Haemodynamic effects of chronic octreotide and tetrandrine administration in portal hypertensive rats

Octreotide is an effective portal hypotensive drug in the control of variceal bleeding. Tetrandrine is a type of calcium channel blocker recently reported to reduce portal hypertension. The present study was undertaken to investigate the haemodynamic effects of octreotide and tetrandrine, alone and in combination, in portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation. Portal hypertensive rats were allocated into one of the four groups: vehicle group (saline, 0.5 mL/day), octreotide group (100 μg/kg per 12 h), tetrandrine group (20 mg/kg per 12 h), and octreotide (100 μg/kg per 12 h) plus tetrandrine (20 mg/kg per 12 h) group. Tetrandrine or saline was administered by gavage, and octreotide by subcutaneous injection. The drug was given for 8 consecutive days, starting 1 day before ligation and continuing onwards. Haemodynamic parameters were measured thereafter, using the radioactive microsphere method. The portal venous pressure and portal tributary blood ?ow were signi?cantly reduced, while portal territory and renal vascular resistances were signi?cantly enhanced, by octreotide, tetrandrine, or octreotide plus tetrandrine in portal hypertensive rats, compared with the vehicle group. Our results showed that long-term administration of octreotide, tetrandrine, or octreotide plus tetrandrine led to portal hypotensive effects in portal hypertensive rats, but octreotide alone exerted better anti-hyperdynamic effects compared with tetrandrine alone. A combination of octreotide and tetrandrine offered no major bene?cial anti-hyperdynamic effects compared with octreotide alone.     

Haemodynamic effects of chronic tetrandrine treatment in portal hypertensive rats

Tetrandrine is a calcium channel antagonist with reported antihypertensive effect. However, the potential role of tetrandrine as a therapeutic agent in portal hypertension has yet to be explored. The present study aimed to investigate the haemodynamic effects of chronic tetrandrine treatment on portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation in Sprague-Dawley rats. Animals were allocated into one of two groups: a tetrandrine group and a vehicle group. Tetrandrine (20 mg/kg) or vehicle was administered by gavage every 12 h for 8 consecutive days, starting 1 day before ligation and continuing thereafter. After 8 days of tetrandrine treatment, systemic haemodynamics, organ blood flows and the degree of portal-systemic shunting were measured after an overnight fast. The portal venous pressure and portal tributary blood flow were significantly decreased, while portal territory as well as hepato-collateral vascular resistance significantly increased in the tetrandrine group compared with the vehicle group. The cardiac index was increased, while systemic vascular resistance was decreased, in the tetrandrine group. Mean arterial pressure, heart rate, portalsystemic shunting and bodyweight were similar between the two groups. Renal blood flow was decreased in the tetrandrine group. In conclusion, long-term treatment of tetrandrine reduced portal venous pressure and alleviated splanchnic hyperaemia in portal hypertensive rats without affecting the portal-systemic shunting.     

Structural and functional changes of the gastric mucosa in rats with portal hypertension

Structural and functional changes of the gastric mucosa were studied in rats made portal hypertensive by partially ligating the portal vein. Studies were carried out at either 3 or 12 days after ligation or sham operation. At 3 days, structural changes were greater than at 12 days, the major effects being vascular congestion in the lamina propria, muscularis mucosa, submucosa, and submucosal oedema. Transmission electron microscopy showed only a mild hyperplasia in the muscularis mucosa. Gastric blood flow appeared to decrease at 3 days post-ligation compared to sham-operated control rats, but was significantly increased by 12 days after ligation (P less than 0.01). Cardiac output also appeared to increase in the portal hypertensive rats by 12 days post-ligation but this was not statistically significant. Portal venous inflow was significantly increased by 12 days (P less than 0.05) but after correction for collateral circulation liver blood flow had returned to normal values by 12 days post-ligation.     

