Intrahepatic portal occlusion by microspheres: a new model of portal hypertension in the rat (original) (raw)
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Journal of Hepatology, 1996
It has been suggested that mechanical pumping of portal blood to the liver may correct portal hypertension while increasing portal flow to the liver, which may enhance liver function in cirrhosis. However, the hemodynamic effects of this procedure are unknown. The present study investigated these issues in rats with portal hypertension due to portal vein stenosis. Methods: Mechanical pumping of portal blood to the liver was established by an extracorporeal shunt bypassing the portal vein stenosis, connected to a continuous withdrawal/infusion pump. Portal pressure, portal-systemic shunting (mesenteric injection of Cr-51 microspheres, n=10), mesenteric artery blood flow (perivascular Transonic flowmeter, n=7) and systemic hemodynamics and regional blood flows (left ventricle injection of Ce-141 microspheres, n=15), were measured at pumping rates of 0, 3 and 6 ml.min-1. Results: Mechanical pumping of portal blood to the liver caused a marked decrease in portal pressure (from 17+1 to 12.6+1 and 9.4+.9 mmHg at pumping rates of 0, 3 and 6 ml.min-1) and portalsystemic shunting (from 97+4 to 70+4 and 51+6% respectively) (p<0.001). However, there were no significant changes in mesenteric artery flow (5.5+3 vs 5.6+3 ml.minq.100 g-l), suggesting that all blood pumped to the liver was withdrawn from that circulating through the collaterals. Moreover, there were no changes in mean arterial pressure, cardiac index, peripheral resistance and splanchnic arteriolar resistance. Conclusions: The short-term mechanical pumping of portal blood to the liver effectively decreases portal pressure and portal-systemic shunting and has no significant effects on systemic and splanchnic hemodynamics in portal hypertensive rats.
Pflügers Archiv, 2001
Intrahepatic shunts regulate portal venous pressure during periods of acute portal hypertension when the transhepatic portal resistance is momentarily increased in the normal rat liver in vivo. Hepatic arterial inflow may also increase the transhepatic portal resistance and activate intrahepatic shunts. In the present study, the transhepatic portal resistance and the activity of intra-hepatic shunts were measured in vitro and the point of confluence between the hepatic artery and portal vein in the rat determined. Livers of male Sprague-Dawley rats were single-pass, dual-perfused in vitro. Total cessation or diversion of the hepatic arterial inflow to the portal venous vasculature, whilst maintaining total hepatic perfusate flow, decreased intrasinusoidal pressure, increased transhepatic portal venous resistance and opened the portal venous intrahepatic shunts in a manner similar to intraportal injection of 15-µm diameter microspheres. Injections of the microspheres into the hepatic arterial circulation increased hepatic arterial pressure dramatically, consistent with complete occlusion of the arterial vasculature. The intrahepatic shunts are located at a pre-sinusoidal level because no increases were detected in hepatic arterial pressure following intraportal injection of microspheres. The hepatic arterial vasculature, unlike the portal supply, does not possess a collateral shunt circulation and coalesces with the portal vein at an intrasinusoidal location
Location and function of intrahepatic shunts in anaesthetised rats
Gut, 2003
Background: In the present study we determined the proportion of shunt flow due to patent intrahepatic portal systemic shunts in the normal rat liver and its relationship with microsphere induced portal hypertension. Methods: Systemic and hepatic haemodynamics were measured continuously before, during, and after intraportal injection of 15 µm diameter microspheres in anaesthetised male Wistar rats. Functional hepatic blood flow and intrahepatic shunt flow were determined by the use of constant intraportal infusion of sorbitol and simultaneous measurements in the portal vein, hepatic vein, and carotid artery. The percentage of large shunts of diameter >15 µm were estimated by intraportal injection of 51 Cr labelled 15 µm diameter microspheres. Results: Hepatic sorbitol uptake was 97.9 (0.5)% in normal control rats, with functional hepatic blood flow equalling total hepatic blood flow (2.52 (0.23) ml/min/100 g body weight). Microsphere injection decreased sorbitol uptake to 12.8 (4.3)% and further to 4.1 (0.7)% when followed by hepatic arterial ligation. In the latter two groups, intrahepatic shunt flow (1.46 (0.15) and 1.16 (0.19) ml/min/100 g body weight, respectively) was not significantly different from portal venous flow (1.36 (0.20) and 1.20 (0.20) ml/min/100 g body weight, respectively). Portal venous flow remained at 70% of basal values and portal venous pressure only increased by 50% from baseline. 51 Cr labelled microsphere shunt fraction through large shunts (>15 µm) was less than 1.0%. Conclusion: The site of confluence between the hepatic artery and portal vein is in zone II. Intrahepatic shunts originate in presinusoidal regions in zone I in the normal liver and, when activated by intraportal injection of microspheres, divert 70% of the total portal blood flow away from zone III and thereby reduce acute increases in portal venous pressure.
