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Inicio Annals of Hepatology Current concepts on the pathophysiology of portal hypertension
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Vol. 6. Issue 1.
Pages 28-36 (January - March 2007)
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Vol. 6. Issue 1.
Pages 28-36 (January - March 2007)
DOI: 10.1016/S1665-2681(19)31950-7
Open Access
Current concepts on the pathophysiology of portal hypertension
Aina Rodríguez-Vilarrupla1,*, Mercedes Fernández1, Jaume Bosch1, Joan Carles García-Pagán1
1 Hepatic Hemodynamic Laboratory, Liver Unit. Institut Malalties Digestives I Metabòliques, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Ciber Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain
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Cirrhosis of the liver is by far the most common cause of portal hypertension in the western world. Portal hypertension is a frequent clinical syndrome, defined by a pathological increase in the portal venous pressure. When the portal pressure gradient (the difference between pressures in the portal and the inferior vena cava veins: normal value below 6 mmHg) increases above 10-12 mmHg, complications of portal hypertension can occur. Increased resistance to portal blood flow, the primary factor in the pathophysiology of portal hypertension, is in great part due to morphological changes occurring in chronic liver diseases. However, more recently a graded and reversible contraction of different elements of the porto-hepatic bed have been shown to play a role modulating intrahepatic vascular resistance which provides a rationale for the intention to reduce intrahepatic resistance and portal pressure by means of pharmacological agents. The subsequent increase in portal blood flow, as a result of the arteriolar vasodilatation of the splanchnic organs, plays a contributory role maintaining and aggravating the portal hypertensive syndrome. This splanchnic arteriolar vasodilatation is a multifactorial phenomenon, which may involve neurogenic, humoral and local mechanisms.

Key words:
endothelial dysfunction
vasoactive mediators
Full Text

Cirrhosis of the liver is by far the most common cause of portal hypertension in the western world. Portal hypertension is a frequent clinical syndrome, defined by a pathological increase in the portal venous pressure. When the portal pressure gradient (the difference between pressures in the portal and the inferior vena cava veins: normal value below 6 mmHg) increases above 1012 mmHg, complications of portal hypertension can occur. These complications represent the first cause of death and the main indication for liver transplantation in patients with cirrhosis.

Pathophysiology of portal hypertension

The portal pressure gradient is determined by the product of portal blood flow and the vascular resistance that opposes that flow. Ohm’s law defines this relationship in the equation:

ΔP = Q x R

in which ΔP is the portal pressure gradient, Q is the flow within the portal venous system, and R is the vascular resistance of the portal venous system, which represents the sum of the resistance of the portal vein, the hepatic vascular bed, and of the portosystemic collaterals.

It follows that portal pressure may be increased by an increase in portal blood flow, an increase in vascular resistance, or a combination of both.1,2 However, it is well established that in cirrhosis, the primary factor leading to portal hypertension is an increased resistance to portal blood flow. Later on, an increase in portal venous inflow will help to maintain and aggravate portal hypertension (Figure 1).

Figure 1.

Pathophysiological mechanisms of portal hypertension.

Increased vascular resistance to portal blood flow

Increased resistance to portal blood flow may occur at any site within the portal venous system.

Although much of the increase in intrahepatic resistance is the mechanical consequence of the architectural disturbances caused by the cirrhotic process, it is clear that on top of these alterations there is an active contraction of several elements in the liver that further contribute to increase resistance. It has been claimed that this dynamic and reversible component may represent up to 40% of the total increased intrahepatic vascular resistance in cirrhosis. Contractile elements influencing the hepatic vascular bed can be located at sinusoidal as well as extrasinusoidal levels and include vascular smooth muscle cells of the intrahepatic vasculature (i.e. small portal venules in portal areas),3 activated hepatic stellate cells (HSCs) (pericyte cells located in the perisinusoidal space of Disse with extensions that wrap around the sinusoids and reduce its caliber after contraction)4,5 and hepatic myofibroblasts that may compress the regenerating nodules or venous shunts within the fibrous septa.

An increased production of vasoconstrictors and an exaggerated response of the hepatic vascular bed to them, as well as an insufficient release of vasodilators together with an insufficient response to vasodilators of the hepatic vascular bed are the mechanisms that have been implicated in the pathogenesis of the dynamic component of the increased intrahepatic resistance of the cirrhotic liver.

Increased production/exaggerated response of the hepatic vascular bed to vasoconstrictors

Different vasoconstrictive factors, that are detailed below, have been involved in the regulation of hepatic vascular tone in cirrhotic livers.6

Adrenergic agonists

The alpha-adrenergic agonist norepinephrine, that is usually elevated in decompensated cirrhosis, has been shown to increase intrahepatic vascular resistance.7,8 This increase in resistance is completely blunted by the administration of a-adrenergic antagonists, such as prazosin. This agent by itself markedly reduces hepatic resistance and portal pressure in patients with cirrhosis. On the other hand, the administration of α-adrenergic agonists, such as isoproterenol, reduces intrahepatic vascular resistance in perfused cirrhotic liver. These data suggest that adrenergic receptors may be involved in the regulation of intrahepatic resistance in cirrhosis, and that β-adrenergic receptor blockers may decrease portal pressure in cirrhosis. In addition, the hepatic vascular bed of cirrhotic livers exhibits an exaggerated response to the β-adrenergic agonist methoxamine. It has been shown that the coupling of different agonists to its membrane G-coupled receptors promote the release of arachidonic acid from the plasma membrane facilitating its metabolization to different vasoactive-derived metabolites, including prostaglandins (PGs), thromboxanes (TXs), and leukotrienes.9,10


Cyclooxygenase (COX) is the key enzyme in the bio-synthetic pathway leading to PGs and TX from arachi-donic acid.11 COX-1 is constitutively expressed but it can also be stimulated by factors similar to those that stimulate the constitutive isoform of nitric oxide (NO) synthase (eNOs).12,13 COX-2 can also be constitutively expressed in some tissues including the liver14,15 and the mesenteric vascular bed.16 COX-2 is an inducible isoform of cyclooxygenase that, similarly to the inducible isoform of NO synthase, is usually expressed or over-expressed after stimulation with proinflammatory agents.17

The hyperresponse of the hepatic vasculature of cirrhotic livers to the vasoconstrictor methoxamine is associated with an overproduction by the isoenzyme COX-1 of thromboxane A2 (TXA2). This hyperresponse is completely corrected by pretreating the livers either with non-selective COX blockers, with COX-1 selective blockers or with TXA2 antagonists. Thus, an increased production of TXA2 markedly enhances the vasoconstrictive response of the cirrhotic hepatic vascular bed to methoxamine.14 Whether this effect is also shared by other vasoconstrictors has not been investigated so far.