汉防己甲素对肝硬化大鼠胃黏膜微循环及超微结构的影响

目的:观察汉防己甲素降低大鼠肝硬化门脉高压(PHT)的疗效和对胃黏膜微循环及其超微结构的影响.方法:制作肝硬化PHT模型,成模后分为模型(M)组、汉防己甲素(T)组、普萘洛尔组(P)及正常对照(N)组,治疗15 d后进行各指标的测定.结果:与M组比较,T组门静脉压力(PVP)明显降低(P<0.01),ALT,HA及PCⅢ指标下降(P<0.05),平均动脉压(MAP)和心率(HR)无明显变化;P组引起了PVP明显降低(P<0.01)和HR的减慢(P<0.05),MAP,ALT,HA及PCⅢ无明显变化;T组、P组光镜下胃黏膜毛细血管最大直径及面积明显减小(P<0.01),透射电镜下胃黏膜超微结构的损伤明显减轻.结论:汉防己甲素能有效、安全地降低大鼠肝硬化门脉压力,可有效改善其胃黏膜微循环及超微的变化,为临床治疗门脉高压性胃病提供实验依据.     

Impaired oxygenation of gastric mucosa in portal hypertension

Increased susceptibility to mucosal damage is a prominent feature of portal hypertensive gastropathy. Since the portal hypertensive gastric mucosa has extensive microvascular changes, we postulated that the increased sensitivity to mucosal damage could have an ischemic basis. We measured distribution of gastric serosal and mucosal oxygenation in a group of portal hypertensive and sham-operated rats, and then studied the effects of intragastric aspirin. In the basal state, gastric mucosa of portal hypertensive rats had significantly reduced oxygenation compared to controls (24±5 vs 45±7 mm Hg PO ₂,P < 0.02), while serosal oxygenation was similar between the two groups. Intragastric aspirin produced significantly greater mucosal damage to portal hypertensive rats and mucosal oxygenation was almost one third that of sham-operated controls. Systemic arterial pressures and oxygenation were similar between the two groups. We conclude that there is impairment of gastric mucosal oxygenation and increased mucosal damage by aspirin in portal hypertensive rats compared with sham-operated controls. These results support our hypothesis that the increased sensitivity of the portal hypertensive mucosa to damage is a consequence of impaired mucosal oxygenation.This study was supported by the Veterans Administration Research Service.This work was presented, in part, at the Plenary Session of the American Association for the Study of Liver Diseases, May 1988, New Orleans, Louisiana.     

汉防己甲素对肝硬化门脉高压大鼠胃粘膜及肝脏的影响

为探讨汉防己甲素对门脉高压性胃粘膜病变的治疗作用，观察了汉防己甲素对门脉高压大鼠门脉压力、胃粘膜屏障功能、肝脏组织学和肝功能的影响，并与普萘洛尔进行了对比。结果表明，汉防己甲素和普萘洛尔均可使门脉高压大鼠的ＰＶＰ下降，胃粘膜ＰＧＥ２含量、ＧＭＢＦ和ＧＡＭ增加。但普萘洛尔使肝细胞坏死增加，ＡＬＴ和ＳＴＢ不能降低，ＡＬＰ反有升高。而汉防己甲素则使肝细胞损害减轻，肝内纤维组织减少，ＡＬＴ、ＡＬＰ和ＳＴＢ降至正常水平。提示，普萘洛尔虽可使ＰＨＴ性ＧＭＬ改善，却可加重肝损害。而汉防己甲素不仅可改善胃粘膜屏障功能，而且还能改善肝功能。     

善得定对门静脉高压性胃病大鼠胃粘膜灌注的影响

目的 观察善得定对门静脉高压性胃病（ｐｏｒｔａｌ ｈｙｐｅｒｔｅｎｓｉｖｅ ｇａｓｔｏｐａｔｈｙ,ＰＨＧ）大鼠胃粘膜血流最（ｇａｓｔｒｉｃ ｍｕｃｏｓａｌ ｂｌｏｏｄ ｆｏｗ,ＧＭＢＦ）的影响,并对其作用机制作初步探讨。方法 部分结扎大鼠门静脉主干２周后,观察善得定对ＰＨＧ大鼠全身血流动力学,ＧＭＢＦ,门静脉压力（ＰＶＰ）的影响,测定了输注善得定３０ｍｉｎ后ＰＨＧ大鼠血浆胰高糖素,血浆和胃粘膜ＮＯ     

