不同剂量氯沙坦治疗大鼠门静脉高压性结肠病的效果

门静脉高压性结肠病(PHC)的发病率约为40.6%~([1]).霍丽娟等~([2])用缬沙坦对PHC大鼠进行治疗,发现其对PHC大鼠结肠黏膜具有明显保护作用.氯沙坦作为缬沙坦的同类药物,对PHC治疗具有较好预期效果.     

Bilioenteric anastomosis reverses hyperkinetic circulation in bile duct-ligated cirrhotic rats

Background/Aims: The chronic bile duct-ligated rat is used to study hemodynamic changes in cirrhosis but suffers from total biliary obstruction and deep jaundice. The extent of reversibility of hemodynamics and histology following bile flow reconnection is controversial. We aimed to characterize the hemodynamics and histology of bile duct-ligated cirrhotic rats in which bile flow was reconnected by a Roux-en-y choledochojejunostomy.Methods: Operations created four groups: double sham (control), bile duct ligated, and two reconnected groups. Cardiac index and regional blood flows were measured by radioactive microspheres 4 weeks following the last operation in the first three groups and 8 weeks afterwards in the second reconnected group. Liver histology was assessed by a computer-aided scoring program.Results: Cardiac index, mean arterial pressure, and systemic vascular resistance in the reconnected groups were different from bile duct-ligated rats and returned to control values. Portal pressures in the reconnected groups (4-week, 10.0±0.5 and 8-week, 9.7±0.6 mmHg) were significantly lower than in bile-duct-ligated rats (13.7±0.6) but remained elevated compared to controls (7.0±0.3). Portal pressure in the reconnected rats was correlated with cardiac index and mesenteric blood flow, r=0.66 and r=0.45, respectively. Liver histology was improved in the reconnected rats, with decreased bile duct proliferation, fibrosis and apoptosis.Conclusions: We conclude that many of the histological features of secondary biliary cirrhosis are reversible after bilioenteric anastomosis. Furthermore, the hyperdynamic circulation is also largely reversible and is related to the degree of portal hypertension.     

Effect of early propranolol administration on portal hypertensive gastropathy in cirrhotic rats

AIM： To investigate any protective effect of early propranolol administration in the development of portal hypertensive gastropathy in cirrhotic rats. METHODS： For the development of liver cirrhosis and portal hypertensive gastropathy, 60 rats underwent ligation of the left adrenal vein and complete devascularization of the left renal vein, followed by phenobarbital and carbon tetrachloride （CCl4） administration. After two weeks of CCl4 administration, the rats were randomly separated into two groups. In group A, propranolol was continuously administered intragastrically throughout the study, whereas in group B normal saline （placebo） was administered instead. Hemodynamic studies and vascular morphometric analysis of gastric sections were performed after complete induction of cirrhosis. RESULTS： Vascular morphometric studies showed higher numbers of vessels in all mucosal layers in the control group. Statistical analysis revealed a significantly higher total vascular surface in the control group compared to the propranolol group, but with no statistically significant difference between the mean vascular surfaces between the groups. Our study clearly shows that the increased mucosal blood flow is manifested by a marked increase of vessel count. CONCLUSION： Early propranolol＇s administration in portal hypertensive cirrhotic rats seems to prevent intense gastric vascular congestion that characterizes portal hypertensive gastropathy.     

Contribution of nitric oxide to the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats

