Decrease In Portal Blood Flow Research Articles

Systemic exposure to propranolol in patients with chronic liver disease and its correlation with portal blood flow.

Propranolol is a beta-blocker used for the prevention of variceal bleeding in cirrhotic patients. We investigated the pharmacokinetics of propranolol in patients with chronic liver disease compared to that in healthy individuals. The relative amount of portal blood flow was measured to investigate the correlation of portal blood flow and the systemic exposure of propranolol. Thirty healthy subjects, 18 patients with chronic active hepatitis (CAH), and 54 patients with cirrhosis were included in this prospective study. Blood samples for pharmacokinetic analysis were taken up to 8 h post-dose. The portal blood flow was estimated by H/L ratio using thallium-201 (201TI) per rectal scintigraphy. A total of 78 subjects completed the study. The area under the concentration-time curve (AUC) to the last measurable time (AUClast, ng⋅h/mL) were 150.2 ± 154.1, 112.2 ± 84.7, and 204.0 ± 137.3 in healthy subjects, CAH patients, and cirrhosis patients, respectively. AUCrmlast showed positive correlation with the H/L ratio in patients with chronic liver disease (r = 0.5817, p < 0.0001). In conclusion, the patients with cirrhosis showed higher systemic exposure to propranolol than healthy subjects or patients with CAH. The increase in systemic exposure to propranolol was correlated with the decrease in portal blood flow.

Evaluation of hepatic tumor portal perfusion using mesenteric angiography: A pilot study in 5 dogs.

BackgroundMesenteric angiography is a sensitive method for visualizing portal perfusion in the dog.ObjectivesTo evaluate hepatic portal perfusion in dogs with incompletely resectable hepatic tumors using mesenteric angiography.AnimalsFive client‐owned dogs with incompletely resectable hepatic tumors evaluated with mesenteric angiography.MethodsRetrospective case series. Electronic medical records at the Animal Medical Center were analyzed to identify dogs that underwent mesenteric portography to determine blood flow to nonresectable hepatic tumors and subsequently determine ideal routes for transarterial embolization, vascular stent placement, or both. The images obtained from mesenteric angiography were analyzed and compared to those obtained from computed tomography angiography.ResultsPortography was accomplished using direct mesenteric venography in 3 dogs with hepatocellular carcinoma (HCC), cranial mesenteric arteriography in 1 dog with hepatic adenoma or well‐differentiated HCC, and via splenic arteriovenous fistula in 1 dog with diffuse hepatic hemangiosarcoma metastases. Mean pixel densities in areas of hepatic tumor growth identified statistically significant decreases in portal blood flow (P = .02) compared to normal hepatic parenchyma.Conclusions and Clinical ImportanceInitial findings indicate that the blood supply to large and metastatic hepatic tumors in dogs may correlate with that in humans, such that the majority of the tumor blood supply arises from the hepatic artery and not the portal vein. Differences in blood supply between normal hepatic parenchyma and hepatic tumors might be exploited by developing selective tumor therapies such as arterial embolization or chemoembolization that largely spare normal liver tissue. Further investigation is warranted.

Constriction rate variation produced by partial ligation of the portal vein at pre-hepatic portal hypertension induced in rats.

BackgroundPartial portal vein ligation causes an increase in portal pressure that remains stable even after the appearance of collateral circulation, with functional adaptation to prolonged decrease in portal blood flow.AimTo assess whether different constriction rates produced by partial ligation of the vein interfere with the results of this experimental model in rats.MethodsThree groups of five rats each were used; in group 1 (sham-operated), dissection and measurement of portal vein diameters were performed. Portal hypertension was induced by partial portal vein ligation, reducing its size to 0.9 mm in the remaining 10 animals, regardless of the initial diameter of the veins. Five animals with portal hypertension (group 2) underwent reoperation after 15 days and the rats in group 3 after 30 days. The calculation of the constriction rate was performed using a specific mathematical formula (1 - π r 2 / π R2) x 100% and the statistical analysis with the Student t test.ResultsThe initial diameter of the animal's portal vein was 2.06 mm, with an average constriction rate of the 55.88%; although the diameter of the veins and the constriction rate in group 2 were lower than in group 3 (2.06 mm - 55,25% and 2.08 mm - 56.51%, respectively), portal hypertension was induced in all rats and no significant macroscopic differences were found between the animals that were reoperated after 15 days and after 30 days respectively, being the shorter period considered enough for the evaluation. Comparing the initial diameter of the vein and the rate of constriction performed in groups 2 and 3, no statistic significance was found (p>0.05).ConclusionPre-hepatic portal hypertension in rat can be induced by the reduction of the portal vein diameter to 0.9 mm, regardless the initial diameter of the vein and the vessel constriction rate.

