当归对肝硬化门脉高压患者全身及门脉血液动力学的影响

为了解当归对肝硬化门脉高压的降压效果，对１１例肝硬化门脉高压患者在输注当归注射液期间（每分钟２０ｍｇ／ｋｇ体重）进行了全身及门脉血液动力学指标的观察。结果表明：静脉滴注当归注射液后，患者全身血液动力学无明显变化，门脉血液动力学则变化显著，表现为肝静脉嵌塞压（ＷＨＶＰ）和肝静脉压力梯度（ＨＶＰＧ）显著下降，门静脉和脾静脉血流量显著减少，但其降压效果与基础ＷＨＶＰ呈反比。提示当归可通过减少门静脉血流量而降低门脉压，但没有全身性副作用     

当归对肝硬化门脉高压影响的临床与实验研究

目的和方法：通过对胆管结扎肝硬化犬门脉系压力的直接测定，超声多普勒监测肝硬化患者的门脉血流，研究当归对肝硬化门脉血流动力学的影响。结果：（１）当归静脉给药，肝硬化犬的门静脉压（Ｐｐｖ）、嵌塞肝静脉压（ＷＨＶＰ）、肝静脉压力梯度（ＨＶＰＧ）显著降低（Ｐ＜００５～００１），平均动脉压（ＭＡＰ）、心率（ＨＲ）无明显变化（Ｐ＞００５）；（２）当归口服用药后（１０～１２周），肝硬化患者门静脉内径（Ｄｐｖ）、脾静脉内径（Ｄｓｖ）、脾静脉血流量（Ｑｓｖ）显著降低（Ｐ＜００５～００１），门静脉血流量（Ｑｐｖ）降低无显著意义（Ｐ＞００５）。结论：用药后，患者症状与肝功能（ＡＬＴ）部分好转，未见副作用。表明，当归为降低门静脉高压安全有效的药物     

当归对肝硬化病人血清胃泌素水平的影响

为探讨当归降低门脉压和影响体液因子代谢之间的关系，我们研究了当归对肝硬化病人血清胃泌素水平的急、慢性影响。结果表明，静滴当归注射液后，病人下腔静脉、肝静脉和外周静脉内血清胃泌素水平均显著下降；慢性用药后，病人外周静脉血清胃泌素水平可降至接近正常水平。由此可见，当归降低血清胃泌素水平的作用对改善门脉血液动力学、尤其是防治门脉高压性胃十二指肠病变可能起有益作用。     

血管活性药物降低肝硬化门脉高压的实验研究

文献中尚未见多种血管活性药物在同一实验条件下进行比较研究的报道,为此,我们在相同条件下进行了中西医血管活性药物可乐定、呱唑嗪、心痛定,汉防己甲素、硝酸甘油及当归注射液对鼠肝硬化门脉高压作用的实验研究。设计及方法雄性大白鼠80只,随机分为正常对照、生理盐水,可乐定、呱唑嗪、心痛定、汉防     

中药8910方对门静脉高压形成作用的试验研究

本实验选用四氯化碳诱导大白鼠所致的肝硬化门静脉压模型，以哌唑嗪作为阳性对照，通过１４周给药，以直接测定门脉压作为观察的主要指标，了解中药８９１０方对大鼠门脉高压形成的影响。结果表明，中药８９１０组门脉压显著低于单纯肝硬化模型组（生理盐水组）而与哌唑嗪相当，免疫组织化学结果显示，中药８９１０方抗Ｉ，Ⅲ型胶原和板层素沉积作用显著优于哌唑嗪，提示其抗门脉主压形成作用与之有不尽相同的作用机理。     

当归对门脉高压症的预防及治疗作用的实验研究

本文研究了当归对CCl_4所致大鼠门脉高压的防治作用。动物被随机分为五组:空白对照(生理盐水);对照组(CCl_4加生理盐水);当归(l)组(CCl_4+当归);当归(5)组(CCl_4、第五周开始加当归);及当归(9)组(CCl_4、第九周开始加当归)。结果表明,各组间体重及死亡率无显著差异,门脉高压形成率分别为0、88.46、41.67、52.9A和58.82%,差异极显著,P<0.001。各组PVP分别为1.19±0.28,2.44±1.21,1.40±0.39,1.61±0.47和1.68±0.43kPa,差异非常显著,P<0.01。结果提示当归对CCl_4所致大鼠门脉高压症有良好的预防及治疗作用。     

