BETA RECEPTORS & VASCULAR ARACHIDONIC ACID METABOLISM

β受体

• 批准号: 3360077
• 负责人: JERRY G WEBB
• 金额: $ 12.31万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3360077
• 关键词: angiotensin II; antihypertensive agents; arachidonate; beta adrenergic receptor; cellular pathology; coronary disorder; fatty acid metabolism; homeostasis; laboratory rat; molecular pathology; norepinephrine; phospholipase A2; prostaglandins; tissue /cell culture; vascular smooth muscle; vasomotion

Beta adrenergic receptor antagonists are widely used to treat hypertension and coronary artery disease, yet the mechanisms responsible for their beneficial effects remain uncertain. We have found that chronic, but not acute, blockade of beta adrenergic receptors decreases neurovascular transmission, lowers arterial pressure and enhances synthesis of the vasodilator prostaglandins, PGI2 and PGE2, in response to norepinephrine (NE), angiotensin II (AII) and bradykinin (Bk). Consequently, the goal of this proposal is to define the cellular and molecular basis for beta adrenergic receptor-mediated regulation of arachidonic acid metabolism in peripheral blood vessels. The working hypothesis is that beta adrenergic receptors tonically modulate vascular prostaglandin synthesis through regulation of arachidonic acid release by phospholipases. Studies will be performed with isolated aorta. Experiments are proposed to: 1) Determine t e effects of acute and chronic beta adrenergic receptor stimulation and blockade on agonist-induced (NE, AII, Bk) synthesis of PGI, and PGE, in vit o and b) on in vivo eicosanoid synthesis as assessed by urinary metabolites (2,3-dinor 6-keto PGF1 alpha and 13,14-dihydro-15-keto tetranor PGE2) which reflect systemic prostaglandin production; 2) Determine the relative contribution of vascular endothelial and smooth muscle cells to beta receptor-induced changes in vascular arachidonic acid metabolism; and 3) Determine the mechanism of beta receptor-induced changes in the storage and release of vascular arachidonic acid. The effects of chronic beta receptor blockade on activation of phospholipases A2 and C and phospho-inositide metabolism will be examined in aorta prelabeled with [3H] arachidonic acid or [3H] myoinositol. Complementary studies will be performed with vascular endothelial and smooth muscle cells in culture wherein the mechanisms of be a receptor control of arachidonic acid metabolism can be directly approached. The long-term objective is to determine the importance of beta receptor regulation of arachidonic acid metabolism to the control of arterial blood pressure. These studies should further the understanding of mechanisms responsible for the therapeutic benefits of beta receptor blocking drugs in cardiovascular diseases and reveal new information on the relationship between beta adrenergic receptors and eicosanoids in vascular homeostasis.

β肾上腺素能受体拮抗剂广泛用于治疗高血压 和冠状动脉疾病，但其机制 有益效果仍不确定。 我们发现有慢性病，但不是 急性，β肾上腺素能受体的阻断会减少神经血管 传输，降低动脉压并增强合成 血管扩张剂前列腺素、PGI2 和 PGE2，对去甲肾上腺素有反应 (NE)、血管紧张素 II (AII) 和缓激肽 (Bk)。 因此，目标是 该提案旨在定义 beta 的细胞和分子基础 肾上腺素受体介导的花生四烯酸代谢调节 外周血管。工作假设是β肾上腺素能 受体通过调节血管前列腺素合成 磷脂酶调节花生四烯酸的释放。研究将是 用孤立的主动脉进行。 建议进行实验： 1) 确定 t e 急性和慢性β肾上腺素能受体刺激的影响 体外阻断激动剂诱导的（NE、AII、Bk）PGI 和 PGE 合成 哦 b) 通过尿液代谢物评估体内类二十烷酸合成 （2,3-二去甲 6-酮 PGF1 α 和 13,14-二氢-15-酮四去甲 PGE2） 反映全身前列腺素的产生； 2）确定亲属关系 血管内皮细胞和平滑肌细胞对β的贡献 受体诱导的血管花生四烯酸代谢变化；和 3) 确定β受体诱导的储存和储存变化的机制 血管花生四烯酸的释放。慢性β受体的影响 阻断磷脂酶 A2 和 C 以及磷酸肌醇的激活 将在用[3H]花生四烯酸预标记的主动脉中检查代谢 或[3H]肌醇。将针对血管进行补充研究 培养中的内皮细胞和平滑肌细胞，其中的机制是 一个 可以直接接近控制花生四烯酸代谢的受体。 长期目标是确定 β 受体的重要性 调节花生四烯酸代谢来控制动脉血 压力。这些研究应进一步加深对机制的理解 负责 β 受体阻断药物的治疗效果 揭示心血管疾病之间关系的新信息 β肾上腺素能受体和类二十烷酸在血管稳态中的作用。