Hemorrhage from varices in hepaticojejunostomy in the fifth and tenth year after surgery for hepatic hilar bile duct cancer: a case report

We report a case of a 64-year-old female patient who underwent a right lobectomy of the liver (including total resection of the caudate lobe), dissection of the group 2 lymph nodes, left hepaticojejunostomy (Roux-en-Y fashion), and reconstruction of the portal vein (end-to-end anastomosis between the main portal vein and the left portal branch) for treatment of hepatic hilar bile duct cancer in 1996. In 2001, the anastomotic site of the hepaticojejunostomy was dissected and re-anastomosed due to gastrointestinal bleeding caused by variceal rupture in the jejunal loop. In 2006, splenectomy was performed for recurrence of gastrointestinal bleeding due to another variceal rupture in the jejunal loop. Portal venography performed perioperatively showed a decrease in portal blood flow into the liver via the jejunal varices and an increase in portal blood flow into the liver via the left gastric vein. She had two jejunal variceal ruptures at five-year intervals after extrahepatic portal obstruction and underwent successful treatments.

The effects of mechanical ventilation on the gut and abdomen

Mechanical ventilation generates an increase in airway pressure and, therefore, in intrathoracic pressure, which may decrease systemic and intraabdominal organ perfusion. Critically ill patients rarely die of hypoxia and/or hypercarbia but commonly develop a systemic inflammatory response that culminates in multiple-organ dysfunction syndrome and death. In the pathogeneses of this syndrome the gastrointestinal tract and liver have received considerable attention. Mechanical ventilation with high positive end-expiratory pressure has been found to decrease splanchnic perfusion. Hepatic arterial buffer response is preserved and an increased hepatic arterial blood flow will compensate the decrease in portal blood flow. Despite an increased cardiac output with an acute moderate increase in arterial PCO2 during protective ventilation it cannot be expected that splanchnic and gut perfusion is improved. In the absence of a significant rise in intraabdominal pressure without impairment in cardiovascular function, splanchnic and gastrointestinal function remained unchanged during short periods of prone positioning. Spontaneous breathing during ventilator support improves systemic blood flow and gastrointestinal and splanchnic perfusion. In critically ill patients mechanical ventilation should be adjusted to avoid conditions known to be associated with decreased gastrointestinal and splanchnic perfusion.

Dysplastic nodules frequently develop into hepatocellular carcinoma in patients with chronic viral hepatitis and cirrhosis

Advances in imaging technology have enhanced the detection of small nodular lesions during the course of chronic liver disease. Between 1995 and 2002, the authors examined 154 consecutive patients with small hepatic nodules without hepatocellular carcinoma (HCC) over a median duration of 2.8 years. The median size of these nodules was 14 mm (range, 7-40 mm). The initial histopathologic diagnosis included high-grade dysplastic nodule (HGDN) (n=13), low-grade dysplastic nodule (LGDN) (n=42), and regenerative nodule (RN) (n=99). A total of 29 (18.8%) nodules developed into HCC during the observation period. Cumulative HCC development rates at the first, third, and fifth year were 46.2%, 61.5%, and 80.8% for HGDN; 2.6%, 30.2%, and 36.6% for LGDN; and 3.3%, 9.7%, and 12.4% for RN, respectively. The rate of HCC development was significantly higher in the HGDN group than for other types (P<0.001). Multivariate analysis disclosed that histopathologic diagnosis (P<0.001) and findings on computed tomographic arterial portography (CT-AP) (P=0.004) were significantly associated with future HCC development. The hazard ratios of HGDN and LGDN were 16.8 (95% confidence interval [CI], 6.19-45.6) and 2.96 (95% CI, 1.20-7.31), respectively. A decrease in portal blood flow also showed a significantly high hazard ratio of 3.04 (95% CI, 1.42-6.50). Approximate annual development rate to HCC was 20% in patients with HGDN and 10% in LGDN. HGDN should be considered a precancerous lesion when it appears during follow-up of chronic viral hepatitis or cirrhosis. Reduced portal blood flow in the nodule on computed tomography-AP is also an important predictor for development of hepatocellular carcinoma.