Cystenyl leukotrienes

Cysteinyl leukotrienes (CT) are a group of highly potent vasoactive substances derived from the oxygenation and dehydration of arachidonic acid by 5-lipoxygenase18,19 that increases intrahepatic vascular resistance in normal and cirrhotic rat livers. However, this response is significantly greater in cirrhotic livers that in addition also have an increased expression of the 5-lipoxygenase mRNA and an increased production of CT. 5-lipoxygenase inhibition produces a marked reduction in portal pressure in cirrhotic livers, which suggests that 5-lipoxygenase—derived eicosanoids also contribute to the increased hepatic vascular resistance in cirrhosis.20


Endothelins are a family of homologous 21-amino acid vasoactive peptides (ET-1, ET-2, and ET-3) that also modulate hepatic vascular tone in cirrhosis.6,21 The biologic properties of endothelins are mediated essentially by two major endothelin receptors, endothelin A (ET-A) and endothelin B (ET-B) receptors. The ET-A receptor shows a high affinity for ET-1, but not for ET-3, and mediates constriction; the ET-B receptor has equal affinity for ET-1 and ET-3. Activation of ET-B receptors located on the vascular smooth-muscle cells promotes vasoconstriction, whereas activation of ET-B receptors located on endothelial cells promotes vasodilation, which is mediated by enhanced NO and prosta-cyclin production by the endothelial cell.

Patients with liver cirrhosis have increased circulating plasma levels of ET-1 and ET-3.22 ET-1 increases portal perfusion pressure by increasing intrahepatic resistance in normal and cirrhotic livers. While some experimental studies reported a slight reduction of portal pressure in cirrhotic animals after the administration of endothelin antagonists,23,24 this was not confirmed by other studies,25 so the role of endothelins increasing the vascular tone in cirrhosis remains unsettled.

Angiotensin II

Angiotensin II (A-II) is a powerful vasoconstrictor that increases hepatic resistance. Increased A-II is the result of the activation of the renin-angiotensin system (RAS), which is commonly observed in patients with cirrhosis. Activation of RAS may also be detrimental for portal hypertension as a result of increased liver fibrogenesis,26 which may worsen the evolution of cirrhosis. All the above suggested that preventing the activation of RAS may have beneficial effects in decreasing portal pressure in cirrhosis. However, current evidence shows that, although A-II blockade may reduce portal pressure, it causes systemic hypotension what reduces its potential as a therapeutic strategy for portal hypertension.27


Endogenous cannabinoids (or endocannabinoids) is a collective term describing a novel class of endogenous lipid ligands, including anandamide (arachidonyl ethanolamide). Anandamide has been reported to induce both vasodilatation and vasoconstriction depending on its concentration as well as the vascular territory being examined. Recent studies suggest that anandamide might be involved in the increased resistance of cirrhotic livers by promoting an increase production of TXA2.28

Endothelial dysfunction of cirrhotic livers

In normal conditions, the endothelium is able to generate vasodilator stimuli in response to increases in blood volume, blood pressure or vasoconstrictor agents, in an attempt to prevent or attenuate the concomitant increase in pressure. In several pathological conditions there is an impairment in this endothelium-dependent vasodilatation, which has been named as «endothelial dysfunction».29,30 Endothelial dysfunction is considered one of the main pathological mechanisms involved in the increased vascular tone observed in several vascular disorders such as arterial hypertension,31 diabetes32 and hypercholesterolemia,33 and has been attributed to a diminished NO bioavailability29,30 and to an increased production of endothelial derived contracting factors (EDCFs), such as PGH2/TXA2,34 endothelin35 or anion superoxide.36 The hepatic vascular bed of cirrhotic livers also exhibits endothelial dysfunction.37 Indeed, contrary to what happens in normal livers, the cirrhotic liver can not accommodate the increased portal blood flow caused by the postprandial hyperemia, which determines an abrupt postprandial increase in portal pressure.38 In addition, in experimental models of cirrhosis, endothelial dysfunction has been further characterized by showing that the cirrhotic liver exhibits an impaired response to the endothelium-dependent vasodilator acetylcholine.15,37 Endothelial dysfunction in cirrhosis has been attributed to reduced NO bioavailability and to increased vasoconstrictor COX-1 derived prostanoids.

Reduced NO bioavailability within the cirrhotic liver

NO is the natural ligand for soluble guanylate cyclase and is responsible for an increase in cyclic guanosine monophosphate (cGMP), the final agent responsible for the relaxation of the vascular wall through the extrusion of cytosolic Ca2+. Endothelial NO synthase (eNOS) is responsible for most of the vascular NO produced in a reaction where L-arginine is oxidized to L-citrulline and NO.39 In cirrhotic liver, there is a reduced NO bioavailability that plays a major role increasing intrahepatic vascular resistance and thereby worsening portal hypertension. In accordance with this concept, the administration of nitrates (exogenous donors of NO) have been shown to decrease portal pressure. In addition, enhancement of the expression of NO synthase in liver cells, through the portal injection of adenovirus coupled with the gene encoding NO synthase, significantly reduces portal pressure.40 More recently, strategies aimed at increasing NO release by enhancing intrahepatic eNOS activity, based on constitutively active Akt gene transfer41 or by simvastatin administration42 have opened new perspectives with potential therapeutic implications.

