Effect of verapamil on portal blood flow in patients with liver cirrhosis.

The effect of acute (80 mg orally) and prolonged (240 mg orally daily for 2 weeks) verapamil administration on portal blood flow was studied in 12 patients with histologically proved alcoholic liver cirrhosis. Portal hemodynamics were examined by the ultrasonic duplex Doppler system. Thirty minutes after acute verapamil administration, the following parameters remained unchanged: (1) cross-sectional area of the portal vein, from 1.52 +/- 0.41 to 1.51 +/- 0.43 cm2; (2) portal blood velocity, from 13.2 +/- 1.6 to 13.4 +/- 1.6 cm/s; (3) estimated volume of portal blood flow, from 931 +/- 96 to 954 +/- 103 mL/min; and (4) congestion index of the portal vein, from 15.1 +/- 8.3 to 15.6 +/- 8.8 cm, respectively (P = > 0.05). In addition, no significant changes in portal blood hemodynamics were noted after prolonged verapamil administration (P > 0.05). These results demonstrated that verapamil did not alter portal blood flow in patients with alcoholic liver cirrhosis.     

硫氮(艹卓)酮加硝酸异山梨酯与硝酸异山梨酯对冠心病患者心功能的影响

应用硫氨(艹桌)酮加硝酸异山梨酯与硝酸异山梨酯,对65例冠心病心绞痛患者进行9项心功能指标及临床疗效观察。结果表明:硫氮革酮与硝酸异山梨酯合用组(治疗组)用药前后,左心收缩功能指标SV、EF、Fs、PEP/LVET,舒张功能指标LA、E、A、A/E、DC均有显著差异(P<0.01),改善心绞痛症状有效率为94％。而单用硝酸异山梨酯组(对照组)用药后除每搏输出量及射血分数有明显差异外(P<0.01),其它各项指标无明显差异,改善心绞痛症状有效率为59％。提示:两药联合应用对改善冠心病患者左心功能疗效好,副作用少,值得在临床进一步观察。     

Effect of somatostatin on liver blood flow and liver metabolic activity in patients with cirrhosis

In a group of 10 patients with cirrhosis, protal hypertension, and previous gastro-intestinal bleedings, hepatic plasma flow, indocyanine green clearance and intrinsic hepatic clearance were determined before and during i.v. infusion of somatostatin (7.5 micrograms/min). The same study protocol was performed in a further seven patients with cirrhosis infused with placebo. All these parameters were significantly decreased by the drug (p less than 0.05; less than 0.01; less than 0.01, respectively) mean decrease being 12, 9 and 8%, respectively, while no significant change occurred in the placebo-infused patients. These data indicate that somatostatin infused at a dose of 7.5 micrograms/min in cirrhotics provokes a slight decrease in hepatic plasma flow and in liver metabolic activity. This effect may contribute to further decrease hepatic removal of harmful substances and may increase systemic concentration of drugs metabolized by the liver.     

Effects of isosorbide dinitrate on the pattern of arterial blood flow in healthy human subjects

1. Blood velocity measurements have been made in the superficial femoral artery, 10 cm downstream of the common femoral artery bifurcation, in healthy human subjects, using a multi-channel Doppler ultrasound device. 2. In a randomized double-blind protocol, the effects of isosorbide dinitrate were examined during a 2 h period. 3. The changes induced by isosorbide dinitrate include: (i) an increase in the width of the artery and a reduction in brachial arterial blood pressure, implying relaxation of arterial smooth muscle; (ii) an increase in reverse flow and a decrease in time-averaged mean velocity associated with a relatively small decrease of the velocity excursion during the cardiac cycle, implying an increase in flow pulsatility; and (iii) an alteration of the flow pattern both in the core and near the vessel walls.     

