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Effect of temperature on alpha2-adrenoceptor-mediated contraction of rat tail veins.

机译:温度对α2-肾上腺素受体介导的大鼠尾静脉收缩的影响。

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摘要

alpha2-Adrenoceptors are G protein-coupled receptors (GPCRs) that are classified to three subtypes, alpha2A/D-, alpha 2B- and alpha2C-subtypes. The alpha2D-subtype in rodent is a species homolog of the human alpha2A-subtype. Constriction of cutaneous veins mediated by alpha2-adrenoceptors plays an important role in thermoregulation. The aim of this work was to understand how cooling affects alpha2-adrenoceptor-mediated venous contraction using the isolated rat tail vein. A series of experimental conditions to study alpha 2-adrenoceptor-mediated contraction of the rat tail vein were established in preliminary studies. Cooling from 37°C to 28°C increased the potencies and maximal contractions to the alpha2-adrenoceptor agonists UK14304, guanabenz, BHT933, and dexmedetomidine; but not to other GPCR agonists including 5-HT, angiotensin II, arginine vasopressin and uridine-5'-triphospate. Thus cooling selectively increased contraction activated by alpha2 -adrenoceptors. The affinities (KB values) of a panel of competitive alpha2-adrenoceptor antagonists (RX821002, non-selective; ARC239, alpha2B-subtype selective; MK912, alpha2C-subtype selective; rauwolscine, alpha2C-subtype selective and BRL44408, alpha 2A/D-subtype selective) were not consistently altered by cooling. The affinities of these antagonists were consistent with the alpha2C-subtype causing contraction at both 37°C and 28°C. The affinity (KA value) of UK14304 was not changed by cooling. However the affinities (KP values) of guanabenz and BHT933 were increased by cooling, in parallel with a change in their potencies. Analysis of receptor occupancy-response relationships for guanabenz and BHT933 indicated that their increased potencies could be explained by increased affinities after cooling. Analysis using the operational model of drug-receptor theory found that cooling increased the relative efficacy of UK14304 but not that of guanabenz and BHT933, suggesting that the increased relative efficacy of UK14304 contributed to its increased potency. Other mechanisms possibly associated with increased contraction caused by cooling were also studied but the results were inconclusive. These studies include new receptors possibly translocated from intracellular receptor pool, receptor coupling to G proteins other than Gi proteins and involvement of Rho kinase activation. The rat tail vein is a useful model for screening alpha 2C-adrenoceptor selective agents and for studying the thermoregulatory function of cutaneous veins.
机译:alpha2-肾上腺素受体是G蛋白偶联受体(GPCR),分为三种亚型,即alpha2A / D-,alpha 2B-和alpha2C亚型。啮齿动物中的alpha2D亚型是人类alpha2A亚型的物种同源物。由α2-肾上腺素受体介导的皮肤静脉收缩在温度调节中起重要作用。这项工作的目的是了解冷却如何使用分离的大鼠尾静脉影响α2-肾上腺素受体介导的静脉收缩。在初步研究中,建立了一系列研究条件,以研究α2-肾上腺素受体介导的大鼠尾静脉收缩。从37°C冷却至28°C,可增强α2肾上腺素受体激动剂UK14304,瓜纳本斯,BHT933和右美托咪定的效力和最大收缩。但对其他GPCR激动剂却没有,包括5-HT,血管紧张素II,精氨酸加压素和尿苷5'-三磷酸酯。因此,冷却选择性地增加了由α2-肾上腺素受体激活的收缩。一组竞争性的α2-肾上腺素受体拮抗剂(RX821002,非选择性; ARC239,α2B-亚型选择性; MK912,α2C-亚型选择性; rauwolscine,α2C-亚型选择性和BRL44408,α2A/ D-亚型(选择性亚型)并未通过冷却持续改变。这些拮抗剂的亲和力与导致在37°C和28°C收缩的alpha2C亚型一致。 UK14304的亲和力(KA值)不会因冷却而改变。但是,通过冷却增加了瓜纳本斯和BHT933的亲和力(KP值),同时还改变了其效力。瓜纳本斯和BHT933的受体占有率-响应关系分析表明,冷却后的亲和力增加可以解释它们的效力增加。使用药物受体理论的操作模型进行的分析发现,冷却增加了UK14304的相对功效,但没有增加瓜纳本斯和BHT933的相对功效,这表明UK14304相对功效的提高有助于其效力的提高。还研究了其他可能与冷却引起的收缩增加有关的机制,但结果尚无定论。这些研究包括可能从细胞内受体库转移的新受体,与Gi蛋白以外的G蛋白偶联的受体以及Rho激酶激活的参与。大鼠尾静脉是筛选α2C-肾上腺素受体选择剂和研究皮肤静脉温度调节功能的有用模型。

著录项

  • 作者

    Yao, Mingyi.;

  • 作者单位

    Creighton University.;

  • 授予单位 Creighton University.;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 182 p.
  • 总页数 182
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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