International Journal of Experimental Pathology, 2008
The characterization of mice models of portal hypertension (PHT) is lacking in the literature. Therefore, the aim of the present study was to make a histological approach during development of PHT in two models of cirrhosis with PHT compared with one model of isolated PHT. The model of isolated PHT was developed by partial portal vein ligation (PPVL). Two portal hypertensive cirrhotic mice models were developed either by common bile duct ligation (CBDL) or administration of carbon tetrachloride (CCl 4 ) subcutaneously (twice weekly, 1 ml ⁄ kg). These models represent, respectively, a secondary biliary cirrhosis and alcoholic cirrhosis. Mice were killed at several time points to evaluate liver changes by histological and ultrastructural methods. A correlation was made with portal pressure measurements. Histology revealed the absence of fibrosis or cirrhosis in PPVL mice. They developed an isolated portal hypertension. After CBDL induction, the mice developed the characteristics of cirrhosis after 6 weeks, with simultaneous increase in portal pressures. Fifty percent of the mice had ascites at that time point. Sixteen weeks after administration of CCl 4 , a micronodular cirrhotic aspect of the liver was seen associated with signs of portal hypertension. This is the first descriptive study of three widely used animal models in mice, allowing the study of pathophysiological changes in cirrhosis and portal hypertension. The PPVL in mice leads to a model of isolated portal hypertension. Secondary biliary cirrhosis developed after 6 weeks of common bile duct ligation in 50% of the mice that developed ascites. Subcutaneous injection of CCl 4 for 16 weeks induces cirrhosis and poral hypertension, without ascites. Moreover, the present study is the first description of a cirrhotic model in mice developed by subcutaneous injections of CCl 4 . Well-described mice models will facilitate use of knock-out or transgenic mice and lead to a better understanding of the underlying molecular pathways in the field of portal hypertension and cirrhosis.
Portal hypertension: from pathophysiology to clinical practice
Liver International, 2005
Portal hypertension (PHT) is responsible for the more severe and often lethal complications of cirrhosis such as bleeding oesophageal varices, ascites, renal dysfunction and hepatic encephalopathy. Because of the combined impact of these complications, PHT remains the most important cause of morbidity and mortality in patients with cirrhosis. Over the years, it has become clear that a decrease in portal pressure is not only protective against the risk of variceal (re)bleeding but is also associated with a lower long-term risk of developing complications and an improved long-term survival. A milestone in therapy was the introduction of non-selective bblockers for the prevention of bleeding and rebleeding of gastro-esophageal varices. However, in practice, less than half the patients under b-blockade are protected from these risks, supporting the overall demand for innovation and expansion of our therapeutic armamentarium. Recent advances in the knowledge of the pathophysiology of cirrhotic PHT have directed future therapy towards the increased intrahepatic vascular resistance, which, in part, is determined by an increased hepatic vascular tone. This increased vasculogenic component provides the rationale for the potential use of therapies aimed at increasing intrahepatic vasorelaxing capacity via gene therapy, liver-selective nitric oxide donors and statines on the one hand, and at antagonizing excessive intrahepatic vasoconstrictor force through the use of endothelin antagonists, angiotensin blockers, a 1 adrenergic antagonists or combined a 1-and non-selective b-blockers or somatostatin analogues on the other. The focus of this review is to give an update on the pathophysiology of PHT in order to elucidate these potential novel strategies subsequently.
