INTESTINE IN CHRONIC PORTAL HYPERTENSION

门静脉高压症，这是一种临床问题，通常是由于 肝硬变或其他形式的肝病，其特征是 门静脉压力、门体分流与高动力循环 州政府。高动力循环的特征之一是强烈的 似乎是由于循环中的升高引起的肠道血管扩张 血管扩张剂和血管收缩敏感度的降低。许多 研究人员认为，高动力的肠道循环是关键 维持门脉高压状态的因素。因此， 门静脉高压症的药物治疗通常涉及使用 通过减少肠道血流量来降低门脉压力的药物。 拟议研究的目的是系统地分析 肠道微血管对门脉高压的适应性研究 肠微血管扩张假说是肠道微血管扩张的结果 对外源性和内源性血管收缩刺激的反应性。为 这些研究表明，正常大鼠和门脉高压大鼠的肠道 通过视频显微镜观察到粘膜、粘膜下层的小动脉 或研究过的肌肉。小动脉直径，红细胞速度， 血管内压和血流量按顺序测量 分支小动脉。由单个小动脉产生的张力可以是 根据压力和直径数据计算得出。具体目标是：1) 确定门脉血管收缩敏感性改变的部位 高血压肠道微循环(肠道反应性 小动脉对去甲肾上腺素、加压素和血管紧张素II的作用 在正常大鼠和门脉高压大鼠身上进行研究，以确定是否减少 在肠道中，血管敏感性仅限于特定的位点 微循环)；2)测定神经体液的贡献 血管收缩系统对静息肠道血管张力的影响 门脉高压大鼠(交感神经的作用 精氨酸加压素和肾素-血管紧张素系统对肠道的影响 动脉张力将通过选择性地去除这些影响来确定 具有特定拮抗剂的这些系统)；3)确定还原 在肠小动脉固有的肌源性反应性中起作用 慢性门静脉高压症患者的血管张力降低(这些研究将 门静脉肠小动脉肌源性反应性分析 高血压大鼠跨壁压力递增。研究将会 也在门腔分流的大鼠身上进行，以确定是否在 肠小动脉的肌源性反应性是 高动力循环或对慢性升高的门静脉的适应 压力)；4)确定肠道反应性是否降低 小动脉与外源性和内源性血管收缩刺激有关 门静脉高压症患者血浆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- 中和胆瘘与肠道反应性 评估小动脉对血管收缩刺激的作用。这些研究将允许 US确定血管收缩敏感性降低是否是对 门静脉高压症或血管扩张介质升高所致 高动力循环。拟议研究的结果将提供 关于高动力肠道循环和意志的新信息 证明在开发门脉高压症的新治疗模式方面是有用的。

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.