INTESTINE IN CHRONIC PORTAL HYPERTENSION

慢性门脉高压中的肠道

• 批准号: 3364599
• 负责人: JOSEPH N BENOIT
• 金额: $ 14.01万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-01 至 1996-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3364599
• 关键词: angiotensin II; arterioles; cholanate compound; chronic disease /disorder; gastrointestinal circulation; glucagon; hemodynamics; intestines; laboratory rat; microcirculation; microscopy; norepinephrine; portal hypertension; renin angiotensin system; sympathetic nervous system; vasodilation; vasopressins

Portal hypertension, a clinical problem that often arises as a result of cirrhosis or other forms of liver disease, is characterized by an elevated portal pressure, portosystemic shunting and a hyperdynamic circulatory state. One of the hallmarks of the hyperdynamic circulation is an intense intestinal vasodilation that appears to be due to elevations in circulating vasodilators and reductions in vasoconstrictor sensitivity. Many investigators believe that the hyperdynamic intestinal circulation is a key factor which maintains the portal hypertensive condition. As such, pharmacological therapy of portal hypertension often involves the use of drugs that decrease portal pressure by decreasing intestinal blood flow. The purpose of the proposed studies is to systematically analyze the intestinal microvascular adaptation to portal hypertension in order to test the hypothesis that intestinal microvessels dilate as a result of a reduced responsiveness to exogenous and endogenous vasoconstrictor stimuli. For these studies, the intestine of normal and portal hypertensive rats is viewed through a video-microscope and arterioles in the mucosa, submucosa or muscularis studied. Arteriolar diameter, erythrocyte velocity, intravascular pressure and blood flow are measured in sequentially branching arterioles. Tension generation by individual arterioles can be calculated from the pressure and diameter data. The specific aims are: 1) To determine the site of altered vasoconstrictor sensitivity in the portal hypertensive intestinal microcirculation (The responsiveness of intestinal arterioles to norepinephrine, vasopressin and angiotensin II will be studied in normal and portal hypertensive rats to determine if reductions in intestinal vascular sensitivity are restricted to specific loci in the microcirculation); 2) To determine the contribution of neurohumoral vasoconstrictor systems to resting intestinal vascular tone in normal and portal hypertensive rats (The contribution of the sympathetic nervous system, arginine vasopressin and the renin-angiotensin system to intestinal arteriolar tone will be determined by selectively removing the influences of these systems with specific antagonists); 3) To determine if reductions in the intrinsic myogenic reactivity of intestinal arterioles contribute to the lower vascular tone in chronic portal hypertension (These studies will analyze the myogenic responsiveness of intestinal arterioles of portal hypertensive rats to step increments in transmural pressure. Studies will also be conducted in portacaval shunted rats to determine if changes in the myogenic reactivity of intestinal arterioles are consequence of the hyperdynamic circulation or an adaptation to a chronically elevated portal pressure); 4) To determine if the reduced responsiveness of intestinal arterioles to extrinsic and intrinsic vasoconstrictor stimuli are related to high plasma levels of glucagon and bile acids in portal hypertension (Plasma glucagon or bile acid levels will be depleted by immuno- neutralization or bile fistula and the responsiveness of intestinal arterioles to vasoconstrictor stimuli evaluated. These studies will allow us to determine if decreased vasoconstrictor sensitivity is a response to portal hypertension or a result of elevated vasodilator mediators of the hyperdynamic circulation. The results of the proposed studies will provide new information regarding the hyperdynamic intestinal circulation and will prove useful in developing new modes of therapy of portal hypertension.

门静脉高压症，一个临床问题，经常出现的结果， 肝硬化或其他形式的肝脏疾病的特征在于升高的 门静脉压力、门体分流和高动力循环 状态 高动力循环的特征之一是 肠血管舒张似乎是由于循环中的 血管扩张剂和血管收缩剂敏感性降低。 许多 研究人员认为，高动力的肠道循环是一个关键， 维持门脉高压状态的因素。 因此，在本发明的一个方面， 门静脉高压的药物治疗通常涉及使用 通过减少肠血流量来降低门静脉压力的药物。 本研究的目的是系统地分析 肠微血管对门脉高压的适应性，以测试 假设肠微血管扩张是由于 对外源性和内源性血管收缩刺激的反应性。 为 在这些研究中，正常大鼠和门脉高压大鼠的肠道 通过视频显微镜和粘膜、粘膜下层中的小动脉观察 或肌层。 小动脉直径，红细胞速度， 依次测量血管内压力和血流 分支小动脉 单个小动脉产生的张力可能是 根据压力和直径数据计算。 具体目标是：1） 确定门静脉血管收缩敏感性改变的部位 高血压肠微循环（肠微循环反应性） 去甲肾上腺素、血管加压素和血管紧张素II的小动脉 在正常和门脉高压大鼠中研究，以确定是否减少 在肠血管敏感性仅限于特定的位点， 微循环）; 2）确定神经体液的贡献 血管收缩系统对静息肠血管张力的影响， 门脉高压大鼠（交感神经对门脉高压的影响 系统、精氨酸加压素和肾素-血管紧张素系统对肠 将通过选择性地去除影响来确定小动脉张力 这些系统与特定的拮抗剂）; 3）以确定是否减少 肠小动脉的内在肌源性反应有助于 慢性门静脉高压症的血管张力降低（这些研究将 分析门静脉肠小动脉的肌源性反应性 高血压大鼠跨壁压逐步增加。 研究将 还在门腔静脉分流的大鼠中进行，以确定 肠小动脉的肌源性反应是 高动力循环或适应慢性抬高门静脉 4）确定肠道反应性的降低是否 小动脉对外源性和内源性血管收缩刺激的反应是相关的 门静脉高压症时胰高血糖素和胆汁酸水平升高 （血浆胰高血糖素或胆汁酸水平将被免疫系统消耗。 中和或胆瘘和肠道反应性 评价小动脉对血管收缩刺激的反应。 这些研究将使 我们来确定血管收缩敏感性降低是否是对 门静脉高压或血管扩张介质升高的结果， 高动力循环 拟议研究的结果将提供 关于高动力肠循环的新信息， 证明在开发门静脉高压症的新治疗模式中是有用的。