Disagreement between acute and chronic haemodynamic effects of nadolol in cirrhosis: a pathophysiological interpretation

The acute effects of beta-blockers may be different from chronic; mechanisms underlying this difference are poorly elucidated. To assess portal pressure and its pathophysiological determinants after acute and chronic administration of nadolol. In 24 patients with cirrhosis and portal hypertension hepatic venous pressure gradient, portal blood flow and resistance to portal blood flow were measured before, 60-90 min after acute administration of nadolol, and after 1 month. Patients were good-responders if hepatic venous pressure gradient was < or =12 mmHg, or decreased by at least 20%. Eleven and 13 patients were good- and poor-responders to acute administration, respectively. Acute poor-responders showed a lower decrease in portal blood flow (P = 0.04) and a less evident decrease in mean arterial pressure (P < 0.001). Eleven and 13 patients were good- and poor-responders to chronic administration, respectively. Chronic poor-responders showed a larger increase in resistance to portal blood flow compared with good-responders (P = 0.01). Disagreement between acute and chronic effects was seen in 12 patients: six were acute good-responders chronic poor-responders and six were acute poor-responders chronic good-responders. Acute good-responders chronic poor-responders patients had the smallest decreases in portal blood flow and in mean arterial pressure after acute administration, while acute poor-responders chronic good-responders showed the largest (P = 0.05 and 0.01). Disagreement between acute and chronic effects of nadolol on hepatic venous pressure gradient is common. The mechanism responsible is complex, the acute effect being mainly modulated by arterial hypotension and the chronic effect by changes in portal resistance.

Hepatic microcirculation after continuous 7-day elevated intra-abdominal pressure in cirrhotic rats

It is well known that IAP elevation, even at the level of 10mmHg used for laparoscopic surgery leads to an increase in portal pressure and decrease in portal blood flow. Since hepatic hemodynamics are already disturbed in cirrhotics, we decided to investigate the possible role of chronically elevated intra-abdominal pressure thus simulating ascites under tension-in liver perfusion and function in cirrhotic portal hypertensive rats. Four groups of 10 rats each were studied, including two control and two CCl(4)(-) induced cirrhotic groups. These were subdivided into normal and increased IAP. Elevation and maintenance of increased IAP to 20mmHg for 7 consecutive days was achieved by means of an intraperitonially placed balloon filled with water. Liver microcirculation was assessed by means of laser-Doppler technique, while venous blood samples were obtained for determination of the biochemical parameters of liver function. Cirrhotic rats showed a significant decrease in liver microcirculation in relation to controls (15.7+/-2.5 versus 23.2+/-2.2, p=0.001). Elevation of IAP led to a significant decrease (p=0.001) of liver microcirculation in both groups, i.e. from 15.7+/-2.5 to 12.7+/-1.7 units of flow in cirrhotics and from 23.2+/-2.2 to 15.9+/-2.6 units of flow in control rats. Alkaline phosphatase, alanine aminotransferase and bilirubin concentrations were found increased in cirrhotics in comparison to controls (p=0.05). IAP elevation resulted in a further impairment of liver function, but the differences, were not statistically significant. In conclusion, chronically elevated IAP in cirrhotic rats is associated with a significant impairment of the already decreased hepatic blood flow due to liver cirrhosis. Thus, the possible consequences of decreased liver perfusion must be taken under consideration in any case of severe cirrhosis presented with ascites under tension.

