INTESTINE IN CHRONIC PORTAL HYPERTENSION

描述：本建议旨在探索潜在的机制 肝硬化门脉高压大鼠高动力循环的研究 门静脉高压症是由于门静脉血管阻力增加所致 床，导致门体分流的情况。 PI建议， 血管扩张物质，特别是胰高血糖素，在肝脏周围分流 并有助于小动脉血管舒张和增加全身血流量， 血液循环的特征 第二主 这种病理生理反应的机制是出现小动脉， 对血管收缩物质如去甲肾上腺素不太敏感。 这两种机制，增加循环血管扩张剂和减少 对血管收缩剂的反应，会导致或促成 门静脉高压症的血管异常 实验 在这些研究中使用的模型将是一种体外制备的小 取自对照大鼠或大鼠的肠系膜动脉（直径150-200 μ m） 用四氯化碳使之变成胶状。 容器环将安装在 来测量收缩。 将进行相同的血管准备 加载钙敏感的Flo（Flo 3 AM），以允许测量 胞内钙 使用这个实验模型，PI建议 检验五个主要假设：1）门静脉高压抑制受体， 非受体介导的细胞内钙（Cai）和张力增加 在小阻力动脉; 2）门静脉高压改变的速度， 血管平滑肌中钙的释放和隔离。 钙 穿过质膜和肌浆网的运动 将研究使用激动剂和拮抗剂; 3）将研究是否 胰高血糖素干扰非肾上腺素的血管收缩作用， 血管平滑肌，以及这种作用是否由 cAMP依赖性机制; 4）将检查腺苷酸的抑制是否 环化酶或蛋白激酶A恢复血管反应， 去甲肾上腺素或血管加压素; 5）将检查是否释放NO从 血管内皮增强cAMP依赖性血管扩张事件 门脉高压大鼠的阻力动脉。

DESCRIPTION: This proposal is aimed at exploring the mechanisms underlying the hyperdynamic circulation in rats with cirrhosis and portal hypertension. Portal hypertension results from increased vascular resistance in the portal bed, a condition that leads to portasystemic shunting. The PI proposes that vasodilator substances, particularly glucagon, are shunted around the liver and contribute to arteriolar vasodilation and increased systemic blood flow, hallmarks of the cirrhotic hyperdynamic circulation. A second major mechanism in this pathophysiologic response is that small arterioles appear to be less sensitive to vasoconstrictor substances such as norepinephrine. These two mechanisms, increased circulating vasodilators and diminished response to vasoconstrictors, would be additive in causing or contributing to the vascular abnormalities of portal hypertension. The experimental model to be used in these studies will be an in vitro preparation of small mesenteric arteries (150-200 um diameter) taken from control rats or rats made cirrhotic with carbon tetrachloride. The vessel rings will be mounted in a myograph to measure contraction. The same vessel preparation will be loaded with a calcium sensitive flo (Flo 3 AM) to permit measurement of intracellular calcium. Using this experimental model, the PI proposes to test five major hypotheses: 1) portal hypertension depresses receptor and non receptor-mediated increases in intracellular calcium (Cai) and tension in small resistance arteries; 2) portal hypertension alters the rate of release and sequestration of calcium in vascular smooth muscle. Calcium movement across the plasma membrane and across the sarcoplasmic reticulum using agonists and antagonists will be studied; 3) will investigate whether glucagon interferes with the vasoconstrictor effect of non-epinephrine on vascular smooth muscle, and whether this effect is mediated by cAMP-dependent mechanisms; 4) will examine whether inhibition of adenylyl cyclase or protein kinase A restores the vascular responses to norepinephrine or vasopressin; 5) will examine whether release of NO from vascular endothelium augments cAMP-dependent vasodilator events in resistance arteries from portal hypertensive rats.