Mechanisms underlying tissue selectivity of anandamide and other vanilloid receptor agonists

被引:41
作者
Andersson, DA
Adner, M
Högestätt, ED [1 ]
Zygmunt, PM
机构
[1] Lund Univ, Univ Lund Hosp, Dept Clin Pharmacol, SE-22185 Lund, Sweden
[2] Lund Univ, Univ Lund Hosp, Inst Lab Med, Lund, Sweden
[3] Lund Univ, Malmo Univ Hosp, Dept Otorhinolaryngol, Lund, Sweden
关键词
D O I
10.1124/mol.62.3.705
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
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页码:705 / 713
页数:9
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