Splanchnic hemodynamics: cirrhotic versus non‐cirrhotic portal hypertension

Abstract Portal hypertension, defined as an increase in the hepatic venous pressure gradient above 5 mmhg, can be related to cirrhosis as well as non‐cirrhotic disorders. Based on the site of increased resistance, portal hypertension can be classified as presinusoidal, sinusoidal and postsinusoidal. Wedged hepatic venous pressure (WHVP) measurement distinguishes between presinusoidal (low WHVP reflecting normal sinusoidal pressure) and sinusoidal portal hypertension (high WHVP).According to the equation portal pressure = portal venous flow × portal venous outflow resistance, increase in pressure can result from an increase in inflow into the portal vascular system or by an elevated portal outflow resistance. Both, blood flow and resistance to flow can be estimated by means of Doppler ultrasound. The congestion index increases with the outflow resistance in the portal vein and the hepatic and splenic arterial resistance index reflects the outflow resistance in the downstream vascular region (i.e. the hepatic parenchyma or the whole portal vascular system).In cirrhosis, a sinusoidal form of portal hypertension, the hepatic venous pressure gradient (HVPG) is increased while portal blood flow is decreased. The congestion index of the portal vein as well as the resistance index of the hepatic artery and the spleen parenchyma are increased.Prehepatic portal hypertension due to an increased inflow through an enlarged spleen is characterized by an increased portal blood flow, a decreased splenic resistance index and an only slightly elevated HVPG. Vice versa, splenomegaly of portal hypertensive origin is characterized by a decrease in portal blood flow and an increase in the splenic artery resistance index. In idiopathic portal hypertension or non‐cirrhotic portal fibrosis, portal and splenic blood flow are increased and there is a gradient between elevated intrasplenic and normal or only slightly elevated wedged hepatic venous pressure. Schistosomiasis, the other presinusoidal intrahepatic form of portal hypertension, is characterized by a normal wedged hepatic venous pressure and portal blood flow seems to be preserved, too.Posthepatic portal hypertension, such as the Budd–Chiari syndrome, shows a very low HVPG due to an increase in both FHVP and WHVP together with a decrease in portal blood flow and sometimes a compensatory increase in hepatic artery flow.

Strategy for Hepatic Hyperplastic Nodules in Heavy Drinkers

Background: Increased detection of nodular lesions that have not yet been definitively diagnosed as hepatocellular carcinoma (HCC) has occured with the use of advanced imaging techniques. In heavy drinkers, the differential diagnosis between a hyperplastic nodule and early HCC on the basis of results of fine‐needle biopsy is often difficult. Negation of diagnosis of HCC after surgical resection has been reported, and nodular lesions have been found to decrease during follow‐up observation. On the basis of findings, a suitable strategy for the management of such lesions is suggested.Methods: We identified six patients who had hepatic nodular lesions on ultrasonography and were heavy drinkers. This group included five men and one woman with a mean age of 45.3 ± 3.8 years. Two patients had solitary lesions; four had multiple lesions, and of these, two were hepatitis C virus antibody positive (C+). In the five men, the nodular lesions were detected during hospitalization for ruptured or prophylactic treatment of gastroesophageal varices.Results: Five of the six patients had hypervascular lesions characterized by increased hepatic artery blood flow. However, dynamic computed tomography and magnetic resonance imaging studies during late‐phase imaging could not confirm any decrease in portal blood flow. HCC was diagnosed by detailed imaging studies and liver biopsy in one C+ patient with a solitary nodule. In two of the other four patients, imaging findings were compatible with hypervascular HCC. Findings on liver biopsy do not always permit an easy differential diagnosis between a regenerative lesion (hyperplastic nodule) and a dysplastic or neoplastic lesion. One patient with a hypovascular lesion was C+, and liver biopsy showed a dysplastic nodule.Conclusion: Heavy drinkers with alcoholic liver disease often develop hypervascular, hyperplastic nodules. The accurate diagnosis of these nodules requires careful consideration of clinical factors, including a combination of images and histologic examination. However, some cases were still difficult to distinguish between HCC by applying advanced imaging techniques and biopsy results.

