PROSTAGLANDINS AND LOCAL CONTROL OF THE CIRCULATION

前列腺素和局部循环控制

• 批准号: 3336452
• 负责人: ALAN S. NIES
• 金额: $ 15.92万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-04-01 至 1987-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3336452
• 关键词: antihypertensive agents; antiinflammatory agents; diuresis; drug adverse effect; free radicals; furosemide; gas chromatography; gastrointestinal circulation; gastrointestinal hormones; hemodynamics; histamine release; kidney circulation; kidney metabolism; mass spectrometry; nitrates; prostaglandins; radioimmunoassay; radiotracer; renin

In spite of the recent discovery of new arachidonic acid products, the cyclooxygenase products are likely to be the major substances of importance in the control of the circulation and function of several organs. The long term objective of this proposal is to define the role of endogenously synthesized prostaglandins (PGs) in controlling the circulation and modulating organ function. The studies will focus on the kidney, the peripheral vasculature, and the stomach as sites where PGs play an important role. The renal studies include 1) clinical studies to define the role of the renal PGs system in the initiation and maintenance of a water diuresis; 2) studies in the isolated perfused rat kidney to determine whether PGE2 or PGI2 is more important in renin release; and 3) studies in the whole dog to determine the role of PGs in mediating tubulo-glomerular feedback. The vascular studies include clinical studies to 1) determine the role of prostacyclin (PGI2) in mediating the antihypertensive effects of propranolo, hydrochlorothiazide, or hydralazine; 2) determine the mechanism of furosemide-induced venodilation including the role of the renin-angiotensin system and the PG system; and 3) determine whether organic nitrates enhance PGI2 synthesis in man, and if so, whether PGI2 is necessary for the clinical effects. The gastric studies will further define the control of PG synthesis in the parietal cell in vitro and determine whether gastric secretagogues, calcium, and/or acid secretion per se is the important trigger. In vivo the interactions between the PG system, histamine release, the gastric seretagogues, and the polypeptide inhibitors of acid secretion will be investigated. Methods include the use in the clinical studies of gas chromatographic-mass spectrometric assays for PGE2 and the major urinary metabolite of PGI2, dinor-6-keto-PGF1Alpha. Only when validated will the radioimmunoassay for PGE2 be used. Additional assays include RIA for thromboxane B2 and plasma renin activity, radioenzymatic assay for histamine, radiochromatographic studies to assess arachidonic acid conversion into its products in the kidney and parietal cells, and cellular 14C-aminopyrine uptake to assess acid production by parietal cells. Cyclooxygenase inhibitors will be used along with these assays to determine the functional significance of the cyclooxygenase products in the systems studied. The emphasis of these studies is on clinically relevant observations. The therapeutic use of cyclooxygenase inhibitors is commonplace and unwanted side effects are not rare. These studies should not only increase our understanding of physiologic processes but should help us anticipate the adverse or beneficial effects of non-steroidal antiinflammatory agents as well as their interactions with other therapeutic agents and natural substances.

尽管最近发现了新的花生四烯酸产物， 环氧合酶产物可能是重要的主要物质 在控制几个器官的循环和功能。 长 本提案的长期目标是确定 合成的洋地黄素（PGs）在控制循环和 调节器官功能 这些研究将集中在肾脏， 外周血管和胃作为PG发挥作用的部位， 重要的作用 肾脏研究包括1）临床研究，以确定 肾PGs系统在启动和维持一个 水利尿; 2）在离体灌注大鼠肾脏中的研究，以确定 PGE 2或PGI 2在肾素释放中是否更重要;以及3） 以确定PGs在介导肾小管-肾小球 反馈 血管研究包括临床研究，以1）确定 前列环素（PGI_2）在介导抗高血压效应中的作用 普萘洛尔、氢氯噻嗪或肼屈嗪; 2）确定 呋塞米诱导的静脉扩张机制，包括 肾素-血管紧张素系统和PG系统;和3）确定是否 有机硝酸盐增强人体PGI 2的合成，如果是这样，PGI 2是否是 为临床效果所必需。 胃研究将进一步 定义体外壁细胞中PG合成的控制， 确定胃促分泌素、钙和/或酸分泌是否 SE是重要的触发器。 在体内，PG与 系统、组胺释放、胃促泌剂和多肽 将研究酸分泌的抑制剂。 方法包括在临床研究中使用气相色谱-质谱联用 PGE 2和PGI 2的主要尿代谢物的光谱测定， 二去甲-6-酮-PGF 1 α。 只有经过验证， 使用PGE 2。 其他测定包括血栓素B2和血浆的RIA 肾素活性，组胺的放射酶测定，放射色谱法 研究评估花生四烯酸转化成其产品， 肾脏和壁细胞，以及细胞14 C-氨基比林摄取，以评估 由壁细胞产生酸。 将使用环氧合酶抑制剂 沿着这些测定以确定这些蛋白的功能意义。 环氧合酶产物的系统研究。 这些研究的重点是临床相关观察结果。 的 环氧合酶抑制剂的治疗用途是常见的和不需要的 副作用并不罕见。 这些研究不仅可以增加我们的 了解生理过程，但应该帮助我们预测 非甾体类抗炎药的不利或有益作用， 以及它们与其他治疗剂和天然药物的相互作用。 物质.