Beta-blocker selectivity at cloned human beta1- and beta2-adrenergic receptors
Beta-blocker selectivity at cloned human beta1- and beta2-adrenergic receptors
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DOI：
10.1023/a:1007784109255
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发表时间：
1999-04-01
影响因子：
3.4
通讯作者：
Teitler, M
中科院分区：
文献类型：
--
作者：
Smith, C;Teitler, M
β受体阻滞剂对β(2)-和β(1)-受体的亲和力之比通常用于预测肾上腺素受体阻滞剂阻断β(2)-受体介导作用的心脏选择性和潜在后果。这些比率传统上是通过各种β(2)和β(1)受体拮抗剂活性的体外模型来确定的，包括分离的器官制剂和来自不同物种的组织中的放射性配体结合。这些研究的数据虽然有用，但由于使用不同的制剂、技术和非人类模型而变得复杂。已经开发出表达人β(2)和β(1)受体的重组细胞系，允许在相同条件下直接比较β(2)和β(1)受体的β受体阻滞剂的亲和力，并允许精确测定β受体阻滞剂的β(1)受体选择性。利用重组细胞制备的膜，对比索洛尔、阿替洛尔、心得洛尔、倍他洛尔、美托洛尔、卡维地洛尔和ICI 118、551的β受体选择性进行了比较。重组细胞有选择地表达人β(2)和β(1)受体。比索洛尔对β a1受体具有最高的选择性，β (2)/ β(1)比值为19（对β受体的亲和力比β(2)受体高19倍）。阿替洛尔、美托洛尔和倍他洛尔对β(1)受体的选择性虽然显著，但较低，而心得洛尔和卡维地洛则没有显著的β -肾上腺素能选择性。ICI 118,55对β(2)受体具有选择性。β受体阻滞剂对β a1和β(2)受体的平衡解离常数通常与先前报道的值相似。亲和比也与先前报道的值大致相似。
The ratio between the affinities of beta-blockers for the beta(2)- and beta(1)-receptors is often used to predict the cardioselectivity and the potential consequences of blocking beta(2)-receptor-mediated effects of adrenergic receptor blockers. These ratios have been traditionally determined using various in vitro models of beta(2) and beta(1)-receptor antagonist activity, including isolated organ preparations and radioligand binding in tissues from various species. The data from these studies, while useful, are complicated by the use of different preparations, techniques, and nonhuman models. Recombinant cell lines expressing human beta(2) and beta(1) receptors have been developed, allowing for the direct comparison of the affinities of the beta-blockers for the beta(2) and beta(1) receptors under identical conditions, and allowing a precise determination of the beta(1)-receptor selectivity of the beta-blockers. Bisoprolol, atenolol, propranolol, betaxolol, metoprolol, carvedilol, and ICI 118, 551 were compared for their beta-receptor selectivity using membranes prepared from recombinant cells selectively expressing human beta(2) and beta(1) receptors. Bisoprolol was found to have the highest selectivity for the beta1 receptor, displaying a beta(2)/beta(1) ratio of 19 (a 19-fold higher affinity for the beta receptor than for the beta(2) receptor). Atenolol, metoprolol, and betaxolol displayed lower, although significant, selectivity for the beta(1) receptor, whereas propranolol and carvedilol displayed no signiicant beta-adrenergic selectivity. ICI 118,55 was selective for the beta(2) receptor. The equilibrium dissociation constants of the beta-blockers for the beta1 and beta(2) receptors were generally similar to previously reported values. The affinity ratios were also generally similar to previously reported values.