BACKGROUND & AIMS: Decreased cardiac contractility and beta-adrenergic responsiveness have been observed in cirrhosis, but the etiology remains unclear. We aimed to test the role of nitric oxide (NO), a negative inotropic agent, in the pathogenesis of cirrhotic cardiomyopathy in a rat model. METHODS: Cirrhosis was induced by bile duct ligation. Four weeks after ligation or sham operation, cardiac levels of tumor necrosis factor (TNF)-alpha, guanosine 3,5'-cyclic monophosphate (cGMP), inducible NOS (NOS2), and endothelial constitutive NOS (NOS3) messenger RNA (mRNA) and protein were determined. Serum nitrite/nitrate level was measured. Cardiac contractile function was evaluated in isolated left ventricular papillary muscles in the absence and presence of the NOS inhibitor nitro-L-arginine methyl ester (L-NAME). RESULTS: Cardiac TNF-alpha, NOS2 mRNA and protein, cGMP, and serum interleukin (IL)-1beta and nitrite/nitrate levels were significantly higher in cirrhotic rats than sham controls. No significant differences in NOS3 mRNA or protein were found between cirrhotic and sham control rats. Baseline isoproterenol-stimulated papillary muscle contractile force was significantly lower in the cirrhotic group; with L-NAME incubation, contractile force increased significantly in cirrhotic rats but was unaffected in the controls. In normal papillary muscles, IL-1beta attenuated the contractility, but coincubation with L-NAME again reversed this attenuation. Incubation with the exogenous NO donor S-nitroso-N-acetyl-penicillamine also blunted papillary muscle contractility. CONCLUSIONS: These results suggest that cytokine-induced stimulation of NOS2 plays a significant role in the pathogenesis of cirrhotic cardiomyopathy.     

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.     

Endotoxin-induced mortality in bile duct-ligated rats after administration of reconstituted high-density lipoprotein

Cholestatic patients have substantial morbidity because of increased susceptibility to endotoxin (lipopolysaccharide [LPS]). Although reconstituted high-density lipoprotein (rHDL) can bind and neutralize LPS, cholestasis is associated with a near complete absence of HDL. Effects of rHDL infusion on the outcome of LPS-induced inflammatory responses in cholestatic rats were determined. Bile duct-ligated (BDL) and sham rats were treated with rHDL or saline and challenged with LPS. Distribution of cholesterol over the lipoprotein subclasses changed by ligation: levels in low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) were increased 2-fold and 5-fold, respectively, and were decreased in HDL 2-fold. rHDL treatment did not affect cholesterol distribution. LPS was mainly found in the HDL fraction, and ligation affected only levels of HDL-bound LPS (50% decrease; P<.05). Although rHDL infusion effectively normalized the lipoprotein-bound LPS distribution, it resulted in increased sensitivity (mortality: 88% in the ligation + rHDL group versus 44% in the ligation + saline group, 25% in the sham + saline group, and 0% in the sham + rHDL group, P <.05). In accordance with these results, plasma tumor necrosis factor (TNF) was significantly highest in the BDL + rHDL group at several hours after LPS challenge as well as the accumulation of LPS in the liver (P<.05). rHDL infusion leads to increased LPS-induced mortality in cholestatic rats. These results sharply contrast with the protective effects of rHDL suppletion in experimental endotoxemia in animals and human volunteers without biliary obstruction and suggest that there may be danger in administration of rHDL to cholestatic patients.     

肝硬化门静脉高压症的诊断

门静脉高压症是消化系统常见病,指门静脉血流压力增高。肝硬化引起的门静脉高压症患病率高,目前认为由门静脉阻力(R)增加和门静脉血流量(Q)增加所致,肝脏结构改变所致的机械梗阻与神经、体液及代谢因素一同发挥着重要作用。临床表现包括腹腔积液、脾大、侧支循环形成与开放。诊断时须符合以下条件:满足肝硬化及门静脉高压症的诊断,但除外其他病因。     