门脉高压性胃病患者胃黏膜Ghrelin的表达

目的研究Ghrelin在门脉高压性胃病(PHG)胃黏膜上的表达。方法用免疫组化方法检测36例门脉高压患者和15例对照组(内镜检查胃黏膜大致正常)胃黏膜Ghrelin的表达。结果门脉高压组胃黏膜Ghrelin表达阳性细胞面积(18.89%±5.47%)与对照组(8.51%±5.31%)比较,差异有显著性(P<0.001);PHG组胃黏膜Ghrelin表达阳性细胞面积(20.82%±6.35%)与单纯门脉高压症(PHT)组(17.51%±4.40%)比较有增高趋势,但无显著性差异(P>0.05)。结论Ghrelin可能参与了门脉高压时高动力循环的形成和发展,分泌Ghrelin的内分泌细胞对PHG时胃黏膜损害具有相当的抵抗力。     

Measurement of liver volume and its clinical significance in cirrhotic portal hypertensive patients

ＮＴＲＯＤＵＣＴＩＯＮＡｃｃｕｒａｔｅａｓｓｅｓｓｍｅｎｔｏｆｈｅｐａｔｉｃｒｅｓｅｒｖｅｆｕｎｃｔｉｏｎｉｎｃｉｒｒｈｏｔｉｃｐｏｒｔａｌｈｙｐｅｒｔｅｎｓｉｖｅｐａｔｉｅｎｔｓｉｓｉｍｐｏｒｔａｎｔｆｏｒｓｅｌｅｃｔｉｏｎｏｆｓｕｒｇｉｃａｌｐｒｏｃｅｄｕｒｅａｎｄｅｖａｌｕａｔｉｏｎｏｆｐｒｏｇｎｏｓｉｓ．ＴｈｅｍｅａｓｕｒｅｍｅｎｔｏｆｌｉｖｅｒｖｏｌｕｍｅｈａｓｂｅｅｎａｐｐｌｉｅｄｉｎｃｌｉｎｉｃａｓｗｉｄｅｌｙａｓＣｈｉｌｄ′ｓｃｌａｓｓ［１,２］．Ｌｉｍｉｔｅｄｂｙｔｅｃｈｎｉｃ…     

Effect of laparoscopic splenectomy on portal hypertensive gastropathy in cirrhotic patients with portal hypertension

Aim:  This study investigated the relationship between portal hypertensive gastropathy (PHG) and splenomegaly, and the effect of laparoscopic splenectomy on PHG in cirrhotic patients with portal hypertension.
Methods:  Seventy patients with liver cirrhosis and portal hypertension were prospectively studied. Indication for laparoscopic splenectomy was bleeding tendency in 10 patients, induction of interferon in 45, treatment of hepatocellular carcinoma in seven, and treatment for endoscopic injection sclerotherapy-resistant esophagogastric varices in eight. The severity of PHG was classified into none, mild, or severe according to the classification by McCormack et al. The severity of liver disease was classified using the Child–Pugh score. All patients underwent upper gastrointestinal endoscopy before and 1 month after the operation.
Results:  The prevalence of PHG was significantly correlated with the severity of liver disease using the Child–Pugh score. The severity of PHG was significantly correlated with the resected spleen volume. One month after the operation, PHG was improved in 16 of 17 patients with severe PHG and in 12 of 32 with mild PHG. The Child–Pugh score showed a significant improvement (6.8 ± 1.4 to 6.2 ± 1.2) at 3 months after laparoscopic splenectomy ( P  < 0.0001).
Conclusions:  PHG may be associated with splenomegaly, and laparoscopic splenectomy may have a beneficial effect on PHG, at least for a short time.     