Decreased NO production occurs despite a normal expression of eNOS mRNA and normal levels of eNOS protein37,43 and has been attributed, at least in part, to reduced eNOS activity caused by several posttranslational alterations in the regulation of the enzyme such as increased caveolin expression, or a defect of the essential cofactor of eNOS, tetrahydrobioterin.44,45

Like in other vascular disorders characterized by the presence of endothelial dysfunction, oxidative stress has been implicated in the increased vascular tone that exhibit cirrhotic livers.46 It is well known that superoxide is capable of reacting with NO-, leading to peroxynitrite (ONOO-) formation,47,48 with an ongoing decrease in NO bioavailability.49-53 Reactive oxygen species (ROS) can also affect NO biology by its capacity to oxidize, and therefore inactivate, the NO synthase cofactor tetrahydro-biopterin (BH4),31 leading to a situation that has been called eNOS uncoupling,54-56 in which the NO synthases are incapable of transferring electrons to L-arginine and start using oxygen as a substrate leading to O2.- formation instead of NO. It has been suggested that because of that antioxidant therapy may contribute to correct this abnormality.57

Increased production of vasoconstrictor prostanoids

Endothelial dysfunction was also shown to be associated with an increased production of TXA2 and completely prevented by selective COX-1 blockers and by TXA2 antagonists. These results suggest that an increased production of a COX-1 derived vasoconstrictor prostanoid probably TXA2, is, at least in part, responsible for endothelial dysfunction.15 All these findings suggest that in cirrhotic livers there is an over-activation of the COX-1 pathway with an increased production of their vasoconstrictor-derived compounds.

Hydrogen sulphyde (H2S)

H2S is produced endogenously from desulphydration of cysteine by three different enzymes; cystathione-β-lyase (CSE), cystathionine-β-synthase (CBS), or 3-mercapto-sulphurtransferase.58 Although NO and CO are the first two identified gasotransmitters, recently, different arguments have pointed out hydrogen sulphyde (H2S) as the third gasotransmitter that can modulate vascular tone.59 Indeed, it has been recently suggested that H2S regulates HSCs contraction and that a decreased expression of CSE in HSCs may be responsible for the increased intrahepatic resistance in rodent models of liver cirrhosis.60

Increased splanchnic blood flow

Development of a hyperdynamic splanchnic circulatory state is a major component of portal hypertension. The increase in blood flow in splanchnic organs draining into the portal vein, and the subsequent increase in portal venous inflow, aggravates and perpetuates the portal hypertensive syndrome, especially when portal-systemic collaterals are extensive.2 The mechanisms underlying this splanchnic hyperemia are not fully understood, but it has been shown that it is associated with an overproduction of endogenous vasodilators and a decreased vascular reactivity to vasoconstrictors.2 Recent studies have demonstrated that an increased neovascularization in splanchnic organs, through a vascular endothelial growth factor (VEGF)-dependent angiogenic process, plays an important role in allowing such an increased splanchnic blood inflow, since suppression (blockade) of VEGF signalling markedly attenuates the increase in splanchnic blood flow, as well as the increased splanchnic vascularization observed in portal hypertensive animals.61,62 Interestingly, this VEGF-dependent angiogenesis also contributes significantly to the formation of portal-systemic collateral vessels in portal hypertensive animals, as described later on. Therefore, modulation of angiogenesis may represent a potential target in the treatment of portal hypertension.

Increased production of circulating/local paracrine vasodilators. Excessive response to vasodilators/Resistance to endogenous vasoconstrictors

Various evidence suggest that there is an interrelationship between different vasoactive systems, which are coupled to cause the splanchnic vasodilation. Furthermore, it appears that none of these vasoactive factors is the only factor responsible for the splanchnic vasodilation present in portal hypertension, which is likely to be multifactorial in origin.

Circulating vasodilatorsGlucagon

Many studies have demonstrated that plasma glucagon levels are elevated in patients with cirrhosis and experimental models of portal hypertension. Hyper-glucagonemia results, in part, from a decreased hepatic clearance of glucagon, but more importantly from an increased secretion of glucagon by pancreatic a cells.63 Glucagon may promote vasodilation by a dual mechanism: relaxing the vascular smooth muscle and decreasing its sensitivity to endogenous vasoconstrictors, such as norepinephrine, angiotensin II, and vaso-pressin.64,65 The role of glucagon in the splanchnic of portal hypertension provides a rationale for the use of somatostatin and its synthetic analogues to treat portal hypertension.66


Recent data suggest a role for endocannabinoids in the hyperdynamic circulation of portal hypertension.67,68 Increased levels of endogenous cannabinoid anandamide have been found in the monocyte fraction of blood from cirrhotic humans and rats and an increased expression of the cannabinoid CB1 receptors was found in hepatic human endothelial cells.69 In addition, CB1 receptor blockade reduced portal blood flow and pressure and increased arterial pressure in cirrhotic rats.69,70 The mechanism of action is not well understood. It has been suggested that it could be due, at least in part, to an increased NO production, mediated by the activation of endothelial CB1 receptors.69 Recently, Moezi et al. have demonstrated that the role of anandamide in the pathogenesis of hyperdynamic circulation in cirrhosis are primarily mediated via stimulation of CB1 and VR1 receptor pathways.68

Several other circulating vasodilators have been implicated in splanchnic vasodilatation. Bile acids are increased in portal hypertension and have vasodilator properties. However, the data in the literature are controversial, and the role of bile acids in the hyperdynamic circulation is not well defined.71,72 Likewise, the role of the capsaicin-calcitonin gene-related peptide (CGRP) vasodilator pathway in the systemic and splanchnic vasodilatation of portal hypertension is controversial.73 Other candidates, including neuropeptides, adenosine, endotoxin, and a variety of vasodilator gastrointestinal hormones, have also been studied. However, evidence is scarce for most of them.

Local paracrine vasodilators

Most investigators now agree on that local paracrine/autocrine vasodilators, mainly nitric oxide (NO), but also carbon monoxide (CO) and prostacyclin, play a major role in the pathogenesis of the circulatory abnormalities associated with chronic portal hypertension.