Effect of mesocaval shunt on survival of small-for-size liver grafts

We read with great interest the communication by Smyrniotis et al. recently published in Transplantation (1). In their communication, Smyrniotis et al. assume that the mesocaval shunt has protective effects on the liver graft. However, maintenance without specific precautions of a mesocaval shunt may be expected to induce atrophy accompanied by a rapid secondary deterioration of the transplanted liver. This is known to be the unavoidable consequence of a portocaval shunt on any normal liver (2). A controlled calibration of the shunt might overcome such problems. However, this procedure will be difficult to manage. The decrease in portal blood flow and its concentrations in hepatic mitogens might impair regeneration of the transplant. To avoid such difficulties, it is absolutely necessary to perform a simultaneous ligation of the mesenteric vein downstream from the mesocaval shunt (3) to have the graft perfused by a venous inflow reduced to the gastroduodenosplenopancreatic blood. Despite this reduction, rapid hypertrophy of the transplant will nevertheless be obtained (3), likely as a result of the properties of the gastroduodenosplenopancreatic blood, which has been shown to be enriched with trophic factors such as insulin and with hepatic mitogens originating from the duodenum and the exocrine pancreas. Michel Pouyet Christian Paquet

The physiologic effect of the pneumoperitoneum on radiofrequency ablation.

Radiofrequency ablation (RFA) is gaining widespread acceptance as a safe and effective method for liver tumor ablation. Complete tumor ablation is essential for the success of the procedure. Multiple modalities have been explored in an effort to increase the size of the lesion created by RFA. The purpose of this study was to determine the physiologic effects of the pneumoperitoneum on RFA lesion size. A total of 32 RFA lesions were created in eight pigs. After the induction of anesthesia, pneumoperitoneums of 2, 12, and 24 mmHg were established sequentially in each animal. After an equilibration period of 2 min, RF was administered with a constant saline-infused (0.9%) needle at 25 W for 3 min. In subsequent and complementary experiments, both before and during RF administration at each intraperitoneal pressure (IPP), Doppler flow was measured by laparoscopic ultrasound in the portal vein and hepatic artery while blood pressure was monitored by a femoral arterial line. The animals were then killed humanely and the livers were harvested. Measurements were taken in three dimensions of the ablated areas, and the volume was calculated. Statistical analyses were performed using analysis of variance (ANOVA) and repeated measures test. The average volumes of the lesions (in cm3) were 3.1 +/- 1.8, 5.2 +/- 1.7, and 6.7 +/- 3.3 for IPP of 2, 12 and 24 mmHg, respectively; there was a significant difference between the area of lesion at an IPP of 2 mmHg and an IPP of 24 mmHg ( p < 0.05). Blood flow in the portal vein also decreased significantly from 1.8 +/- 0.6, 0.98 +/- 0.5, and 0.43 +/- 0.2 at IPP of 2, 12, and 24 mmHg, respectively ( p < 0.001). Hepatic artery blood flow and peripheral blood pressure did not change significantly in the respective IPP groups. This study indicates that the volume of liver ablated by RF can be increased by augmenting the IPP. Our data support the theory that a decrease in portal blood flow results in decreased heat dissipation during RFA. The laparoscopic approach to RFA offers the advantage of allowing control of the IPP, which may result in a larger volume of ablated tissue per treatment than can be achieved with the percutaneous technique. These preliminary data on normal hepatic tissue must be confirmed clinically in the setting of hepatic tumors.

Role of Heparin and Nitric Oxide in the Cardiac and Regional Hemodynamic Properties of Protamine in Conscious Chronically Instrumented Dogs