Captopril reduces portal pressure effectively in portal hypertensive patients with low portal venous velocity

Background The effect of an angiotensin II blockade in lowering the portal pressure in patients with liver cirrhosis and portal hypertension is controversial. This prospective study was undertaken to evaluate the portal hypotensive effect of captopril compared to that of propranolol, and to determine the factors that contribute to a successful reduction in the portal pressure after longterm captopril administration in patients with liver cirrhosis.Methods The hepatic venous pressure gradient (HVPG) and portal venous velocity (PVV) were measured both before and 3 months after initiation of the administration of captopril (n = 29) or propranolol (n = 29) in cirrhotic patients with a variceal bleeding episode. Patients who showed a reduction in the HVPG of more than 20% of the baseline were defined as being responders.Results At 3 months, the mean reduction in the HVPG after captopril was less than that after propranolol (–3.0 ± 9.3% vs –28.5% ± 4.1%; P 0.05). However, of the 29 patients receiving captopril, 9 were classified as being responders. On multivariate analysis with parameters including age, cause, Child-Pugh score, HVPG, and PVV, only low PVV was found to be a significant independent factor for responders (PVV 12cm/s; odds ratio [OR], 12.2; 95% confidence interval [CI], 1.47–102.40) in the captopril group.Conclusions Longterm captopril administration reduces the portal pressure effectively in cirrhotic patients with a low PVV. This suggests that the reduction in portal pressure after captopril administration is a result of improved portal venous outflow brought about by a decrease in the intrahepatic vascular resistance. When the PVV is below 12cm/s, a captopril trial might be useful in preventing variceal bleeding in portal hypertensive patients.Part of this work has appeared in abstract form, in J Hepatol 2002;36 (Suppl 1):64     

Systemic and splanchnic hemodynamics following hemorrhage and volume restitution with Haemaccel in portal hypertensive rats: The effect of propranolol

BACKGROUND AND AIMS: Recently, we found in a portal hypertensive rat model that hemorrhage and volume restitution with Haemaccel, a low viscosity plasma expander, induced an increase in cardiac output and portal venous inflow. The present study was conducted to evaluate whether pretreatment with propranolol will attenuate these hyperdynamic changes. METHODS: Portal hypertension was induced by portal vein constriction. Treatment was initiated 14--21 days later. Propranolol (30 mg/kg per day) or water were administered for 7 days via a gastric gavage. Under ketamine anesthesia, 18 h after the last given dose, blood was withdrawn at a constant rate of 0.3 mL/min for 15 min followed by a 15-min stabilization. Haemaccel was infused at the same rate and volume used for withdrawal. Hemodynamic measurements were performed after volume restitution in both groups by using radioactive microspheres. RESULTS: Eight rats were studied in each group. In the propranolol-treated animals, portal venous inflow was decreased (2.4 +/- 0.8 vs 3.8 +/- 0.7 mL/min per 100 g bodyweight; P < 0.01), while splanchnic arteriolar and porto-collateral resistance were increased (52.8 +/- 21.0 vs 32.8 +/- 13.0 and 6.0 +/- 1.4 vs 4.1 +/- 0.7 mmHg x min x 100 g bodyweight/mL; P < 0.05, respectively). Cardiac output, mean arterial pressure, heart rate, total peripheral resistance and portal pressure were not significantly different between the two groups. CONCLUSION: In this model, pretreatment with propranolol prevented the increase in portal venous inflow, which occurs following hemorrhage and volume restitution with Haemaccel. Although caution should be taken in extrapolating data from animal models to humans, our results suggest that volume replacement during a portal hypertensive-related bleeding episode may be safer in a patient treated with non-selective beta-adrenoreceptor antagonists.     

Effects of collagen solution on the prevention of acute gastric mucosa injuryin rats