Nitric oxide

Experimental studies using specific NO inhibitors have shown that NO is involved in the regulation of splanchnic and systemic hemodynamics in portal hypertensive and normal animals. The splanchnic vasoconstrictive effect caused by NO inhibitors is significantly greater in portal hypertensive than in control animals, which suggests that an excessive production of NO may be responsible, at least in part, for the vasodilatation observed in portal hypertension.74,75 In addition, an overproduction of NO has been clearly demonstrated in vitro in perfused mesenteric artery preparations from portal hypertensive rats.76 The finding in patients with cirrhosis of increased serum and urinary concentrations of nitrite and nitrate, which are products of NO oxidation, also supports a role for NO in the genesis of the circulatory disturbances of portal hypertension.77

The increased production of NO is due both to an increased expression and to an increased activity of eNOS.78,79 Factors likely to activate the constitutive eNOS include shear stress, circulating vasoactive factors (endothelin, angiotensin II, vasopressin, and norepinephrine) and overexpression of the angiogenic factor VEGF.61,62 In portal hypertensive animals NO overproduction by eNOS in the splanchnic circulation precedes the development of the hyperdynamic circulation.80

The posttranslational regulation of eNOS in portal hypertension has been further evidenced by recent studies in the partial portal vein ligated model of portal hypertension, showing that upregulation of eNOS catalytic activity, rather than eNOS overexpression, is the initial event that induces NO overproduction in the splanchnic circulation. Indeed, eNOS phosphorylation by AKT seems to be the mechanism of the initial upregulation of eNOS activity and NO-mediated hyporesponsiveness to vasoconstrictors.81 Later on, other mechanisms for an increased production of NO become important, including an enhanced signalling of the molecular chaperone heat shock protein 90 (Hsp90).82,83

Carbon monoxide

Recent studies have shown an increased expression and activity of the inducible form of heme oxygenase (HO-1) in splanchnic tissues from portal hypertensive animals.84,85 In addition, the simultaneous inhibition of NO and HO has been shown to reverse completely the reduced vasoconstrictor response to potassium chloride of the mesenteric vascular bed.85

Altogether, these data suggest that the splanchnic vasodilatation present in portal hypertension is likely to be multifactorial in origin, being promoted in part by an excessive release of NO, CO and other vasoactive-mediators. In addition, experimental studies suggest that when one of the vasoactive mediators is chronically inhibited, the enhancement of other vasoactive pathways may prevent the correction of splanchnic vasodilatation.86

Hydrogen sulphyde (H2S)

A growing body of recent evidence suggests that H2S is a potent vasodilator in aorta and mesenteric arteries.87 Increased activity of CSE has been demonstrated in rats with liver injury due to carbon tetrachloride.88 Recently, it has been postulated a role of H2S in the development of a hyperdynamic circulation in cirrhosis. This is based on the idea that endotoxaemia leads to increased NO synthesis and upregulation of the enzyme responsible for H2S production.


Several studies support a role for prostaglandins in the hyperdynamic circulation of portal hypertension.89-91 Prostacyclin is an endogenous vasodilator produced by vascular endothelial cells. It causes vascular smooth-muscle relaxation by activating adenylate cyclase and augmenting the intracellular level of cyclic adenosine monophosphate.92

COX-1 and COX-2 are involved in the biosynthesis of prostacyclin.12,17,92 It has been shown that patients with cirrhosis have increased systemic levels of prostacyclin93 and prostacyclin has also been found to be increased in the portal vein91 and aorta16 of portal-hypertensive rats. In addition, the inhibition of prostaglandin biosynthesis by indomethacin reduces the hyperdynamic circulation and portal pressure in patients with cirrhosis and portal hypertension,94 as well as in experimental models of portal hypertension,95,96 and attenuates the vascular hypore-sponsiveness to vasoconstrictors of the mesenteric vascular bed.96,97

Portal-systemic collateral circulation

The development of portal-collateral circulation is one of the main complications of portal hypertension.2 Formation of collaterals is a complex process involving the opening, dilatation, and hypertrophy of preexisting vascular channels.98 Collaterals develop in response to the increased portal pressure. A minimum HVPG threshold of 10 mmHg should be reached for the development of portal-systemic collaterals and esophageal varices.99,100

In addition to the increased portal pressure, recent studies have shown that formation of portal-systemic collateral vessels in portal hypertension is influenced by a VEGF-dependent angiogenic process, and can be markedly attenuated by interfering with the VEGF/VEGF receptor-2 signalling pathway.61,62 These studies have opened a new perspective in the understanding of the pathophysiology of portal hypertension, with potential clinical relevance, since indicate that manipulation of the VEGF may be of therapeutic value.

The collateral circulation may carry as much as 90% of the blood entering the portal system. In this circumstance, the vascular resistance of these vessels becomes a major component of the overall resistance to portal blood flow, and therefore may be very important determining portal pressure. Also, although traditionally it has been thought that the hyperdynamic splanchnic circulatory state associated with portal hypertension was the consequence of active splanchnic vasodilatation, recent data suggests that the increased neovascularization in splanchnic organs is playing an important role allowing the increase in splanchnic blood inflow.62

The elements that modulate collateral resistance are not well known. Vasoconstrictive agents (including vaso-pressin and non-selective β-blockers) may increase significantly the collateral resistance. The increase in portal collateral resistance brought about by these agents attenuates the reduction in portal pressure achieved by reducing the splanchnic blood flow.101 Another circumstance in which active changes in portal collateral resistance appear to modulate changes in portal pressure is the restitution of blood volume following haemorrhage, during which a paradoxical increase in portal pressure occurs in portal hypertensive animals.