Urinary excretion of bile acids in bile duct-ligated rats

Background. In patients with complete bile duct obstruction, the only pathway of bile acid elimination is through the urine. However, the urinary excretion of various bile acid conjugates in the presence of bile duct obstruction has not been clarified. Given this factor, the urinary excretion of various bile acids was compared in rats that were bile duct-ligated for 3 days. Methods. After urinary bladder cannulation, radiolabeled bile acids were intravenously injected, and urine samples were collected every 2 h for 6 h, and radioactivity was counted. Results. Urinary excretion (cumulative percent dose during 6 h) of taurocholate and cholate was similar (19.3% and 16.8%). Urinary excretion of tauroursodeoxycholate, lithocholate, and taurolithocholate-sulfate was less effective (12.7%, 9.8% and 2.1%, respectively). Cholate was mostly conjugated with taurine, and lithocholate was mostly conjugated with taurine and further hydroxylated. Conclusions. These results indicate that unconjugated bile acids were taken up by the liver and excreted into the blood after further biotransformation even under conditions of complete bile duct obstruction. Although bile acid sulfates are the major bile acids in the urine of patients with obstructive jaundice, monohydroxylated bile acids are considered not to be so effectively excreted into the urine, even with conjugation with taurine and sulfate, in rats. Received: October 4, 2002 / Accepted: November 8, 2002 RID="*" ID="*" Reprint requests to: H. Takikawa Acknowledgments. This work was partly supported by a Grant-in-Aid by the Japan Society for the Promotion of Science (C2-14570510).     

经颈静脉肝内门体分流术对肝硬化门静脉高压症患者血流动力学的影响

[目的]观察经颈静脉肝内门体分流术(Transjugular intrahepatic portosystemic shunt,TIPS)对肝硬化门脉高压症患者门脉血流动力学的影响,探讨TIPS治疗肝硬化门脉高压症的有效性及机制。[方法]30例肝硬化门脉高压症患者,TIPS术前及术后,彩色多普勒超声测量门脉主干压、内径、血流速度及脾静脉内径。放射免疫法测定血浆肾素(PRA)、血管紧张素Ⅱ(ATⅡ)和血管内皮素(ET)浓度。[结果]30例患者术后的门脉压(24.8±3.6)cmH2O(1 cmH2O=0.098 kPa)与术前的(44.6±5.8)cmH2O比较;门脉内径(1.28±0.06)cm与术前的(1.65±0.09)cm比较;门脉血流速度(43.5±13.2)cm/s与术前的(11.6±3.8)cm/s比较;脾静脉内径(0.92±0.06)cm与术前的(1.24±0.04)cm比较,均P<0.01。血浆ET、PRA、ATⅡ浓度分别为(84.52±28.15)、(89.92±35.46)、(159.65±62.42)ng/L,与术前的(126.25±40.36)(、186.32±68.74)、(253.48±106.57)ng/L比较,均P<0.01。术后腹水较术前明显减少。[结论]TIPS能有效降低门脉压,降低血浆ET、PRA及ATⅡ的浓度,改善患者门脉系统及全身的血循环。     

Protective effect of omeprazole on gastric mucosal of cirrhotic portal hypertension rats

Objective:To observe the protective effect of omeprazole on gastric mucosal of cirrhotic portal hypertension rats.Methods:All rats were randomly divided into normal control group,cirrhosis and treatment group.Thioacetamide was used to establish rat model of cirrhotic portal hypertension.The necrotic tissue of gastric mucosa ulcer focus,degree of neutrophils infiltration at the ulcer margin,portal pressure,portal venous flow,abdominal aortic pressure,abdominal aortic blood flow at front end,gastric mucosal blood flow(GMBF),glycoprotein(GP)of gastric mucosa,basal acid secretion,H' back-diffusion,gastric mucosal damage index,NO,prostaglandin E_2(PGE_2) and tumor necrosis factor-α(TNF-α) were determined respectively,and the pathological changes of gastric mucosa were also observed by microscope.Results:Compared with cirrhosis group and the control group,the ulcer bottom necrotic material,gastric neutrophil infiltration and UI of the treatment group were all decreased significantly(P0.01),GMBF value,GP values,serum NO,PGE_2,TNF- a were all significantly increased.Conclusions:Omeprazole has an important protective effect on gastric mucosal and it can increase gastric mucosal blood flow and related to many factors.     

The effect of alcohol-induced hepatomegaly on portal hypertension in cirrhotic rats.