丹参对肝硬化门脉高压血流动力学影响的临床研究

食管曲张静脉破裂出血是肝硬化门脉高压症(PHT)常见而凶险的并发症，亟需探讨能有效预防食管静脉曲张出血的药物。已有的研究发现，丹参可降低犬和人肝硬化门脉高压，其降压作用较当归强，较钙离子拮抗剂持久，且无不良反应。为进一步评价丹参预防肝硬化食管静脉曲张破裂出血的疗效，本文应用彩色多普勒超声和食管曲张静脉无创性测压技术，探讨丹参对门脉血流动力学及食管曲张静脉压力(EVP)的影响。     

当归对肝硬化患者全身及门脉血液动力学的影响

我们的研究证实,当归可有效地预防及治疗CCl_4肝硬化大鼠的门脉高压症,可显著降低胆管结扎肝硬化犬的门脉压。为证实当归降低肝硬化病人门脉压的疗效,并了解有关的全身性副作用,我们研究了当归对肝硬化病人全身及门脉血液动力学的影响。     

狗肝硬化门脉高压症血浆儿茶酚胺浓度变化的实验研究

本研究通过结扎狗胆总管形成肝硬化门脉高压症的动物模型，对模型成前后门静脉压力、肝静脉压力、门静脉血流量、肝动脉血流量、门静脉血管阻力，肝动脉血管阻力和门静脉、肝静脉、脉主动脉。下腔静脉四部位血浆儿茶酚胺浓度的变化进行了自身对照性对比研究。结果：①肝硬化形成后门脉压力明显增高，肝静脉嵌塞压也明显增高，门脉血流量减少而肝动脉血流量增加，门脉血管阻力增加而肝动脉血管阻力则下降，这些变化与人类肝硬化门脉高压症相同。②门静脉、肝静脉。腹主动脉和下腔静脉血浆去甲肾上腺素的含量均在门脉高压形成后明显增加。提示肝硬化时血浆去甲肾上腺素的增加可能参与门脉高压症的某些病理生理过程，并进一步支持用a受体阻滞剂降低门脉压力和门脉血管阻力，治疗肝硬化食道静脉曲张破裂出血或预防出血。     

门脉高压肝脏小叶间动脉与小叶间静脉血管内皮生长因子受体的分布

目的:明确肝硬化门脉高压前后VEGFR-1、2在肝脏血管的分布变化.方法:SD♂大鼠30只,体质量180-220g.动物随机分为肝硬化门脉高压模型组(n=20)和随正常对照组(n=10).正常对照组正常饮水饮食,实验组采用硫代乙酰胺皮下注射法制作肝硬化门脉高压模型.12wk后经组织病理学检查证实肝脏有假小叶形成和门静脉压力大于1.57kPa的大鼠共12只纳入本研究.采用免疫组织化学染色法,分别观察VEGFR-1和VEGFR-2的变化特点.结果:VEGFR-2在肝硬化门静脉高压组大鼠的小叶间动脉和静脉中的表达均显著高于正常对照组(t=24.306,54.776,均P<0.05).VEGFR-1在肝硬化门静脉高压组大鼠的小叶间动脉和静脉中的表达也显著高于正常对照组(t=20.669,33.210,均P<0.05).VEGFR-2在肝硬化门脉高压组大鼠的小叶间静脉的表达显著高于小叶间动脉(t=23.424,P<0.05);而VEGFR-1在门脉高压组大鼠的小叶间动脉和小叶间静脉的表达几乎无明显差异(t=1.434,P>0.05).结论:VEGFR-2可能通过促进肝内小叶间静脉的新生血管生成代偿性降低门静脉高压.     

A new rat model of portal hypertension induced by intraportal injection of microspheres

ＡｎｅｗｒａｔｍｏｄｅｌｏｆｐｏｒｔａｌｈｙｐｅｒｔｅｎｓｉｏｎｉｎｄｕｃｅｄｂｙｉｎｔｒａｐｏｒｔａｌｉｎｊｅｃｔｉｏｎｏｆｍｉｃｒｏｓｐｈｅｒｅｓＬＩＸｉａｎｇＮｏｎｇ１,ＩＳＢｅｎｊａｍｉｎ２ａｎｄＢＡｌｅｘａｎｄｅｒ２Ｓｕｂｊｅｃｔｈｅａｄ...     

Pharmacologic treatment of portal hypertension.

