PHOSPHATIDYL INOSITOL, PROSTAGLANDINS, AND EXCITATION

这项提案的总体目标是阐明生理上的 磷脂酰肌醇的意义及其生化机制 (PI)不同测试体系中的磷脂酸循环。最初有三个 模型系统-外分泌胰腺对大脑皮层、蓝斑的反应 对乙酰胆碱(ACh)的反应，以及胰岛对 高血糖-将被用来检验该假说的总体正确性 PI的分解是前列腺素(PG)的生成器，而前列腺素又 调节激动剂引起的反应。我们还将详细研究 这些系统中PI效应的生化方面。基本技术 将预先标记[14C]花生四烯酸(AA)，最好是在 刺激条件，白蛋白和白蛋白拮抗剂 第一种激动剂(或洗涤)，最后与第二种激动剂孵化 (或洗涤后的第一种激动剂)。所有受试者的放射性变化 将测定磷脂、中性脂和PG的含量(超过95% 回收的总脂质放射性)和编制资产负债表。在……里面 这样，从PI到其他脂质和/或PG的放射性流动可以 要下定决心。磷脂酶C和磷脂酶A的作用 将确定AA及其代谢物的释放途径。这个 阿司匹林类药物对胰岛素分泌的假定刺激作用 学习。初步证明甘油三酯(TG)显示出 ACh刺激大脑皮层脑片时AA的大量释放 与PGF2Alpha的形成显著增加相关的将是 进一步研究。胰岛素分泌的可能负反馈 PGS和阿司匹林类药物对这种负反馈的阻断可能是 对我们理解和治疗II型糖尿病很重要。 对大脑皮层的研究可能会揭示阿尔茨海默氏症，这表明 大脑皮层ACh缺乏。因为刺激的前列腺素E_2的形成 PI通过扩张导管来增加外分泌胰腺的分泌， 这些研究可能对急性胰腺炎有影响。

The overall aim in this proposal is to elucidate both the physiological significance and the biochemical mechanism of the phosphatidyl inositol (PI) phosphatidic acid cycle in different test systems. Initially three model systems-the exocrine pancreas in response to caeruleim, brain cortex in response to acetylcholine (ACh), and pancreatic islets in response to high glucose - will be used to test the general validity of the hypothesis that PI breakdown is a prostaglandin (PG) generator, which in turn modulates agonist-evoked responses. We will also study in detail biochemical aspects of the PI effect in these systems. The basic technique will be prelabelling with [14C]arachidonic acid (AA), preferably under stimulating conditions, quenching with albumin and an antagonist of the first agonist (or washing), and finally incubating with a second agonist (or the first agonist after washing). The changes in radioactivity in all of the phospholipids, neutral lipids, and PGs will be determined (over 95% of total lipid radioactivity recovered) and a balance sheet drawn up. In this way, the flow of radioactivity from PI to other lipids and/or PGs can be determined. The contribution of phospholipase C and phospholipase A pathways to the release of AA and its metabolites will be determined. The putative stimulation of insulin secretion by aspirin-like drugs will be studied. The preliminary demonstration that triglyceride (TG) shows a massive release of AA on stimulation of brain cortex slices with ACh - associated with a marked increase in the formation of PGF2Alpha - will be further studied. The possible negative feedback of insulin secretion by PGs and the blockade of this negative feedback by aspirin-like drugs may be important in our understanding and treatment of Type II diabetes mellitus. Studies in brain cortex may throw light on Alzheimer's disease, which shows deficiency of ACh in brain cortex. Since the stimulated PGE2 formation from PI augments secretion in the exocrine pancreas by dilation of ducts, these studies may have implications for acute pancreatitis.