Immediate effects of different schedules of somatostatin on portal pressure in patients with liver cirrhosis

What is known and Objective: Somatostatin (SST) is used for the treatment of acute variceal bleeding based on its ability to decrease portal pressure and collateral blood flow. To date, no studies have focused on the immediate–early effects (between 1 and 30 min) of SST. The aim of this study was to compare the efficacy of different schedules of SST therapy with placebo on portal pressure in patients with portal hypertension treated with portal‐azygous disconnection and to test whether an increase in bolus or infusion dose can improve the clinical efficacy of SST therapy. Methods: Patients were treated with four different schedules: (a) standard dose (n = 11): one 250 μg bolus + a continuous infusion of 250 μg/h; (b) medium dose (n = 10): 500 μg bolus + a continuous infusion of 250 μg/h; (c) high dose (n = 10): 250 μg bolus + a continuous infusion of 500 μg/h; (d) control (n = 10): an injection of placebo (saline) followed by a placebo infusion. Following SST or placebo administration, portal pressure, central venous pressure (CVP), systemic blood pressure and heart rate (HR) were measured at 1, 3, 5, 7, 10 and 30 min. Results and Discussion: The three schedules of SST induced a marked, rapid and highly significant decrease in portal pressure. The decline in portal pressure was moderate at 1 min (P < 0·040), achieved a peak effect at 5 min (P < 0·009) and remained decreased at 30 min. The effect of SST on portal pressure was significantly greater than placebo from 1 min after administration. There were no significant differences in portal pressure decrease between the three schedules of SST. The three schedules of SST and the placebo schedule did not induce significant changes in HR, systemic blood pressure and CVP. What is new and Conclusion: This study shows that SST is effective in decreasing portal pressure within 30 min of administration in patients with liver cirrhosis. The clinical schedule used in this study was reasonable and safe.     

Effect of propranolol on hepatic blood flow in patients with cirrhosis

The effect of propranolol on systemic and hepatic hemodynamics was studied in patients with cirrhosis. One hour after 40 mg propranolol by mouth as well as during continuous oral dosing at doses that reduced heart rate 25%, cardiac output and the hepatic venous pressure gradient fell significantly, whereas arterial pressure and hepatic blood flow did not change significantly. In six patients with cirrhosis and surgical end-to-side portacaval shunts, cardiac output and the hepatic venous pressure gradient also decreased 15 minutes after intravenous propranolol (5 mg), whereas hepatic blood flow did not change significantly. In the patients with surgical shunts, systemic vascular resistance rose significantly but hepatic arterial vascular resistance fell. Our data show that in patients with cirrhosis, propranolol induces an increase in the fraction of cardiac output reaching the liver.     

胶原酶门静脉灌注对兔肝硬化及组织中星状细胞激活的影响

目的 CCl4皮下注射建立兔肝硬化动物模型,观察Ⅳ型胶原酶门静脉灌注对肝硬化及肝组织中α-平滑肌动蛋白(α-SMA)表达的影响。方法取雄性新西兰大白兔,采用臀部皮下注射50%CCl4橄榄油0.23ml/kg,每周2次,共12周制作肝硬化动物模型,注射等量橄榄油作为对照。12周后各组动物均建立门静脉给药通路,将已形成肝硬化并门静脉插管成功的33只兔随机分为两组(组1,组2),组1为16只、组2为17只。组1经门静脉给药通路注入0.1%Ⅳ型胶原酶1.5ml,组2注入等量0.9%氯化钠,5次/周,共4周。将造模对照组中门静脉插管成功的30只兔同样随机分为两组(组3,组4),每组15只,处理方法同前。4周后,将各组动物处死后留取肝脏组织,观察其病理学及羟脯氨酸含量变化,标本固定后,行α-SMA免疫组织化学染色,行积分光密度、面密度分析。结果肝硬化动物肝脏α-SMA表达显著增强;门静脉灌注0.1%Ⅳ型胶原酶肝硬化动物肝脏纤维化程度明显降低,羟脯氨酸含量显著降低,但α-SMA表达强度显著增高。结论采用门静脉灌注0.1%Ⅳ型胶原酶可显著降低肝纤维化程度,但α-SMA表达增高,可能与肝脏星状细胞激活有关。     

