PROSTAGLANDINS AND LOCAL CONTROL OF THE CIRCULATION

前列腺素和局部循环控制

• 批准号: 3336454
• 负责人: ALAN S. NIES
• 金额: $ 22.03万
• 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 1991-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3336454
• 关键词: antihypertensive agents; antiinflammatory agents; atrial natriuretic peptide; diuresis; dogs; drug adverse effect; free radicals; furosemide; gas chromatography; gastrointestinal circulation; gastrointestinal hormones; hemodynamics; histamine receptor; histamine release; kidney circulation; kidney metabolism; laboratory rat; mass spectrometry; nitrates; prostaglandins; radioimmunoassay; radiotracer; renin

The objective is to define the role of endogenously synthesized prostaglandins and other autocoids in control of the circulation and modulation of organ function. The grant will focus on the kidney, the peripheral vasculature and the stomach. The renal studies include: 1) Studies on the mechanism of renal vasoconstriction during the infusion of hypertonic saline into the kidney. This in vivo model of tubuloglomerular feedback will be used to determine a) the role of adenosine in mediating the response; b) the role of atrial natriuertic factor in blocking or "resetting" the response during salt loading and c) the role that A1-adenosine and A2-adenosine receptors have in mediating the response under varying conditions of salt balance. 2) Studies on the renal secretion of platelet activating factor (PAF) to test the hypothesis that renal synthesis of PAF and prostaglandins are linked. The vascular studies include 1) clinical studies to test the hypothesis that the antihypertensive drugs propranolol, hydralazine and thiazides enhance vascular prostacyclin synthesis, which accounts for the ability of cyclooxygenase inhibitors to reduce the antihypertensive efficacy and 2) clinical studies on furosemide induced venodilation and its relation to the prostaglandin and renin-angiotensin systems. The gastric studies will examine the factors controlling histamine release from the gastric mucosa since both the prostaglandins and H2-histamine blockers specifically act by inhibiting histamine-induced acid secretion by the parietal cell. Methods for the renal studies include in vivo canine models that will allow intrarenal infusions of hypertonic saline and drugs, and sampling of the renal vein for secretion of PAF; the isolated perfused rat kidney will also be used to complement the in vivo studies. For gastric studies, a canine model with isolation of the circulation of the gastric fundus and corpus will be used so that substances inducing or blocking histamine release can be studied without production of systemic effects. The clinical studies will be performed in normal and hypertensive volunteers. Analytical methodology includes negative ion chemical ionization gas chromatography-mass spectrometry (NICI GC-MS) for analysis of the major oxidative metabolite of prostacyclin, 2,3-dinor-6-keto-PGF1Alpha, in the urine and PAF in the blood and urine. Radioimmunoassay will be used for urinary PGE2. A radioenzymtic assay is used for the histamine analysis. These studies should increase our understanding of the physiologic role of prostaglandins and related substances in the control of the renal and peripheral vasculature and gastric function and will provide data relevant to common human diseases including hypertension and peptic ulcer disease.

目的是确定内源性合成的 控制血液循环的肾上腺素和其他autocoids， 调节器官功能。 这笔赠款将集中在肾脏， 外周脉管系统和胃。 肾脏研究包括：1） 静注盐酸利多卡因引起肾血管收缩机制的研究 高渗盐水注入肾脏 这种肾小管肾小球的体内模型 反馈将用于确定a）腺苷在介导 反应; B）心房钠尿因子在阻断或 在盐加载期间“重置”响应，以及c） A1-腺苷和A2-腺苷受体介导的反应 在不同的盐平衡条件下。 2)肾脏研究 血小板活化因子（PAF）的分泌，以检验假设， 肾合成的PAF与肾上腺素有关。 血管研究 包括1）临床研究，以检验假设， 抗高血压药物普萘洛尔、肼苯哒嗪和噻嗪类可增强 血管前列环素合成，这解释了 环氧合酶抑制剂降低抗高血压疗效; 2） 速尿所致静脉扩张的临床研究 前列腺素和肾素-血管紧张素系统。 胃研究将 检查控制胃粘膜组胺释放的因素 因为胡枝子素和H2-组胺阻滞剂都通过 抑制壁细胞组胺诱导的酸分泌。 肾脏研究的方法包括体内犬模型， 高渗盐水和药物的肾内输注，以及 肾静脉分泌PAF;离体灌流大鼠肾脏也将 用于补充体内研究。 对于胃部研究， 胃底体循环分离模型 以使诱导或阻断组胺释放的物质可以 在不产生全身效应的情况下进行研究。 临床研究 将在正常和高血压志愿者中进行。 分析 方法包括负离子化学电离气体 色谱-质谱法（NICI GC-MS）用于分析 前列环素的氧化代谢产物2，3-二去甲-6-酮-PGF 1 α， 血液和尿液中的血小板活化因子。 放射免疫分析将用于 尿PGE 2。 放射酶测定法用于组胺分析。 这些研究应该增加我们对 在控制肾脏和肾脏疾病中的洋地黄素和有关物质 外周血管系统和胃功能，并将提供相关数据 包括高血压和消化性溃疡在内的常见人类疾病。