Mechanisms underlying tissue selectivity of anandamide and other vanilloid receptor agonists.
Mechanisms underlying tissue selectivity of anandamide and other vanilloid receptor agonists.
复制标题
anandamide 和其他香草素受体激动剂的组织选择性机制。
DOI：
10.1124/mol.62.3.705
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发表时间：
2002
影响因子：
3.6
通讯作者：
P. Zygmunt
中科院分区：
文献类型：
--
作者：
D. Andersson;M. Adner;E. Högestätt;P. Zygmunt
大麻素在许多生物测定系统中充当完全香草素受体激动剂，但它是气道初级传入神经的弱激活剂。为了解决这一差异，我们比较了不同的香草酸受体激动剂在豚鼠的离体气道和肠系膜动脉中使用含有不同表型的辣椒素敏感的感觉神经的制剂的效果。我们发现花生四烯酸对肠系膜动脉有强的舒张作用，但对主支气管有弱的收缩作用。大麻素的这些作用是由初级传入的香草素受体介导的，不涉及大麻素受体。花生四烯酸乙醇胺也收缩离体肺条，这是花生四烯酸乙醇胺水解和随后形成环氧合酶产物引起的效应。虽然辣椒素在支气管和肠系膜动脉中同样有效，但大麻素、树脂毒素，特别是奥瓦尼在支气管中的效力明显较低。与香草酸受体拮抗剂辣椒平的竞争实验没有提供香草酸受体异质性的证据。花生四烯酰-5-甲氧基色胺（VDM 13），大麻素膜转运蛋白的抑制剂，减弱反应奥瓦尼和大麻素，但不是辣椒素和树脂毒素，在肠系膜动脉。VDM 13不影响支气管对这些激动剂的反应，表明在感觉神经的这种表型中不存在大麻素膜转运蛋白。使用激动作用的操作模型的计算机模拟是一致的，内在功效和受体含量的差异是组织之间激动剂效力的剩余差异的原因。这项研究描述了香草素受体激动剂之间的差异，关于组织选择性，并提供了一个概念框架，开发组织选择性香草素受体激动剂缺乏支气管收缩活性。
Anandamide acts as a full vanilloid receptor agonist in many bioassay systems, but it is a weak activator of primary afferents in the airways. To address this discrepancy, we compared the effect of different vanilloid receptor agonists in isolated airways and mesenteric arteries of guinea pig using preparations containing different phenotypes of the capsaicin-sensitive sensory nerve. We found that anandamide is a powerful vasodilator of mesenteric arteries but a weak constrictor of main bronchi. These effects of anandamide are mediated by vanilloid receptors on primary afferents and do not involve cannabinoid receptors. Anandamide also contracts isolated lung strips, an effect caused by the hydrolysis of anandamide and subsequent formation of cyclooxygenase products. Although capsaicin is equally potent in bronchi and mesenteric arteries, anandamide, resiniferatoxin, and particularly olvanil are significantly less potent in bronchi. Competition experiments with the vanilloid receptor antagonist capsazepine did not provide evidence of vanilloid receptor heterogeneity. Arachidonoyl-5-methoxytryptamine (VDM13), an inhibitor of the anandamide membrane transporter, attenuates responses to olvanil and anandamide, but not capsaicin and resiniferatoxin, in mesenteric arteries. VDM13 did not affect responses to these agonists in bronchi, suggesting that the anandamide membrane transporter is absent in this phenotype of the sensory nerve. Computer simulations using an operational model of agonism were consistent, with differences in intrinsic efficacy and receptor content being responsible for the remaining differences in agonist potency between the tissues. This study describes differences between vanilloid receptor agonists regarding tissue selectivity and provides a conceptual framework for developing tissue-selective vanilloid receptor agonists devoid of bronchoconstrictor activity.
N-花生四烯乙醇酰胺对牛冠状动脉的松弛作用不是由 CB1 大麻素受体介导的。
DOI：
10.1152/ajpheart.1998.274.1.h375
发表时间：
1998
期刊：
The American journal of physiology
影响因子：
--
作者：
Pratt,PF;Hillard,CJ;Edgemond,WS;Campbell,WB
通讯作者：
Campbell,WB
影响因子：
56.9
作者：
DEVANE, WA;HANUS, L;MECHOULAM, R
通讯作者：
MECHOULAM, R