ADMA correlates with portal pressure in patients with compensated cirrhosis

BACKGROUND: Chronic liver diseases are frequently complicated by portal hypertension, an important component of which is the increased intrahepatic vascular resistance, in part related to endothelial dysfunction. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is an established mediator and marker of endothelial dysfunction. We therefore investigated the possible implication of ADMA in chronic liver diseases-induced portal hypertension. MATERIALS AND METHODS: We studied 39 consecutive patients with compensated hepatitis C virus (HCV) related chronic liver diseases. All patients underwent hepatic venous pressure gradient (HVPG) measurement, and simultaneous blood sampling from the hepatic vein and the pulmonary artery, for ADMA and nitrite/nitrate (NOx) plasma level determinations. RESULTS: A positive correlation between HVPG and ADMA concentrations in hepatic veins (ADMA-h) was found (r = 0.77, P < 0.0001). Moreover, a negative correlation between HVPG and NOx concentrations in the hepatic veins (NO-h) (r = -0.50, P = 0.005), and between ADMA-h and NO-h was observed (r = -0.40, P = 0.02). ADMA concentrations in pulmonary artery (ADMA-p) (0.55 +/- 0.13 micromol L(-1)) were significantly higher than in hepatic veins (0.47 +/- 0.09 micromol L(-1)) (P < 0.0001). CONCLUSIONS: These results suggest that ADMA may play a pathophysiological role in portal hypertension by contributing to the relative intrahepatic NO deficiency typical of endothelial dysfunction.     

Renal blood flow in cirrhosis: relation to systemic and portal haemodynamics and liver function

The RBF was measured by means of the 133Xe washout method in seventy patients with cirrhosis. The average RBF in controls was 3.72 ml/g-min compared with 2.34 in the patients without ascites, 1.82 in the decompensated patients, 1.47 in the patients with azotaemia and 1.13 in the patients with additional oliguria. The RBF was not significantly correlated to changes in the systemic or portal haemodynamics. Likewise it was not correlated to any biochemical test of liver function except the serum albumin concentration (P less than 0.01). From the present results it can be concluded that a reduction in RBF in cirrhosis frequently is present before sodium and water retention is clinically evident and before laboratory proof of impairment of renal function, and that a subnormal serum albumin concentration may be a factor among several leading to renal hypoperfusion in cirrhosis.     

Impaired sympathetic regulation of cerebral blood flow in patients with cirrhosis of the liver

Continuous recording of mean cerebral blood flow velocity (MCBFV) by Doppler ultrasound allows detection of low-frequency (LF) oscillations, which reflect sympathetic activity in the cerebral circulation. To establish whether the sympathetic drive to the cerebral circulation is altered in patients with compensated cirrhosis, and, if so, where alterations take place, LF oscillations of MCBFV, heart rate (RR interval) and systolic arterial pressure (SAP) were analysed in 10 patients with cirrhosis and 10 control subjects during supine rest and on stimulation of carotid baroreceptors using a neck chamber applying sinusoidal suction. Bivariate analysis was used to study the relationship between pairs of oscillations. In the case of a significant association, the delay in the appearance of the oscillation in MCBFV, SAP and RR was calculated. Baroreceptor stimulation induced significant increases in SAP LF and RR LF power in both groups, while MCBFV LF power increased only in controls. During baroreceptor stimulation, the lag phase between SAP LF and MCBFV LF power was significantly lower in cirrhotic patients than in control subjects (0.96 compared with 1.59 rad; P<0.01), indicating altered sympathetic regulation of the cerebral circulation. The baroreflex arc was intact, as indicated by the similar pattern of RR-SAP interval in patients and controls. Plasma noradrenaline levels increased significantly in both groups in response to head-up tilt. These results indicate that patients with cirrhosis have an altered sympathetic regulation of the cerebral circulation that is characterized by an inadequate response of resistance microvessels, despite adequate baroreceptor function.     

Portal blood flow in cirrhosis of the liver

Direct measurements of portal flow and pressure in a relatively large number of patients with cirrhosis show a marked reduction in flow associated with a nearly constant plateau of portal pressure. This lack of correlation indicates the complex relationships of resistances in the splanchnic, collateral, and hepatic circuits determining the division of the available splanchnic flow between the portal vein and the collateral pathways. Subtracting the measured portal flow from well-established estimates of total hepatic blood flow in cirrhosis suggests that the hepatic artery contributes more than one-half of the blood perfusing the cirrhotic liver. There was no instance of retrograde portal flow during the preshunt measurements, although such reversal was frequent after side-to-side portacaval anastomosis. Attempting to explain the plateau of portal pressure in the face of an increasing outflow resistance presumably associated with progress of the disease, we postulate that an augmented inflow resistance to the splanchnic chamber reduces splanchnic flow in cirrhosis. End-to-side portacaval anastomosis did not return normal portal flow, although it decreased pressure to accepted control levels. The assumption is that most of the splanchnic blood was flowing through the shunt, leading to a high splanchnic resistance in the immediate postshunt status. If this resistance was previously elevated, as suggested by the plateau of portal pressure, the mechanism responsible for the elevation was not immediately deactivated after the shunt, and the true effect of the operation upon splanchnic flow may not be measurable at such time.     

