Inverse agonism of histamine H-2 antagonists accounts for upregulation of spontaneously active histamine H-2 receptors
Inverse agonism of histamine H-2 antagonists accounts for upregulation of spontaneously active histamine H-2 receptors
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DOI：
10.1073/pnas.93.13.6802
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发表时间：
1996-06-25
影响因子：
11.1
通讯作者：
Timmerman, H
中科院分区：
文献类型：
--
作者：
Smit, MJ;Leurs, R;Timmerman, H
在中国仓鼠卵巢（CHO）细胞中转染的组胺H-2受体在暴露于H-2拮抗剂西咪替丁和雷尼替丁后呈时间和剂量依赖性上调。这种作用似乎是H-2受体介导的，因为在H-1或H-3拮抗剂处理后或与西咪替丁的结构类似物VWF 8299孵育后，没有观察到受体密度的变化，VWF 8299没有H-2拮抗作用，Bq使用表达不同密度的野生型H-2受体或未偶联的H（2）Leu（124）Ala受体的转染的CRO细胞，发现组胺H-2受体显示出相当大的激动剂非依赖性H-2受体活性。西咪替丁和雷尼替丁均诱导H-2受体上调，实际上在显示自发激动剂非依赖性H-2受体活性的那些细胞系中充当反向激动剂，另一方面，布瑞米特显示充当中性拮抗剂，并且如预期的那样在长期暴露后不诱导H-2受体上调，所显示的H-2拮抗剂的反向激动作用似乎是在转染的CHO细胞中观察到的H-2拮抗剂诱导的H-2受体上调的机制基础，这些观察结果为H-2拮抗剂的药理学分类提供了新的线索，并为长期临床使用后观察到的耐受性发展提供了合理的解释。
Histamine H-2 receptors transfected in Chinese hamster ovary (CHO) cells are time- and dose-dependently upregulated upon exposure to the H-2 antagonists cimetidine and ranitidine. This effect appears to be H-2 receptor-mediated as no change in receptor density was observed after H-1 or H-3 antagonist treatment or after incubation with the structural analogue of cimetidine, VWF 8299, which has no H-2 antagonistic effects, Bq using transfected CRO cells expressing different densities of wild-type H-2 receptors or an uncoupled H(2)Leu(124)Ala receptor, the histamine H-2 receptor was found to display considerable agonist-independent H-2 receptor activity. Cimetidine and ranitidine, which both induce H-2 receptor upregulation, actually functioned as inverse agonists in those cell lines displaying spontaneous agonist-independent H-2 receptor activity, Burimamide, on the other hand, was shown to act as a neutral antagonist and did as expected not induce H-2 receptor upregulation after long-term exposure, The displayed inverse agonism of H-2 antagonists appears to be a Mechanistic basis for the observed H-2 antagonist-induced H-2 receptor upregulation in transfected CHO cells, These observations shed new light on the pharmacological classification of the H-2 antagonists and mag offer a plausible explanation for the observed development of tolerance after prolonged clinical use.