Increased plasma volume and hyperkinetic circulation

Splanchnic vasodilatation is typically associated with peripheral vasodilatation and a systemic hyperkinetic syndrome, which is characterized by reduced arterial pressure and peripheral resistance and increased plasma volume and cardiac output. The pathophysiologic mechanisms involved in peripheral vasodilatation are similar to those previously described for splanchnic vasodilatation.2 Peripheral vasodilatation plays a major role in the activation of endogenous neurohumoral systems that cause sodium retention and expansion of the plasma volume, followed by an increase in the cardiac index.102

Expansion of the plasma volume is a necessary step to maintain an increased cardiac index, which in turn aggravates portal hypertension.102 This provides the rationale for using a low-sodium diet and diuretics in the treatment of portal hypertension.


This study was supported by grants from the Ministerio de Educación y Ciencia (SAF:04/04783) and from the Fondo de Investigaciones Sanitarias (FIS 05/1285, 06/0623).

Bosch J., Pizcueta P., Feu F., Fernandez M., Garcia-Pagan J.C..
Pathophysiology of portal hypertension.
Gastroenterol Clin North Am, 21 (1992), pp. 1-14
Bosch J., Garcia-Pagan J.C..
Complications of cirrhosis.
I. Portal hypertension. J Hepatol, 32 (2000), pp. 141-156
Kaneda K., Ekataksin W., Sogawa M., Matsumura A., Cho A., Kawada N..
Endothelin-1-induced vasoconstriction causes a significant increase in portal pressure of rat liver: localized constrictive effect on the distal segment of preterminal portal venules as revealed by light and electron microscopy and serial reconstruction.
Hepatology, 27 (1998), pp. 735-747
Zhang J.X., Pegoli W., Clemens M.G..
Endothelin-1 induces direct constriction of hepatic sinusoids.
Am J Physiol, 266 (1994), pp. G624-G632
Kawada N., Tran-Thi T.A., Klein H., Decker K..
The contraction of hepatic stellate (Ito) cells stimulated with vasoactive substances.
Possible involvement of endothelin 1 and nitric oxide in the regulation of the sinusoidal tonus. Eur J Biochem, 213 (1993), pp. 815-823
Garcia-Pagan J.C., Bosch J., Rodes J..
The role of vasoactive mediators in portal hypertension.
Semin Gastrointest Dis, 6 (1995), pp. 140-147
Ballet F., Chretien Y., Rey C., Poupon R..
Differential response of normal and cirrhotic liver to vasoactive agents - a study in the isolated perfused rat-liver.
Journal of Pharmacology and Experimental Therapeutics, 244 (1988), pp. 283-289
Lautt W.W., Greenway C.V., Legare D.J..
Effect of hepatic nerves, norepinephrine, angiotensin, and elevated central venous-pressure on post-sinusoidal resistance sites and intrahepatic pressures in cats.
Microvascular Research, 33 (1987), pp. 50-61
Xing M., Insel P.A..
Protein kinase C-dependent activation of cytosolic phospholipase A2 and mitogen-activated protein kinase by alpha 1-adrenergic receptors in Madin-Darby canine kidney cells.
J Clin Invest, 97 (1996), pp. 1302-1310
Athari A., Hanecke K., Jungermann K..
Prostaglandin F2 alpha and D2 release from primary Ito cell cultures after stimulation with noradrenaline and ATP but not adenosine.
Hepatology, 20 (1994), pp. 142-148
Miyamoto T., Ogino N., Yamamoto S., Hayaishi O..
Purification of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes.
J Biol Chem, 251 (1976), pp. 2629-2636
Smith W.L..
Prostanoid biosynthesis and mechanisms of action.
Am J Physiol, 263 (1992), pp. F181-F191
Smith W.L., Garavito R.M., DeWitt D.L..
Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2.
J Biol Chem, 271 (1996), pp. 33157-33160
Graupera M., Garcia-Pagan J.C., Abraldes J.G., Peralta C., Bragulat M., Corominola H., Bosch J., Rodes J..
Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers.
Hepatology, 37 (2003), pp. 172-181
Graupera M., Garcia-Pagan J.C., Pares M., Abraldes J.G., Rosello J., Bosch J., Rodes J..
Cyclooxyenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers.
J Hepatol, 39 (2003), pp. 521
Potenza M.A., Botrugno O.A., De Salvia M.A., Lerro G., Nacci C., Marasciulo F.L., Andriantsitohaina R., Mitolo-Chieppa D..
Endothelial COX-1 and -2 differentially affect reactivity of MVB in portal hypertensive rats.
Am J Physiol Gastrointest Liver Physiol, 283 (2002), pp. G587-G594
Smith W.L., Langenbach R..
Why there are two cyclooxygenase isozymes.
J Clin Invest, 107 (2001), pp. 1491-1495
Samuelsson B., Dahlen S.E., Lindgren J.A., Rouzer C.A., Serhan C.N..
Leukotrienes and lipoxins: structures, biosynthesis, and biological effects.
Science, 237 (1987), pp. 1171-1176
Keppler D..
Leukotrienes: biosynthesis, transport, inactivation, and analysis.
Rev Physiol Biochem Pharmacol, 121 (1992), pp. 1-30
Graupera M., Garcia-Pagan J.C., Titos E., Claria J., Massaguer A., Bosch J., Rod S.J..
5-Lipoxygenase inhibition reduces intrahepatic vascular resistance of cirrhotic rat livers: A possible role of cysteinyl-leukotrienes.
Gastroenterology, 122 (2002), pp. 387-393
Angus P.W..
Role of endothelin in systemic and portal resistance in cirrhosis.
Gut, 55 (2006), pp. 1230-1232
Moller S., Gulberg V., Henriksen J.H., Gerbes A.L..
Endothelin-1 and endothelin-3 in cirrhosis: relations to systemic and splanchnic haemodynamics.