Regional blood flow and hemodynamics in the rabbit with adriamycin cardiomyopathy: effects of isosorbide dinitrate, dobutamine and captopril

We have studied the effects of captopril, nitrates and dobutamine on hemodynamics and regional blood flow in the conscious rabbit with adriamycin cardiomyopathy. Rabbits were injected twice weekly with adriamycin (1 mg.kg-1 bw.) for 8 weeks and subsequently maintained for 2 weeks without adriamycin in order to allow recovery from any noncardiac effects. Doses of drug for investigation (captopril, 300 micrograms.kg-1.min-1; isosorbide dinitrate, 10 micrograms.kg-1.min-1; and dobutamine, 10.9 micrograms.kg-1.min-1) were chosen in anticipation of a 20% increase of cardiac output in animals with heart failure. In animals with heart failure myocardial blood flow was increased by dobutamine and to a lesser extent by captopril. Renal blood flow was increased only by captopril and nitrates. Cerebral blood flow was reduced by captopril in control animals but unaltered in animals with heart failure. The observed alterations of blood flow were similar to those known to occur in humans and indicate that this is a useful model of heart failure for the evaluation of new drugs.     

Chronic administration of ursodeoxycholic acid decreases portal pressure in rats with biliary cirrhosis

Liver cirrhosis is characterized by increased IHR (intrahepatic resistance) and lipid peroxidation, and decreased antioxidative defence. The present study investigates the effects of administration for 1 month of the antioxidant UDCA (ursodeoxycholic acid) in BDL (bile-duct-ligated) cirrhotic rats. Splanchnic haemodynamics, IHR, hepatic levels of TBARS (thiobarbituric acid-reacting substances), GSH (glutathione), SOD (superoxide dismutase) activity, nitrite, PIIINP (N-terminal propeptide of type III procollagen) and collagen deposition, histological examination of liver, mRNA expression of PIIIP-alpha1 (type III procollagen) and TGF-beta1 (transforming growth factor-beta1), protein expression of TXS (thromboxane synthase) and iNOS (inducible NO synthase), and TXA2 (thromboxane A2) production in liver perfusates were measured. The results showed that portal pressure and IHR, hepatic levels of PIIINP, hepatic collagen deposition, mRNA expression of PIIIP-alpha1 and TGF-beta1, protein expression of iNOS and TXS, and production of TXA2 in liver perfusates were significantly decreased in UDCA-treated BDL rats. The increased levels of hepatic GSH and SOD activity and decreased levels of TBARS and nitrite were also observed in UDCA-treated BDL rats. In UDCA-treated BDL rats, the reduction in portal pressure resulted from a decrease in IHR, which mostly acted through the suppression of hepatic TXA2 production and lipid peroxidation, and an increase in antioxidative defence, leading to the prevention of hepatic fibrosis.     

人血白蛋白输注速度对肝硬化门静脉高压患者血流动力学的影响

目的：探讨肝硬化门静脉高压患者输入人血白蛋白的适宜速度。方法选择门静脉高压需输入人血白蛋白的患者58例,均输入20％人血白蛋白50 ml,采用抛硬币发随机将患者分为对照组（n＝30）和实验组（n＝28）。对照组患者输注速度为25 gtt/min,输入时间为45 min;实验组输注速度为33 gtt/min,输入时间为30 min。采用彩色多普勒超声诊断仪测量不同时间点门静脉内径（ Dpv）、平均血流速度（Vpv）、血流量（Qpv）及门静脉压力,比较两组差异。结果对照组输入白蛋白结束时,Dpv为（13．03±2．01）mm,Vpv为（9．40±2．06）cm/s,Qpv为（782．29±313．02）ml/min,门静脉压力为（2．747±0．348）kPa,与实验组比较差异均无统计学意义（t 值分别为-0．04,0．81,0．46,0．55;P ＞0．05）。结论在30 min内给肝硬化门静脉高压患者输入20％人血白蛋白50ml是可行的。     

Effect of cisapride on portal haemodynamics in patients with liver cirrhosis using duplex Doppler ultrasonography.

