations of propranolol, and coincided with decreased intracellular calcium fluxes, phospholipase A2 (PLA2) activity and synthesis of platelet-activating factor (PAF). Propranolol possessed neither cytotoxic nor superoxide-scavenging properties but, using a haemolytic assay of membrane-stabilizing activity, this agent neutralized the membrane-disruptive effects of the bioactive phospholipids, lysophosphatidylcholine (LPC), PAF, and lysoPAF(LPAF). A mechanistic relationship between the anti-oxidative and membrane-stabilizing properties of propranolol was suggested by the observation that pretreatment of neutrophils with LPC or PAF eliminated the inhibitory effects of the drug on superoxide generation by PMA-activated neutrophils. Dexpropranolol, a stereoisomer with minimal beta-blocking activity, and propranolol were equally effective with respect to their membrane-stabilizing and anti-oxidative interactions with neutrophils, but several other beta-blocking agents (atenolol, metoprolol, sotalol, and timolol) did not possess these activities. Inhibition of oxidant generation is, therefore, not a common property of beta-blocking agents and, in the case of propranolol, appears to occur as a consequence of membrane-stabilization rather than by beta-receptor-directed effects.
我们研究了β-肾上腺素受体阻断剂普萘洛尔（9 - 300微摩尔）对人中性粒细胞多种促炎活性的体外影响。钙离子载体（A23187）激活的中性粒细胞产生超氧化物的过程对该药物的低浓度（9 - 18.7微摩尔）抑制特别敏感。然而，仅在普萘洛尔浓度较高时，佛波酯肉豆蔻酸酯（PMA）、调理酵母聚糖（OZ）和花生四烯酸（AA）激活的中性粒细胞产生超氧化物才受到抑制，同时细胞内钙通量、磷脂酶A2（PLA2）活性及血小板活化因子（PAF）合成均降低。普萘洛尔既无细胞毒性也无超氧化物清除特性，但通过溶血法检测膜稳定活性时，该药物可中和生物活性磷脂溶血磷脂酰胆碱（LPC）、PAF和溶血PAF（LPAF）的膜破坏作用。观察到用LPC或PAF预处理中性粒细胞可消除该药物对PMA激活的中性粒细胞产生超氧化物的抑制作用，提示普萘洛尔的抗氧化和膜稳定特性之间存在机制联系。右旋普萘洛尔是一种β阻断活性极小的立体异构体，其与中性粒细胞的膜稳定和抗氧化相互作用方面与普萘洛尔同样有效，但其他几种β阻断剂（阿替洛尔、美托洛尔、索他洛尔和噻吗洛尔）不具备这些活性。因此，抑制氧化剂生成并非β阻断剂的共同特性，就普萘洛尔而言，其抑制作用似乎是膜稳定的结果，而非β受体导向效应所致。