AIM To investigate the effects of collagen solution on the prevention of acute gastric mucosal injury inrestricted rats inflicted by cooling in low temperature (4℃),METHODS Thirty healthy Wistar rats were randomly divided into normal (N, n = 10),injury (I, n = 10)and prevention (P, n = 10) groups. The rats were fasted for 48 h but free access to water without restrictionand cooling in normal group, fasted for 48 h but free access to water with restriction of rats onto the fixationframe for cooling in 4℃ for 4 h, so to cause stress injury of gastric mucosal membrane in I group and fed with3 mL of collagen solution 30min before injury in P group in addition to the procedures in I grobp. Gastricmucosal potential difference, blood flow volume, content of nitrite (NO2-) and hydrogen ion concentration(H+ ) in gastric juice were determined under aneasthesia at 48 h after fast in N group and at 4 h after injuryin I and P groups to evaluate the degree of injury (injury index).RESULTS Gastric mucosal potential difference was 22.10±5.27 in N group and 11.46±5.25 in I groupwith obvious difference (P<0.01), but 16.98±4.84 in P group which was remarkably improved whencompared to that in I group. Gastric mucosal blood flow volume was 23.65±10.65 in I group and 57.20±11.75 in N group with evident difference (P<0.01), but 37.49±5.87 in P group with sound effects incontrast to that in I group (P<0.01). Gastric injury index was 18.40±8.35 in I group and 7.9±2.13 in Pgroup with significant difference (P<0.01). Hydrogenion concentration in gastric juice was 118.0±41.2mmol/L in N group, 186.9±74.7 mmol/L in I group and 96.4±57.2 mmol/L in P group with prominentdifference (P< 0.01 ) between those in I and P group. Gastric mucosal nitrite concentration was 1.15±0.46in N group, 0.69±0.15 in I group and 1.04±0.44 in P group with obvious differences between N and Igroups (P<0.01) and between I and P group (P<0.01).CONCLUSION Ischemic and hypoxic injury of gastric mucosal due to low blood perfusion during restrictionand cooling injury at 4℃ was supposed to be an important factor in inducing gastric mucosal stress injury. Butcollagen solution could maintain the integrity of gastric mucosal barrier, buffer gastric acid, promotethrombocytic agglutination and ameliorate direct injury to gastric mucosa caused by various factors.     

Medical treatment of portal hypertension

In this chapter we give a quick review of the rationale for treatment of portal hypertension. The different scenarios for treatment of variceal bleeding will be discussed-that is, primary and secondary prophylaxis of variceal bleeding as well as the treatment of the acute bleeding episode. The role of the pharmacological, endoscopic and derivative treatments in each one of these scenarios will be discussed. Particular attention will be devoted to the potential role of the combination therapy of beta-blockers with isosorbide-5-mononitrate for preventing re-bleeding and to the best approach to patients with intolerance or contraindications to beta-blockers. We also give a rational review of the data comparing sclerotherapy against ligation as well as the potential role of the latter on primary prophylaxis.     

肝硬化门脉高压大鼠胃粘膜屏障功能的观察

建立两组门脉高压症(PH)动物模型,并与对照组(SO组)比较,以观察胃粘膜屏障功能的改变.结果显示,与SO组比较,门静脉狭窄组(PVS组)大鼠内脏血流量明显增加(Ρ＜0.001),胃粘膜处于缺血状态,胃壁结合粘液(GP)显著下降(P＜0.01);肝硬化门脉高压症组(PL组)较PVS组降低更明显(P＜0.05);三组间胃基础泌酸量(BAS)无差异.PVS组、PL组大鼠H+返渗量(H+BD)均明显高于SO组(P＜0.001),表明PVS大鼠胃粘膜屏障功能破坏严重,尤以PL大鼠为甚;门脉高压胃病(PHG)与胃粘膜屏障功能严重减弱有关,其肝功能受损参与胃粘膜病变的发生.     

肝硬化患者结肠镜下表现及其相关因素分析

目的探讨肝硬化患者结肠镜下表现,及这些病变与肝功能Child-Pugh分级、食管静脉曲张程度、肝纤维化指标（APRI指数）等相关因素的关系。方法回顾性分析本院2009年1月至2012年5月收治的172例肝硬化住院患者临床资料,23例患者行结肠镜检查,同时分析肠镜表现与肝功能,食管静脉曲张程度以及APRI指数的关系。结果 172例患者中共23例患者行结肠镜检查,最常见病变为门静脉高压性结肠病（PHC）（9/23,39.1%）,完全正常比例仅有8.7%（2/23）。PHC的发生与患者中重度食管静脉曲张有相关趋势（P=0.086）,与患者严重肝纤维化（APRI指数大于1.08）和肝功能Child-Pugh评分无关。结论多达91.3%的肝硬化患者结肠镜表现异常,39.1%患者表现为PHC,需要对肝硬化患者进行结肠镜检查。     