PURPOSE: Cisapride, a benzimide derivative, is a gastrointestinal prokinetic agent without dopamine-antagonistic or cholinomimetic effects. This study aims at assessing the effect of cisapride oral administration on portal flow in patients with advanced post hepatitic cirrhosis using duplex Doppler ultrasound (US). METHODS: A total of 12 patients with post-hepatitic liver cirrhosis were included in the study. Duplex Doppler sonographic examinations were performed before and after treatment. The subjects received 10 mg cisapride before starting the measurement procedure and then three times a day for 2 days. Portal haemodynamics including vessel diameters (mm), mean flow velocities (cm/s), blood flows (ml/min) were investigated. RESULTS: Mean portal vein diameters, mean portal flow velocity and portal blood flow volume showed decreases of 18.6, 22.1 and 43.6% (P<0.001), respectively. After cisapride administration the portal vein diameter did not change in two patients and the portal vein velocity did not change in three patients. No significant change was found in systolic blood pressure, diastolic blood pressure or pulse rate after the administration of cisapride. CONCLUSION: In this study, it was demonstrated that oral administration of cisapride results in a significant reduction of portal blood flow but there were no changes in heart rate or systolic pressure in patients with cirrhosis of the liver.     

Effect of vasopressin and somatostatin on hemodynamics and blood gases in patients with liver cirrhosis

The effects of somatostatin and vasopressin on blood gases, pulmonary and systemic hemodynamics, and portal pressure assessed by the gradient between occluded and free hepatic vein pressures, were investigated in 18 patients with liver cirrhosis. In the first 10 patients, an iv bolus of 250 microgram somatostatin, followed by an infusion of 125 microgram somatostatin over 30 min, caused a sudden rise in pulmonary and systemic vascular pressures lasting 2 to 5 min and accompanied by bradycardia. There was a slight and transient increase in venous admixture (Qsp/Qt) and alveolar-arterial oxygen tension gradients (P(A-a)O2), and a transient reduction in O2 delivery (O2 del) (-11% of the baseline values) and portal pressures (-14%). In the next 8 patients, vasopressin, 0.4 U/min infused over 30 min, caused a more persistent pulmonary and systemic hypertension and bradycardia, a slight increase in P(A.a)O2 and Qsp/Qt, a reduction in O2 del (-27%) and a decrease in portal pressures (-32%). These effects were marked during the entire vasopressin infusion period. Both somatostatin and vasopressin had vasoconstrictive properties and exerted negative effects on hemodynamics and blood gases. Vasopressin appeared to be a more potent drug than somatostatin.     

Antianginal effect of isosorbide dinitrate spray in patients with exercise-induced stable angina

Ten patients with stable exercise-induced angina took part in this study. Isosorbide dinitrate and placebo sprays were administered in a double-blind, randomized crossover study. The dose of isosorbide dinitrate given was two squirts (= 2.5 mg) 2 min before testing. When taken before exercise it significantly improved (p less than 0.014) exercise tolerance. Significant (p less than 0.0005) ischaemic changes in the electrocardiogram also occurred. These effects occurred later than with placebo. Exercise time was prolonged with the active drug. The results of this study show that isosorbide dinitrate spray improves the exercise tolerance of patients with ischaemic heart disease.     

Effect of two different preparations of somatostatin on intra-portal pressure in patients with liver cirrhosis

Summary. Somatostatin has been found by most authors to reduce splanchnic blood flow and hepatic venous wedge pressure. High success rates in treating oesophageal varicose bleeding have been reported by some authors, while others have been unable to confirm these findings. A reason for the discrepancies might be that different preparations of somatostatin were used. Consequently, two preparations of somatostatin were administered to three cirrhotic patients as 60-min infusions at a dosage of 250 μg/h. The intra-portal pressure was measured before and during the infusions and found to be unaffected by both preparations. The findings suggest that previously demonstrated reductions in portal pressure may have been of brief duration, possibly due to vascular autoregulation.