Severe complications of liver cirrhosis are mostly related to portal hypertension. At the base of the pathogenesis of portal hypertension is the increase in hepatic vascular resistance to portal blood flow with subsequent development of hyperdynamic circulation, which, despite of the formation of collateral circulation, promotes progression of portal hypertension. An important role in its pathogenesis is played by the rearrangement of vascular bed and angiogenesis. As a result, strategic directions of the therapy of portal hypertension under liver cirrhosis include selectively decreasing hepatic vascular resistance with preserving or increasing portal blood flow, and correcting hyperdynamic circulation and pathological angiogenesis, while striving to reduce the hepatic venous pressure gradient to less than 12 mmHg or 20% of the baseline. Over the last years, substantial progress in understanding the pathophysiological mechanisms of hemodynamic disorders under liver cirrhosis has resulted in the development of new drugs for their correction. Although the majority of them have so far been investigated only in animal experiments, as well as at the molecular and cellular level, it might be expected that the introduction of the new methods in clinical practice will increase the efficacy of the conservative approach to the prophylaxis and treatment of portal hypertension complications. The purpose of the review is to describe the known methods of portal hypertension pharmacotherapy and discuss the drugs that may affect the basic pathogenetic mechanisms of its development.
International Journal of Molecular Sciences
It is unclear to what extent systemic arterial blood pressure influences portal pressure. This relationship is clinically important as drugs, which are conventionally used for therapy of portal hypertension, may also influence systemic arterial blood pressure. This study investigated the potential correlation between mean arterial (MAP) and portal venous pressure (PVP) in rats with healthy livers. In a rat model with healthy livers, we investigated the effect of manipulation of MAP on PVP. Interventions consisted of 0.9% NaCl (group 1), 0.1 mg/kg body weight (bw) Sildenafil (low dose), an inhibitor of phosphodiesterase-5 (group 2), and 1.0 mg/kg bw Sildenafil (high dose, group 3) in 600 µL saline injected intravenously. Norepinephrine was used to increase MAP in animals with circulatory failure while PVP was monitored. Injection of the fluids induced a transient drop in MAP and PVP, probably due to a reversible cardiac decompensation. The drop in MAP and drop in PVP are significantl...
A model of prehepatic portal hypertension in rats
Ukrainian Scientific Medical Youth Journal
During the study, the methodology of the prehepatic portal hypertension (PPH) development model in Wistar rats was set, using partial portal vein ligation (PPVL). It was followed by the analysis of model stability and its prolongation over time using the indicator of the portal vein constriction rate (PVCR) and the portohepatic perfusion (PHP) dependence on it. It was found that in 4-week-old rats with a body weight of 99.6±2.0 g there was no mortality in PPVL at 53.45%; the reduction of PHP was critical at 69.13% of PPVL; in a group of 6-week-old rats with a body weight of 155±3.5 g, where the median PPVL was 58.67 (95% CI 56.3-59.82) after PPVL, there was no mortality. At the same time, a delay in the physical development of rats was noted in comparison with the control subgroup and the subgroup with false ligation. Parenchymal and vessel changes were registered on serial ultrasound examination.
Abdomen, 2018
Neoangiogenesis in the small intestine mesentery is the trigger of portosystemic collateral circulation in portal hypertension. It leads to the severe complications, in particular, bleeding from esophageal varices. However, the types of blood vessels involved in this process have not been established. The aim of this study was to determine which type of the mesenteric microvessels participates in angiogenesis in portal hypertension. The present study included 12 adult outbred female rats divided into two groups: sham-operated (n = 5) and experimental (n = 7). Intravital microscopy allowed assessing the mesenteric microcirculation of rats in both groups during the first laparotomy and relaparotomy on the 15th day of the experiment. In contrast to the sham-operated animals, we induced prehepatic portal hypertension in rats of the experimental group by partial portal vein ligation during the first operation. The portal pressure in rats of the experimental group at the time of the second operation was significantly higher than in sham-operated rats: 12,53 ± 1,26 mm Hg and 9,34 ± 0,14 mm Hg, respectively (p<0,01). There was a significant increase in the number of capillaries (p <0,05) and total vascular density (p <0,05) in rats of both groups on the 15th day of the experiment. At the same time, a greater increase in the capillary network was in rats of the experimental group (p <0,05), whereas there was no significant difference in the vascular density values of the other types of blood vessels. Therefore, changes in the mesenteric microvasculature in portal hypertension lay in the increase in the vascular density values, which occur mostly at the expense of capillaries. This data allows to understand the pathogenesis of portal hypertension deeper, which is essential for the development of the treatment aimed at prevention of portosystemic shunting leading to the severe complications, such as bleeding from esophageal varices.