J Hepatol, 23 (1995), pp. 135-144
Rockey D.C., Weisiger R.A..
Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance.
Hepatology, 24 (1996), pp. 233-240
Reichen J., Gerbes A.L., Steiner M.J., Sagesser H., Clozel M..
The effect of endothelin and its antagonist Bosentan on hemodynamics and microvascular exchange in cirrhotic rat liver.
J Hepatol, 28 (1998), pp. 1020-1030
Poo J.L., Jimenez W., Maria M.R., Bosch-Marce M., Bordas N., Morales-Ruiz M., Perez M., Deulofeu R., Sole M., Arroyo V., Rodes J..
Chronic blockade of endothelin receptors in cirrhotic rats: hepatic and hemodynamic effects.
Gastroenterology, 116 (1999), pp. 161-167
Rockey D.C..
Vasoactive agents in intrahepatic portal hypertension and fibrogenesis: implications for therapy.
Gastroenterology, 118 (2000), pp. 1261-1265
Gonzalez-Abraldes J., Albillos A., Banares R., Del Arbol L.R., Moitinho E., Rodriguez C., Gonzalez M., Escorsell A., Garcia-Pagan J.C., Bosch J..
Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis.
Gastroenterology, 121 (2001), pp. 382-388
Yang Y.Y., Lin H.C., Huang Y.T., Lee T.Y., Hou M.C., Wang Y.W., Lee F.Y., Lee S.D..
Roles of anandamide in the hepatic microcirculation in cirrhotic rats.
American Journal of Physiology-Gastrointestinal and Liver Physiology, 290 (2006), pp. G328-G334
Harrison D.G..
Cellular and molecular mechanisms of endothelial cell dysfunction.
J Clin Invest, 100 (1997), pp. 2153-2157
Harrison D.G..
Endothelial function and oxidant stress.
Clin Cardiol, 20 (1997), pp. II-7
Landmesser U., Dikalov S., Price S.R., McCann L., Fukai T., Holland S.M., Mitch W.E., Harrison D.G..
Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension.
J Clin Invest, 111 (2003), pp. 1201-1209
Dixon L.J., Hughes S.M., Rooney K., Madden A., Devine A., Leahey W., Henry W., Johnston G.D., McVeigh G.E..
Increased superoxide production in hypertensive patients with diabetes mellitus: role of nitric oxide synthase.
Am J Hypertens, 18 (2005), pp. 839-843
Ohara Y., Peterson T.E., Harrison D.G..
Hypercholesterolemia increases endothelial superoxide anion production.
J Clin Invest, 91 (1993), pp. 2546-2551
Ge T., Hughes H., Junquero D.C., Wu K.K., Vanhoutte P.M., Boulanger C.M..
Endothelium-dependent contractions are associated with both augmented expression of prostaglandin H synthase-1 and hypersensitivity to prostaglandin H2 in the SHR aorta.
Circ Res, 76 (1995), pp. 1003-1010
Lerman A., Holmes D.R. Jr, Bell M.R., Garratt K.N., Nishimura R.A., Burnett J.C. Jr..
Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans.
Circulation, 92 (1995), pp. 2426-2431
Tagawa H., Tomoike H., Nakamura M..
Putative mechanisms of the impairment of endothelium-dependent relaxation of the aorta with atheromatous plaque in heritable hyperlipidemic rabbits.
Circ Res, 68 (1991), pp. 330-337
Gupta T.K., Toruner M., Chung M.K., Groszmann R.J..
Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats.
Hepatology, 28 (1998), pp. 926-931
Bellis L., Berzigotti A., Abraldes J.G., Moitinho E., Garcia-Pagan J.C., Bosch J., Rodes J..
Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis.
Hepatology, 37 (2003), pp. 378-384
Moncada S., Higgs A..
The L-arginine-nitric oxide pathway.
N Engl J Med, 329 (1993), pp. 2002-2012
Fevery J., Roskams T., Van de C.M., Omasta A., Janssens S., Desmet V., Nevens F..
NO synthase in the liver: prospects of in vivo gene transfer.
Digestion, 59 (1998), pp. 58-59
Morales-Ruiz M., Cejudo-Martn P., Fernandez-Varo G., Tugues S., Ros J., Angeli P., Rivera F., Arroyo V., Rodes J., Sessa W.C., Jimenez W..
Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats.
Gastroenterology, 125 (2003), pp. 522-531
Zafra C., Abraldes J.G., Turnes J., Berzigotti A., Fernandez M., Garca-Pagan J.C., Rodes J., Bosch J..
Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis.
Gastroenterology, 126 (2004), pp. 749-755
Mittal M.K., Gupta T.K., Lee F.Y., Sieber C.C., Groszmann R.J..
Nitric oxide modulates hepatic vascular tone in normal rat liver.
Am J Physiol, 267 (1994), pp. G416-G422
Miller D.R., Collier J.M., Billings R.E..
Protein tyrosine kinase activity regulates nitric oxide synthase induction in rat hepatocytes.
Am J Physiol, 272 (1997), pp. G207-G214
Shah V., Toruner M., Haddad F., Cadelina G., Papapetropoulos A., Choo K., Sessa W.C., Groszmann R.J..
Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat.
Gastroenterology, 117 (1999), pp. 1222-1228
Gracia-Sancho J., Lavina B., Rodriguez-Vilarrupla A., Garcia H., Bosch J., Garcia-Pagan J.C..
Oxidative stress reduces nitric oxide biodisponibility and may contribute to endothelial dysfunction of cirrhotic livers.
J Hepatol, 44 (2006), pp. S75
Huie R.E., Padmaja S..
The reaction of no with superoxide.
Free Radic Res Commun, 18 (1993), pp. 195-199
Fridovich I..
Superoxide radical: an endogenous toxicant.
Annu Rev Pharmacol Toxicol, 23 (1983), pp. 239-257
Cai H., Harrison D.G..
Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress.
Circ Res, 87 (2000), pp. 840-844
Madamanchi N.R., Vendrov A., Runge M.S..
Oxidative stress and vascular disease.
Arterioscler Thromb Vasc Biol, 25 (2005), pp. 29-38
Lum H., Roebuck K.A..
