INTESTINE IN CHRONIC PORTAL HYPERTENSION

描述：这项提议旨在探索潜在的机制 肝硬变门脉高压大鼠的高动力循环。 门静脉高压症是由于门脉血管阻力增加所致 床，一种导致门体分流的情况。公安局建议， 血管扩张剂物质，特别是高血糖素，在肝脏周围分流。 有助于动脉血管扩张和增加全身血流量， 这是肝硬变高动力循环的特征。第二个大调 这种病理生理反应的机制是出现小动脉。 对去甲肾上腺素等血管收缩物质不那么敏感。 这两种机制，增加了循环血管扩张剂和减少了 对血管收缩药的反应，在引起或促成 门静脉高压症的血管异常。实验性的 这些研究中使用的模型将是一种体外制备的小鼠 肠系膜动脉(直径150-200微米)取自正常大鼠或大鼠 用四氯化碳造成肝硬变。将安装容器环 在肌电图仪上测量收缩。同样的血管准备将是 加载钙敏感的Flo(Flo 3 AM)以允许测量 细胞内钙离子。利用这个实验模型，PI建议 检验五个主要假说：1)门脉高压抑制受体和 非受体介导的细胞内钙(CaI)和张力增加 在小阻力动脉中；2)门脉高压改变 血管平滑肌中钙的释放和封存。钙 跨质膜和跨肌浆网的运动 将研究使用激动剂和拮抗剂；3)将调查 高血糖素干预非肾上腺素的血管收缩作用 血管平滑肌，以及这一作用是否由 CAMP依赖的机制；4)将检查是否抑制腺苷 环化酶或蛋白激酶A可恢复血管反应 去甲肾上腺素或加压素；5)将检查NO是否从 血管内皮细胞增加cAMP依赖的血管扩张事件 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.