Variceal formation and rupture are dreaded complications of chronic liver disease and portal hypertension. The pharmacologic treatment of portal hypertension should be able to stop as well as to prevent variceal hemorrhage. There are two principal types of vasoactive drugs in the treatment of portal hypertension: vasoconstrictors and vasodilators. Vasoconstrictors reduce the splanchnic blood flow, thereby decreasing the portal blood flow and portal pressure. Vasodilators act by different mechanisms, including by relaxation of myofibroblasts in the fibrous septa and presinusoidal areas of the liver and by direct vasodilation of the collateral circulation. In addition, paradoxically, they could decrease portal flow and pressure by inducing a baroreflex-mediated mesenteric arterial vasoconstriction. A miscellaneous group of drugs is also available. These drugs reduce the blood flow and pressure in the gastroesophageal variceal system by mechanisms other than vasoconstriction or vasodilation. The success of these pharmacologic agents is limited once the varices have ruptured. The use of beta-blockers in the prophylaxis of the first variceal bleeding has been proven of benefit in this respect. Future research should be aimed at elucidating the role that humoral and endothelial factors play in development of the hyperdynamic circulatory state that characterizes patients with portal hypertension. Once these etiologic factors have been identified and new knowledge is acquired about their role in the complications of chronic liver disease, the challenge will rest on developing novel pharmacologic therapies specifically targeting these factors.     

Effects of somatostatin analog on splanchnic hemodynamics and plasma glucagon level in portal hypertensive rats

ＥｆｅｃｔｓｏｆｓｏｍａｔｏｓｔａｔｉｎａｎａｌｏｇｏｎｓｐｌａｎｃｈｎｉｃｈｅｍｏｄｙｎａｍｉｃｓａｎｄｐｌａｓｍａｇｌｕｃａｇｏｎｌｅｖｅｌｉｎｐｏｒｔａｌｈｙｐｅｒｔｅｎｓｉｖｅｒａｔｓＷＵＺｈｉＹｏｎｇ,ＺＨＡＮＧＸｉａｏＪｉｅ,ＪＩ...     

Beneficial long term effect of a phosphodiesterase-5-inhibitor in cirrhotic portal hypertension: A case report with 8 years follow-up

Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis. Inhibitors of phosphodiesterase-5(PDE-5-inhibitors) reduce portal pressure in the acute setting by 10% which may suggest a long-term beneficial effect. Currently, there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors. This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored. In the acute setting, the PDE-5-inhibitor Vardenafil lowered portal pressure by 13%. The portal blood flow increased by 28% based onDoppler sonography and by 16% using MRI technique. As maintenance medication the PDE-5-inhibitor Tadalafil was used for eight consecutive years with comparable effects on portal pressure and portal blood flow. There were no recurrence of bleeding and no formation of new varices. Influencing the NO-pathway by the use of PDE-5 inhibitors may have long-term beneficial effects in compensated cirrhosis.     

Effect of verapamil on splanchnic haemodynamics in a portal hypertensive rat model

To elucidate the effects of verapamil on splanchnic haemodynamics in rats with portal hypertension, verapamil was given at a low dose (0.2 mg/kg) and a high dose (2 mg/kg) to the rat model after portal vein ligation. Approximately 10% decrease in arterial pressure was caused by the low dose of verapamil, with significant decreases in cardiac output and portal venous inflow as well as reduced portal pressure; these were all indicative of a rise in portal vascular resistance. In contrast, the marked fall in both arterial pressure and cardiac output in the high dose, accompanied by a significant decrease in the portal pressure and the unchanged portal venous inflow, suggested a reduction in portal vascular resistance. This study shows that the acute effects of verapamil on portal hypertension may vary with the dosage used. These results also demonstrate that, since the therapeutic efficacy and safety of verapamil is only in a very limited range of dose, caution should be taken in its clinical use in the treatment of cirrhosis with portal hypertension.     

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs.Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.     

Management of portal hypertension based on portal hemodynamics

Portal hypertension is most commonly caused by chronic liver disease. As liver damage progresses, portal pressure gradually elevates and hemodynamics of the portal system gradually change. In normal liver, venous returns from visceral organs join the portal trunk and flow into the liver (hepatopetal blood flow). As portal pressure increases due to liver damage, congestion of some veins of the visceral organ occurs (blood flow to and from). Finally, the direction of some veins (the left gastric vein in particular) of the visceral organ change (hepatofugal blood flow) and develop as collateral veins (portosystemic shunt) to reduce portal pressure. Therefore, esophagogastric varices serve as drainage veins for the portal venous system to reduce the portal pressure. In chronic liver disease, as intrahepatic vascular resistance is increased (backward flow theory) and collateral veins develop, adequate portal hypertension is required to maintain portal flow into the liver through an increase of blood flow into the portal venous system (forward flow theory). Splanchnic and systemic arterial vasodilatations increase the blood flow into the portal venous system (hyperdynamic state) and lead to portal hypertension and collateral formation. Hyperdynamic state, especially around the spleen, is detected in patients with portal hypertension. The spleen is a regulatory organ that maintains portal flow into the liver. In this review, surgical treatment, interventional radiology, endoscopic treatment, and pharmacotherapy for portal hypertension (esophagogastric varices in particular) are described based on the portal hemodynamics using schema.     