Oxidant stress and endothelial cell dysfunction.
Am J Physiol Cell Physiol, 280 (2001), pp. C719-C741
Jay D., Hitomi H., Griendling K.K..
Oxidative stress and diabetic cardiovascular complications.
Free Radic Biol Med, 40 (2006), pp. 183-192
Heistad D.D..
Oxidative stress and vascular disease: 2005 Duff lecture.
Arterioscler Thromb Vasc Biol, 26 (2006), pp. 689-695
Vasquez-Vivar J., Kalyanaraman B., Martasek P., Hogg N., Masters B.S., Karoui H., Tordo P., Pritchard K.A. Jr..
Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors.
Proc Natl Acad Sci USA, 95 (1998), pp. 9220-9225
Kuzkaya N., Weissmann N., Harrison D.G., Dikalov S..
Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase.
J Biol Chem, 20 (2003), pp. 22546-22554
Stroes E., Hijmering M., van Zandvoort M., Wever R., Rabelink T.J., van Faassen E.E..
Origin of superoxide production by endothelial nitric oxide synthase.
FEBS Lett, 438 (1998), pp. 161-164
Hernandez-Guerra M., Garcia-Pagan J.C., Turnes J., Bellot P., Deulofeu R., Abraldes J.G., Bosch J..
Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension.
Hepatology, 43 (2006), pp. 485-491
Stipanuk M.H., Beck P.W..
Characterization of the enzymic capacity for cysteine desulfhydration in liver and kidney of the rat.
Biochemical Journal, 206 (1982), pp. 267-277
Wang R..
Two’s company, three’s a crowd: can H2S be the third endogenous gaseous transmitter?.
Faseb Journal, 16 (2002), pp. 1792-1798
Fiorucci S., Antonelli E., Mencarelli A., Orlandi S., Renga B., Rizzo G., Distrutti E., Shah V., Morelli A..
The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis.
Hepatology, 42 (2005), pp. 539-548
Fernandez M., Vizzutti F., Garcia-Pagan J.C., Rodes J., Bosch J..
Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice.
Gastroenterology, 126 (2004), pp. 886-894
Fernandez M., Mejias M., Angermayr B., Garcia-Pagan J.C., Rodes J., Bosch J..
Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats.
Journal of Hepatology, 43 (2005), pp. 98-103
Gomis R., Fernandez-Alvarez J., Pizcueta P., Fernandez M., Casamitjana R., Bosch J., Rodes J..
Impaired function of pancreatic islets from rats with portal hypertension resulting from cirrhosis and partial portal vein ligation.
Hepatology, 19 (1994), pp. 1257-1261
Pizcueta M.P., Garcia-Pagan J.C., Fernandez M., Casamitjana R., Bosch J., Rodes J..
Glucagon hinders the effects of somatostatin on portal hypertension.
A study in rats with partial portal vein ligation. Gastroenterology, 101 (1991), pp. 1710-1715
Wiest R., Tsai M.H., Groszmann R.J..
Octreotide potentiates PKC-dependent vasoconstrictors in portal-hypertensive and control rats.
Gastroenterology, 120 (2001), pp. 975-983
Garcia-Pagan J.C., Escorsell A., Moitinho E., Bosch J..
Influence of pharmacological agents on portal hemodynamics: basis for its use in the treatment of portal hypertension.
Semin Liver Dis, 19 (1999), pp. 427-438
Domenicali M., Ros J., Fernandez-Varo G., Cejudo-Martin P., Crespo M., Morales-Ruiz M., Briones A.M., Campistol J.M., Arroyo V., Vila E., Rodes J., Jimenez W..
Increased anandamide induced relaxation in mesenteric arteries of cirrhotic rats: role of cannabinoid and vanilloid receptors.
Moezi L., Gaskari S.A., Liu H., Baik S.K., Dehpour A.R., Lee S.S..
Anandamide mediates hyperdynamic circulation in cirrhotic rats via CB(1) and VR(1) receptors.
Br J Pharmacol, 149 (2006), pp. 898-908
Batkai S., Jarai Z., Wagner J.A., Goparaju S.K., Varga K., Liu J., Wang L., Mirshahi F., Khanolkar A.D., Makriyannis A., Urbaschek R., Garcia N J.r., Sanyal A.J., Kunos G..
Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis.
Nat Med, 7 (2001), pp. 827-832
Ros J., Claria J., To-Figueras J., Planaguma A., Cejudo-Martin P., Fernandez-Varo G., Martin-Ruiz R., Arroyo V., Rivera F., Rodes J., Jimenez W..
Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat.
Gastroenterology, 122 (2002), pp. 85-93
Pak J.M., Lee S.S..
Vasoactive effects of bile-salts in cirrhotic rats - in-vivo and in-vitro studies.
Hepatology, 18 (1993), pp. 1175-1181
Genecin P., Polio J., Colombato L.A., Ferraioli G., Reuben A., Groszmann R.J..
Bile-acids do not mediate the hyperdynamic circulation in portal hypertensive rats.
American Journal of Physiology, 259 (1990), pp. G21-G25
Fernandez M., Casadevall M., Schuligoi R., Pizcueta P., Panes J., Barrachina M.D., Donnerer J., Pique J.M., Esplugues J.V., Bosch J..
Neonatal capsaicin treatment does not prevent splanchnic vasodilatation in portal-hypertensive rats.
Hepatology, 20 (1994), pp. 1609-1614
Pizcueta P., Pique J.M., Fernandez M., Bosch J., Rodes J., Whittle B.J., Moncada S..
Modulation of the hyperdynamic circulation of cirrhotic rats by nitric oxide inhibition.
Gastroenterology, 103 (1992), pp. 1909-1915
Pizcueta M.P., Pique J.M., Bosch J., Whittle B.J., Moncada S..
Effects of inhibiting nitric oxide biosynthesis on the systemic and splanchnic circulation of rats with portal hypertension.
Br J Pharmacol, 105 (1992), pp. 184-190
Wiest R., Hori N., Cadelina G., Das S., Groszmann R.J..
Increased nitric oxide release in response to vasoconstrictors in the superior mesenteric arterial bed of cirrhotic rats.
Hepatology, 26 (1997), pp. 1045