Because protamine is administered to reverse heparin, a drug that might itself affect the pharmacologic properties of protamine, this study was designed to assess the properties of protamine alone and in the presence of heparin in conscious dogs. Twelve dogs were instrumented to continuously record cardiac and regional hemodynamics. On separate occasions, a dose of protamine (0.5, 1, 3, 5, and 8 mg/kg) was randomly administered either alone or in the presence of heparin (ratio 100 IU/mg). Heparin (300 IU/kg) and protamine (3 mg/kg) were administered in the presence of N-methyl-L-arginine, a specific nitric oxide synthase inhibitor. Identical experiments were performed with protamine (8 mg/kg) in the absence of heparin on a separate occasion. Protamine alone produced limited cardiac and regional changes. In the presence of heparin, protamine produced hypotension at 3, 5, and 8 mg/kg, vasodilatation at 3 and 5 mg/kg, and a more pronounced dose-dependent increase in pulmonary pressure at 3, 5, and 8 mg/kg. Simultaneously, transient carotid vasodilatation at 3 and 5 mg/kg, coronary and hepatic vasodilatation at 3, 5, and 8 mg/kg, as well as a decrease in vertebral vascular resistance were recorded at 1, 3, and 8 mg/kg. Protamine produced an immediate increase followed by a secondary decrease in renal vascular resistance. Protamine-induced secondary pulmonary pressor effects were attenuated. In the presence of heparin, nitric oxide synthase blockade selectively attenuated protamine-induced immediate hypotension, systemic vasodilatation, and coronary, mesenteric, and hepatic vasodilations as well as the decrease in portal blood flow and accentuated the renal vasoconstriction. The presence of heparin accentuated the decrease in cardiac function induced by protamine as well as its effects on regional circulation. The data provide evidence that the nitric oxide pathway is involved in the systemic and selective regional heparin-protamine-mediated vasodilatation in conscious dogs.

Early changes in liver perfusion caused by occult metastases in rats: detection with quantitative CT.

To determine whether computed tomography (CT) can depict liver hemodynamic changes caused by occult hepatic micrometastases in rat. Liver micrometastases (mean diameter, 500 micrometer +/- 300) were produced in seven BD IX rats by injecting 10(7) DHDK12 PROb colorectal carcinoma cells into the spleen. Macrometastases (mean diameter, 7 mm +/- 3) were produced in four other rats. Five normal rats were studied as controls. CT images were obtained every 300 msec for 30 seconds during the injection of 1 mL per kilogram of body weight of contrast medium. The time-attenuation curves of the aorta, portal vein, and liver were used to calculate liver perfusion with a deconvolution model designed for the dual blood supply. Micrometastases in an apparently normal liver caused a 34% decrease in portal blood flow and a 25% increase in the mean transit time for the blood to pass through the liver. These findings suggest increased resistance in the sinusoidal capillaries. Similar but greater changes were found in the macrometastases. Occult liver micrometastases in rats generate changes in liver perfusion that can be detected with CT.

Effects of Different Octreotide Dosages on Splanchnic Hemodynamics and Glucagon in Healthy Volunteers

Aims: This study evaluated the dependence of portal and mesenteric blood flow and plasma glucagon levels on octreotide dosage and its mode of application. Methods: Two groups of 10 individuals each received octreotide either subcutaneously (placebo, 100 and 200 µg) or intravenously (100-µg bolus i.v., 25 and 100 µg/h) in a double-blind, random order. Using Doppler ultrasound, we examined portal and mesenteric blood flow and measured plasma glucagon levels at regular intervals within a 4-hour period under fasting conditions. Results: Contrary to placebo, octreotide caused a decrease in portal blood flow (PVF) and in superior mesenteric artery blood flow (SMAF) together with an increase in the mesenteric pulsatility index (PI). The same total dose of 100 µg octreotide caused a similar PVF response, averaged over 4 h, given either subcutaneously (–28.0 ± 4.8%), intravenously (–29.4 ± 4.3%) or as a continuous infusion (–29.3 ± 4.6%). As concerns intravenous infusions, 100 µg/h was more effective than 25 µg/h (–37.8 ± 6.2 vs. –29.3 ± 4.6%). The PVF reduction remained constant during intravenous infusion, whereas glucagon levels decreased progressively over the entire observation time. Conclusions: The decrease in PVF is dependent on the octreotide dose. However, this is not constantly paralleled by a decrease in plasma glucagon concentration.

Inhibition of nitric oxide synthesis aggravates hepatic oxidative stress and enhances superoxide dismutase inactivation in rats subjected to tourniquet shock.