Male Sprague-Dawley rats with CCl4-induced cirrhosis (confirmed by increased collagen content and light microscopy) were fed either ethanol (Group A, n = 9) or isocaloric carbohydrate diet (Group B, n = 8) for 4 weeks. Histologic and hemodynamic measurements were obtained in the awake state before (time 1) and after the 4 weeks of diet (time 2). Portal-systemic shunts were evaluated using radiolabelled microspheres. Liver weight was increased in Group A (16.5 +/- 0.5 vs. 14.2 +/- 0.5 g, mean +/- SE, p less than 0.005) as was the ratio of liver weight over total body weight (3.41 +/- 0.05 vs. 2.86 +/- 0.09%, p less than 0.0001, +19.2%). Hepatocytes surface area was increased in the ethanol group (357 +/- 9 vs. 294 +/- 7 microns 2, p less than 0.0001). In Group B, only 9 +/- 2% of hepatocytes had steatosis as opposed to 69 +/- 3% of centronodular and 34 +/- 3% of perinodular hepatocytes in Group A (p less than 0.001). Portal pressure remained stable in both groups (time 1 (A) 16.9 +/- 0.8, (B) 15.8 +/- 1.1 mmHg, n.s.; time 2 (A) 15.9 +/- 0.7, (B) 15.8 +/- 0.6 mmHg, n.s.). Portal-systemic shunts did not change with time or diet (time 1 (A) 10.6 +/- 3.7%, (B) 4.1 +/- 2.1%, n.s.; time 2 (A) 13.4 +/- 5.9%, (B) 10.8 +/- 4.3%, n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)     

骨髓纤维化合并肝硬化门静脉高压1例报告

骨髓纤维化是一种原因不明的造血干细胞异常引起的慢性骨髓增生性疾病,骨髓纤维组织明显增生和髓外造血是骨髓纤维化的病理学基础。其临床进展缓慢,出现进行性贫血、脾脏肿大、外周血幼稚细胞、泪滴状红细胞和骨髓干抽,伴有发热、乏力、盗汗、消瘦等全身症状[1]。临床较少见,大多数在中年以后发病,起病隐匿,临床表现不一,无特异性症状,易误诊、漏诊。本院收治1名骨髓纤维化合并门静脉高压症1例,报道如下。     

采用改良的Sugiura术治疗肝硬化并发门脉高压症患者疗效研究*

目的 探讨采用改良的Sugiura术治疗肝硬化并发门脉高压症患者的疗效及其对门脉血流动力学指标的影响。方法 回忆性分析2013年5月~2015年5月期间我院治疗的56例肝硬化并发门脉高压症患者的临床资料,手术前后采取玻璃管水柱法测量自由门静脉压（FPP）,采用吲哚氰绿15分钟潴留率(ICGR15)检测肝脏储备功能,计算肝脏有效血流（ELBF）,使用B超检测门脉内径、门静脉血流量（PVF）、肝动脉血流（HAF）和肝总血流量（THF）的变化。结果 经过改良的Sugiura术治疗,56例患者手术成功,出现肺部感染和胸腔积液4例,切口感染2例,门静脉血栓形成5例,吻合口狭窄4例,胃瘘1例。经充分引流、营养支持、抗感染、补充白蛋白或输注血浆等对症支持治疗,病情逐步缓解或痊愈;术后FPP水平为（21.3±3.4） cmH₂O,显著低于术前水平【（32.5±5.0）cmH2O,P<0.05】;在术后,56例患者EHBF、THF和PVF水平分别为（0.5±0.1） ml/min、（1481.1±354.0） ml/min和（1046.1±258.0） ml/min,在术后3 m,分别为（0.5±0.3）ml/min、（1574.1±326.0） ml/min和（1131.0±304.1） ml/min,均显著低于术前水平 [分别为（0.7±0.3） ml/min、（1891.0±392.1） ml/min和（1523.1±291.1）ml/min,P<0.05];术后HAF水平为 （435.0±142.1） ml/min,术后3 m时为（443.0±183.1） ml/min,均显著高于术前水平【（368.1±139.1）ml/min,P<0.05】;术后患者ICGR15为（22.7±7.9）%, 显著高于术前的（19.3±5.5）%,差异显著（F=7.327,P<0.05）;手术前后门静脉内径变化差异无统计学意义（P>0.05）;术后1 m和术后3 m,患者血清白蛋白水平大幅升高【分别为（35.2±2.3） g/L和（36.8±1.7） g/L对（31.8±1.7） g/L,P<0.05】;在术后1 m时,患者外周血PLT和WBC计数分别为（144.5±7.2）×10⁹/L和（13.8±0.6）×10⁹/L,在术后3 m时则分别为（98.1±10.6）×10⁹/L和（4.2±0.8）×10⁹/L,均显著高于术前水平【分别为（75.3±6.7）×10⁹/L和（3.4±0.3）×10⁹/L,P<0.05】。结论 采用改良的Sugiura术治疗肝硬化并发门脉高压症患者能够改善肝功能、血细胞和门脉系统血流动力学指标,降低门静脉压力,对防治病情恶化和消化道出血有帮助,其远期疗效还有待观察。     

