PHARMACOLOGY OF PROSTAGLANDIN PRODUCTION BY NIACIN-ACTIVATED CELLS

烟酸激活细胞产生前列腺素的药理学

• 批准号: 3734704
• 负责人: L Jackson Roberts, II
• 金额: --
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3734704
• 关键词: Kupffer's cell; alveolar macrophages; aspirin; cell type; drug adverse effect; drug metabolism; enzyme inhibitors; fatty acid biosynthesis; gas chromatography mass spectrometry; guinea pigs; high performance liquid chromatography; human subject; indomethacin; ion transport; laboratory rat; niacin; nicotinate; pharmacology; prednisone; prostaglandin endoperoxide synthase; prostaglandin inhibitors; prostaglandins; radioimmunoassay; receptor binding; thromboxanes

Niacin (nicotinic acid) is one of the most effective hypolipidemic agents available. However, its use is greatly limited by side effects, the most prominent of which is intense flushing. We recently demonstrated that niacin induced vasodilation is mediated by a release of prostaglandin (PG) D2. An intriguing discovery was made that pretreatment with a very low dose of aspirin (40 mg) essentially totally inhibits niacin-induced release of PGD2 in vivo. We have obtained a considerable body of preliminary evidence that suggests strongly that tissue macrophages are the cellular source of niacin-induced release of PGD2 in vivo and that PG production by macrophages can be inhibited by very low doses of aspirin. Studies are now proposed to establish more definitively the cells that are activated by niacin in vivo. In particular, resident tissue macrophages isolated from various tissues of guinea pigs and humans will be studied. Experiments will then focus on identifying potential cellular mechanisms involved in niacin induced activation of arachidonic acid metabolism. Studies will then be carried out to determine the molecular basis for the unusual sensitivity of PG production in niacin responsive cells to inhibition by aspirin. Specifically we will address whether this enhanced sensitivity is related to (a) the cyclooxygenase(s) present in these cells, (b) the mechanism by which aspirin inhibits PG biosynthesis, or (c) the intracellular metabolic rate of aspirin. Finally, the effect of treatment of normal volunteers with pharmacologic doses of prednisone on niacin-induced release of eicosanoids in vivo will be determined. The finding that very low doses of aspirin can inhibit niacin-induced release of PGD2 in humans has important therapeutic implications for the use of niacin as a hypolipidemic agent. Further, these studies should provide valuable insights into cell-specific mechanisms involved in activation of arachidonic acid metabolism and factors that can influence the ability of certain pharmacologic agents to inhibit PG biosynthesis in specific cell types.

烟酸（烟酸）是最有效的低脂剂之一 可用的。 但是，它的使用受到副作用的限制，最多 突出的是强烈的冲洗。 我们最近证明了 烟酸诱导的血管舒张是通过前列腺素的释放来介导的 （PG）D2。 提出了一个有趣的发现 低剂量的阿司匹林（40 mg）基本上完全抑制烟酸 PGD​​2在体内的释放。 我们获得了相当大的身体 初步证据表明组织巨噬细胞是 烟酸诱导的PGD2在体内释放的细胞来源， 巨噬细胞产生PG可以被非常低的剂量抑制 阿司匹林。 现在提出了研究以更明确地建立 烟酸在体内激活的细胞。 特别是居民 从豚鼠的各种组织分离出的组织巨噬细胞和 人类将被研究。 然后，实验将专注于识别 烟酸诱导的潜在细胞机制 花生四烯酸代谢。 然后将进行研究 确定PG异常灵敏度的分子基础 烟酸反应性细胞对阿司匹林抑制。 具体而言，我们将解决这种增强的灵敏度是否相关 到（a）这些细胞中存在的环氧合酶，（b）机制 阿司匹林抑制PG生物合成，或（c）细胞内 阿司匹林的代谢率。 最后，正常治疗的影响 用药理学剂量泼尼松在烟酸诱导的志愿者 将确定体内类花生酸的释放。 发现非常 低剂量的阿司匹林可以抑制烟酸诱导的PGD2在人类中的释放 对将烟酸用作使用具有重要的治疗意义 低脂剂。 此外，这些研究应提供有价值的 对参与激活的细胞特异性机制的见解 花生四烯酸代谢和可能影响能力的因素 某些药理学剂抑制特异性PG生物合成 细胞类型。