The role of nitric oxide (NO) on liver oxidative stress and tissue injury in rats subjected to tourniquet shock was investigated. This shock model differs from others in that injury is a consequence of remote organ damage. Liver oxidative stress becomes evident after hind limb reperfusion, as evidenced by the loss of total tissue thiols; by increases in tissue oxidized glutathione (GSSG), lipid peroxidation (LPO), plasma aminotransferases (alanine aminotransferase (ALT) and (aspartate aminotransferase (AST)), and plasma nitrites; and by a 36% loss in total superoxide dismutase (SOD) activity. Portal blood flow is reduced by 54.1% after 2 h of hind limb reperfusion. Inhibition of NO synthesis with Nomega-nitro-L-arginine methyl ester or L-arginine methyl ester increased mean arterial blood pressure; further reduced portal blood flow; and aggravated liver injury as assessed by further loss in total thiols, increased LPO and GSSG content, and further increases in plasma ALT and AST. Total plasma nitrites were lower than in control animals, and total tissue SOD activity decreased by more than 80%. Treatment with the NO donor sodium nitroprusside reverted the decrease in portal blood flow and also reverted tissue thiol loss, LPO, and GSSG increases, as well as the loss of ALT and AST to plasma and of SOD activity to levels comparable to untreated control shock animals. As expected, plasma nitrites were greater than in tourniquet control animals. These data support the hypothesis that endogenous NO formation protects the rat liver from the consequences of oxidative stress elicited by hind limb reperfusion in rats subjected to tourniquet shock.

Effects of nitric oxide on leukotriene D4 decreased bile secretion in the perfused rat liver

Nitric oxide (NO) and leukotrienes are potent vasoactive agents that are involved in the control of portal blood flow. The present study investigated the role of leukotriene D4 and NO in a non-recirculating constant pressure rat liver perfusion model to analyse their interchanges on portal flow and bile secretion. The addition of leukotriene D4 (20 nM) to the perfusate for 5 minutes resulted in a decrease in portal blood flow (−55.3%), in bile flow (−24.4 %) as well as bile acid release (−35.2%). In parallel, leukotriene D4 increased glucose output. The administration of a lower dose of leukotriene D4 (5 nM) reduced the respective parameters to a lesser degree, indicating dose-dependence. The addition of NO via the infusion of sodium nitroprusside (0,05 mM, 1 mM) reduced the effect of leukotriene D4 on portal flow, bile flow and bile acid secretion whereas the leukotriene D4 effects on hepatic glucose output remained unaffected. Correlation coefficient between decrease in portal flow and reduction of bile flow by infusing leukotriene D4 was R = 0.91, while in the presence of sodium nitroprusside R = 0.85. These results suggest that the leukotriene D4-induced cholestasis is dependent on portal flow. In contrast, hepatic vasoconstriction does not contribute to glycogenolyis stimulated by leukotriene D4 in the perfused liver.

Hemodynamic evaluation of the addition of isosorbide-5-mononitrate to nadolol in cirrhotic patients with insufficient response to the ?- blocker alone

The association beta-blockers plus isosorbide-5-mononitrate (I5M) has been proposed for the treatment of portal hypertension in patients with insufficient response to beta-blockers alone, according to hemodynamic criteria. The mechanism of action in these patients is not clearly defined. Fifteen patients with cirrhosis and esophageal varices were evaluated by hepatic venous pressure gradient (HVPG) measurement and duplex-Doppler ultrasonography before and after 1 month of treatment with nadolol. Nine patients who did not exhibit a decrease in HVPG to 12 mm Hg or a percent decrease greater than 20% were classified as poor responders, and were studied again with the same methodology after 3 months of chronic administration of nadolol + I5M 20 mg twice per day. In poor responders, mean HVPG decrease after nadolol was 8.9% +/- 2.8%, and after the combination, it was 25.7% +/- 1.7% (P = .004). All patients except one became good responders to the association. Portal blood flow (PBF) decreased significantly after nadolol (P = .004), and remained unchanged after the addition of nitrates. Resistance to portal blood flow (RPBF) increased after nadolol (P = .02) and returned to baseline values during combined treatment (P = .03). In good responders, an adequate decrease in HVPG was associated with a decrease in PBF (P = .06) but no change in RPBF. A wide spectrum of combined changes in PBF and in RPBF after nadolol was observed in poor responders, ranging from no change in either parameter to a marked decrease in PBF counterbalanced by a marked increase in RPBF. The addition of I5M was followed in most cases by larger effects on resistance than on flow. Doppler parameters were not significantly correlated with the HVPG response to nadolol alone or associated with I5M. It is concluded that good hemodynamic responders to nadolol differ from poor responders in the lack of increase in RPBF after the drug. The addition of nitrates to nadolol is effective in decreasing portal pressure in most poor responders to nadolol alone. A decrease in outflow resistance is the main mechanism involved.