神经肽Y对肝硬化大鼠血流动力学及水钠代谢的影响

近年来，人们发现神经肽Ｙ（ＮＰＹ）与肝脏疾病有密切关系［１，２］。正常肝组织中ＮＰＹ阳性神经纤维分布于门脉系统周围，在肝小叶中ＮＰＹ阳性神经纤维沿肝窦状隙行走，肝硬化时肝纤维化间隔中ＮＰＹ神经纤维显著增多，说明ＮＰＹ神经纤维的改变与肝硬化时病理生理变化有关［２］。本实验测定了肝硬化大鼠血浆和组织中ＮＰＹ的含量，并对其含量变化及对血流动力学和水钠代谢的影响进行了探讨。 １．材料与方迭：（１）动物分组及肝硬化模型的建立：健康雄性ＳＤ大鼠随机分为肝硬化组和假手术组，肝硬化组采用胆管结扎的方活建立模型。…     

Effects of norepinephrine and acetylcholine on portal-systemic collaterals of common bile duct-ligated cirrhotic rat

BACKGROUND: Catecholamine exerts profound vascular effects on vascular smooth muscle, and serum norepinephrine (Nepi) and sympathetic nervous activity are increased in cirrhosis. The vascular response of Nepi and acetylcholine (Ach) in portal-systemic collaterals of cirrhotic rats is unknown. The purpose of the present study was to investigate the effects of Nepi and Ach on portal-systemic collaterals of common bile duct-ligated (BDL) cirrhotic rats. METHODS: Perfusion studies were performed 6 weeks after BDL when hepatic cirrhosis was induced. Three series of experiments were performed in BDL rats: (i) the Nepi (10(-10) mol/L-10(-5) mol/L) vasoconstrictory responses with (n = 6) and without (n = 5) alpha1- (phentolamine, 5 x 10(-6) mol/L) or beta- (propranolol, 10(-5) mol/L) receptor antagonist (n = 6 and 5, respectively); (ii) the Ach (10(-8) mol/L-10(-5) mol/L) vasodilatory responses in Nepi- preconstricted portal-systemic collaterals in the absence (n = 7) or presence (n = 8) of N(pi)- L-nitro-arginine (NNA, 10(-4) mol/L); and (iii) the effect of indomethacin (10(-5) mol/L; n = 6) on Nepi responses. The collateral vascular responses were evaluated by the in situ collateral perfusion. Results: Norepinephrine significantly increased the perfusion pressure and was inhibited by phentolamine (P < 0.05). The constrictive responses of Nepi were not significantly modified in the presence of propranolol (P > 0.05). Acetylcholine produced >50% relaxation of the Nepi-preconstricted collateral vessels and was inhibited by NNA (P < 0.05). In addition, indomethacin significantly enhanced the constrictive response of Nepi (P < 0.05). Conclusion: Norepinephrine has a vasoconstrictive effect on the portal-systemic collaterals of cirrhotic rats and this effect was mediated by alpha1-receptor. Both nitric oxide and prostaglandin are endogenous modulators in the collateral circulation of cirrhotic rats.