肝硬化门静脉高压性胃病的胃镜表现及相关因素分析

目的探讨门静脉高压性胃病(PHG)胃镜下胃黏膜特征及其与食管胃静脉曲张、溃疡病及肝硬化并发症之间的关系。方法回顾性分析2012年8月-2018年6月陆军军医大学大坪医院867例肝硬化患者临床资料,统计其胃镜下食管胃静脉曲张、PHG、溃疡病发生的情况,收集肝硬化并发自发性细菌性腹膜炎、肝性脑病、原发性肝癌的数据资料。计数资料组间比较采用χ2检验,相关性分析采用Spearman相关性检验。结果肝硬化患者PHG发生率高达66.2%(574/867),轻度PHG胃黏膜改变以红点灶(68.6%)和蛇皮征(56.8%)为主,而重度PHG以弥漫红斑为主(76.5%)。PHG在不同程度的食管静脉曲张中发生率差异显著(χ2=304.712,P<0.05),并且随着食管静脉曲张加重,PHG程度亦越来越重(r=0.515,P<0.05)。不同程度胃静脉曲张的患者PHG发生率差异有统计学意义(χ2=81.004,P<0.05),且PHG程度与胃静脉曲张程度相关(r=0.292,P<0.05)。不同部位静脉曲张患者PHG的发生率差异显著(χ2=41.361,P<0.05),当患者仅出现胃静脉曲张时,PHG发生率(34.8%)最低,且均为轻度;而食管和胃均出现静脉曲张时,PHG发生率(85.6%)最高。未合并PHG患者中有71例(24.2%)因呕血和(或)黑便就诊住院,而574例PHG患者中有316例(55.1%)因此而住院,二者差异显著(χ2=74.562,P<0.05)。结论不同PHG严重程度的患者胃黏膜特征差异显著,PHG的发生和严重程度与食管胃静脉曲张程度密切相关,且是肝硬化消化道出血重要原因,应积极治疗和预防PHG以降低消化道出血风险和相关并发症。     

门高压鼠血浆前列环素与门脉压力的关系

目的 探讨门脉压力升高和门体分流在前列环素（ＰＧＩ２）或高中的作用。方法 ３６只雄性ＳＤ大随机分为四组：肝前型（ＰＨＰＨ，ｎ＝８）和肝内型门高压（ＩＨＰＨ，ｎ＝９），端侧门腔分流（ＰＣＳ，ｎ＝８）以及手术对照组（ＳＯ，ｎ＝１１），模型制备后２周；（１）测游离门脉压（ＦＰＰ）；（２）应用核素微球技术研究全身及内脏血流血压学；（３）从股动脉采集血样用放射免疫法测血浆６－酮－前列腺素Ｆ１α（６－ｋｅｔｏ     

Effects of calcium antagonists on hepatic and systemic hemodynamics in awake portal hypertensive rats

The effects of the calcium antagonists diltiazem and nicardipine on portal pressure and splanchnic blood flow were studied in awake, unrestrained portal hypertensive rats. Portal hypertension was induced in rats by partial portal vein ligation. Hemodynamic measurements were done using the radiolabeled microsphere technique. In portal veinligated and sham-operated rats, intraarterial diltiazem and nicardipine reduced mean arterial pressure. No significant changes, however, were observed in portal pressure and cardiac index. In portal vein-ligated rats, diltiazem and nicardipine increased portal tributary blood flow. Portal tributary vascular resistance was also significantly decreased. The decrease in the hepatocollateral vascular resistance prevented an increase in portal pressure. In sham-operated rats, these changes were not observed. It is possible that the vascular responses to calcium antagonists are altered in portal vein-ligated rats. These findings demonstrate that the hemodynamic effects of calcium antagonists occur at two levels. First, the increase in portal tributary blood flow appears to be a selective effect on portal tributary vascular resistance. Secondly, the portal pressure does not increase in parallel with the increase in portal tributary blood flow because of a similar reduction in portocollateral vascular resistance.