Hemodynamic evaluation of the addition of isosorbide-5-mononitrate to nadolol in cirrhotic patients with insufficient response to the beta- blocker alone

The association beta-blockers plus isosorbide-5-mononitrate (I5M) has been proposed for the treatment of portal hypertension in patients with insufficient response to beta-blockers alone, according to hemodynamic criteria. The mechanism of action in these patients is not clearly defined. Fifteen patients with cirrhosis and esophageal varices were evaluated by hepatic venous pressure gradient (HVPG) measurement and duplex-Doppler ultrasonography before and after 1 month of treatment with nadolol. Nine patients who did not exhibit a decrease in HVPG to 12 mm Hg or a percent decrease greater than 20% were classified as poor responders, and were studied again with the same methodology after 3 months of chronic administration of nadolol + I5M 20 mg twice per day. In poor responders, mean HVPG decrease after nadolol was 8.9% +/- 2.8%, and after the combination, it was 25.7% +/- 1.7% (P = .004). All patients except one became good responders to the association. Portal blood flow (PBF) decreased significantly after nadolol (P = .004), and remained unchanged after the addition of nitrates. Resistance to portal blood flow (RPBF) increased after nadolol (P = .02) and returned to baseline values during combined treatment (P = .03). In good responders, an adequate decrease in HVPG was associated with a decrease in PBF (P = .06) but no change in RPBF. A wide spectrum of combined changes in PBF and in RPBF after nadolol was observed in poor responders, ranging from no change in either parameter to a marked decrease in PBF counterbalanced by a marked increase in RPBF. The addition of I5M was followed in most cases by larger effects on resistance than on flow. Doppler parameters were not significantly correlated with the HVPG response to nadolol alone or associated with I5M. It is concluded that good hemodynamic responders to nadolol differ from poor responders in the lack of increase in RPBF after the drug. The addition of nitrates to nadolol is effective in decreasing portal pressure in most poor responders to nadolol alone. A decrease in outflow resistance is the main mechanism involved. (Hepatology 1997 Jul;26(1):34-9)

The NO donor sodium nitroprusside reverses the negative effects on hepatic arterial flow induced by endotoxin and the NO synthase inhibitor L-NAME.

In previous studies we have observed that the nitric oxide synthase inhibitor L-NAME induces a profound deterioration of liver circulation in experimental endotoxemia. Using the same porcine model we now have evaluated the possibility of modulating these effects with the nitric oxide donor sodium nitroprusside. Infusion of endotoxin led to a gradual deterioration of hemodynamic parameters, including liver blood flow. The decreases in portal blood flow paralleled and matched the decreases in cardiac output, and no compensatory increase in hepatic arterial flow occurred. L-NAME had detrimental effects on hemodynamics, including the liver circulation. The latter effects could, however, partially be reversed by sodium nitroprusside. Hepatic arterial flow increased from 1.9 to 7.2 ml/kg/min, with a concomitant decrease in hepatic arterial resistance from 5,364 to 1,746 dyn s/cm5 kg. A control group exhibited no significant change in either flow or resistance. The response to sodium nitroprusside was rapid and vigorous, and probably largely due to relaxation of the hepatic arterioles, and not to abatement of intrahepatic edema or plugging of the sinusoids. Furthermore, we conclude that the endotoxin-induced dysfunction of the hepatic arterial buffer response may be due to a selective inhibition of vascular endothelial function.