Effects of propranolol and sucralfate on ethanol-induced gastric mucosal damage in chronic portal hypertensive rats

In a rat model of chronic portal hypertension we studied ethanol-induced gastric mucosal damage and the effects of pretreatment by propranolol and sucralfate. Susceptibility to ethanol was increased in chronic portal hypertensive rats compared with sham-operated rats (55 +/- 8% vs. 25 +/- 4%). Both acute pretreatment (10 min) and chronic pretreatment (3 weeks) with propranolol reduced gastric mucosal injury induced by ethanol in portal hypertensive rats, compared with saline-treated rats. Acute and chronic pretreatment with propranolol had no protective effect in sham-operated rats. In portal hypertensive rats, sucralfate in two different doses (500 and 125 mg/kg) protected the gastric mucosa against ethanol-induced gastric injury compared with animals receiving saline (2 +/- 1% and 3 +/- 2% vs. 25 +/- 3%). Sucralfate at the higher dose did not reduce portal pressure in portal hypertensive rats. We conclude that: (1) chronic portal hypertension increases ethanol-induced gastric damage; (2) acute and chronic propranolol treatment reduces ethanol-induced gastric injury in portal hypertensive rats, probably by decreasing portal hypertension; (3) sucralfate has a cytoprotective effect in portal hypertensive rats without reducing portal pressure. These results suggest a potential application of sucralfate in patients otherwise treated by sclerotherapy.     

Circulatory effects of somatostatin analogue in two conscious rat models of portal hypertension

A somatostatin analogue, a long-acting octapeptide (SMS 201-995), has been reported to decrease portal pressure, but the mechanism is unclear. To elucidate the effects of this drug on both systemic and splanchnic hemodynamics, it was administered in two conscious rat models of portal hypertension. The dose-response curves showed that the somatostatin analogue significantly decreased portal pressure at a lower dose in rats with cirrhosis than in portal vein-stenosed rats. Calculated ED50 values were significantly different among all groups. Intravenous infusion of 8 micrograms/kg body wt.h of somatostatin analogue significantly decreased cardiac output by approximately 20% in both groups of portal hypertensive rats and increased mean arterial pressure by 7%. Accordingly, systemic vascular resistance markedly increased, indicating vasoconstrictor effects of this drug. The somatostatin analogue also significantly decreased portal tributary blood flow by 18% in portal vein-stenosed rats and 27% in cirrhotic rats. In sham-operated rats, somatostatin analogue had no effect on the systemic or splanchnic circulation. This study shows that somatostatin analogue decreases portal pressure principally by reducing portal tributary blood flow. This reduction may be due to either a direct vasoconstrictive effect or diminution in vasoactive hormone release.     

Effect of verapamil on nitric oxide synthase in a portal veinligated rat model： Role of prostaglandin

AIM: To investigate the effects of verapamil on nitric oxide (NO) synthesis in a portal vein-ligated rat model. METHODS: Systemic and splanchnic hemodynamics were measured by radiolabeled microspheres in portal hypertensive rats after acute administration of verapamil (2 mg/kg) on chronic treatment with Nw-nitro-L-arginine (NNA)(80 mg/kg) and/or indomethacin (2 mg/kg) . RESULTS: Verapamil (2 mg/kg) caused a marked fall in both arterial pressure and cardiac output accompanied by an insignificant change in the portal pressure and no change in portal venous inflow. This result suggested that verapamil did not cause a reduction in portal vascular resistance of portal hypertensive rats, which was similar between NW- nitro-L-arginine-treated and indomethacin-treated groups. CONCLUSION: In portal hypertensive rats pretreated with NNA and/or indomethacin, acute verapamil administration can not reduce the portal pressure, suggesting that NO and prostaglandin play an important role in the pathogenesis of splanchnic arterial vasodilation in portal hypertension.