Guarner C., Soriano G., Tomas A., Bulbena O., Novella M.T., Balanzo J., Vilardell F., Mourelle M., Moncada S..
Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia.
Hepatology, 18 (1993), pp. 1139-1143
Sieber C.C., Lopez-Talavera J.C., Groszmann R.J..
Role of nitric oxide in the in vitro splanchnic vascular hyporeactivity in ascitic cirrhotic rats.
Gastroenterology, 104 (1993), pp. 1750-1754
Wiest R., Das S., Cadelina G., Garcia-Tsao G., Milstien S., Groszmann R.J..
Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility.
J Clin Invest, 104 (1999), pp. 1223-1233
Wiest R., Shah V., Sessa W.C., Groszmann R.J..
NO overproduction by eNOS precedes hyperdynamic splanchnic circulation in portal hypertensive rats.
Am J Physiol, 276 (1999), pp. G1043-G1051
Iwakiri Y., Tsai M.H., McCabe T.J., Gratton J.P., Fulton D., Groszmann R.J., Sessa W.C..
Phosphorylation of eNOS initiates excessive NO production in early phases of portal hypertension.
Am J Physiol Heart Circ Physiol, 282 (2002), pp. H2084-H2090
Garcia-Cardena G., Fan R., Shah V., Sorrentino R., Cirino G., Papapetropoulos A., Sessa W.C..
Dynamic activation of endothelial nitric oxide synthase by Hsp90.
Nature, 392 (1998), pp. 821-824
Shah V., Wiest R., Garcia-Cardena G., Cadelina G., Groszmann R.J., Sessa W.C..
Hsp90 regulation of endothelial nitric oxide synthase contributes to vascular control in portal hypertension.
Am J Physiol, 277 (1999), pp. G463-G468
Fernandez M., Bonkovsky H.L..
Increased heme oxygenase-1 gene expression in liver cells and splanchnic organs from portal hypertensive rats.
Hepatology, 29 (1999), pp. 1672-1679
Fernandez M., Lambrecht R.W., Bonkovsky H.L..
Increased heme oxygenase activity in splanchnic organs from portal hypertensive rats: role in modulating mesenteric vascular reactivity.
Journal of Hepatology, 34 (2001), pp. 812-817
Fernandez M., Garcia-Pagan J.C., Casadevall M., Mourelle M.I., Pique J.M., Bosch J., Rodes J..
Acute and chronic cyclooxygenase blockage in portal-hypertensive rats: influence in nitric oxide biosynthesis.
Gastroenterology, 110 (1996), pp. 1529-1535
Cheng Y.Q., Ndisang J.F., Tang G.H., Cao K., Wang R..
Hydrogen sulfide-induced relaxation of resistance mesenteric artery beds of rats.
American Journal of Physiology-Heart and Circulatory Physiology, 287 (2004), pp. H2316-H2323
Taguchi T., Awata S., Nishioka M., Arakawa Y., Shiraishi N., Ryu S., Kumazawa H., Takano Y., Nakayama K., Yagyu K., Kawamura M., Sato A..
Elevation of cystathionine gamma-lyase activity in the serum of rats treated with a single-dose of carbon-tetrachloride.
Industrial Health, 33 (1995), pp. 199-205
Sitzmann J.V., Bulkley G.B., Mitchell M.C., Campbell K..
Role of prostacyclin in the splanchnic hyperemia contributing to portalhypertension.
Annals of Surgery, 209 (1989), pp. 322-327
Sitzmann J.V., Campbell K.A., Wu Y.P., Cameron J.L..
Effect of portosystemic shunting on Pgi2 and glucagon-levels in humans.
Annals of Surgery, 217 (1993), pp. 248-252
Hamilton G., Phing R.C., Hutton R.A., Dandona P., Hobbs K.E..
The relationship between prostacyclin activity and pressure in the portal vein.
Hepatology, 2 (1982), pp. 236-242
Smith W.L..
The eicosanoids and their biochemical mechanisms of action.
Biochem J, 259 (1989), pp. 315-324
Guarner C., Soriano G., Such J., Teixido M., Ramis I., Bulbena O., Rosello J., Guarner F., Gelpi E., Balanzo J..
Systemic prostacyclin in cirrhotic patients. Relationship with portal hypertension and changes after intestinal decontamination.
Gastroenterology, 102 (1992), pp. 303-309
Bruix J., Bosch J., Kravetz D., Mastai R., Rodes J..
Effects of prostag-landin inhibition on systemic and hepatic hemodynamics in patients with cirrhosis of the liver.
Gastroenterology, 88 (1985), pp. 430-435
Sitzmann J.V., Li S.S., Adkinson N.F..
Evidence for role of prostacyclin as a systemic hormone in portal hypertension.
Surgery, 109 (1991), pp. 149-153
Sitzmann J.V., Li S.S., Lin P.W..
Prostacyclin mediates splanchnic vascular response to norepinephrine in portal hypertension.
J Surg Res, 47 (1989), pp. 208-211
Wu Y.P., Li S.S., Campbell K.A., Sitzmann J.V..
Modulation of splanchnic vascular sensitivity to angiotensin II.
Surgery, 110 (1991), pp. 162-168
Garcia-Tsao G., Groszmann R.J., Fisher R.L., Conn H.O., Atterbury C.E., Glickman M..
Portal pressure, presence of gastroesophageal varices and variceal bleeding.
Hepatology, 5 (1985), pp. 419-424
Rigau J., Bosch J., Bordas J.M., Navasa M., Mastai R., Kravetz D., Bruix J., Feu F., Rodes J..
Endoscopic measurement of variceal pressure in cirrhosis: correlation with portal pressure and variceal hemorrhage.
Gastroenterology, 96 (1989), pp. 873-880
Groszmann R.J., Garcia-Tsao G., Makuch R., Bosch J., Escorsell A., Garcia-Pagan J.C., Grace N., Matloff D.S., Burroughs A., Patch L..
Multicenter randomized placebo-controlled trial of non-selective beta-blockers in the prevention of the complications of portal hypertension: Final results and identification of a predictive factor.
Hepatology, 38 (2003), pp. 206A
Kroeger R.J., Groszmann R.J..
Increased portal venous resistance hinders portal pressure reduction during the administration of betβ-adrenergic blocking agents in a portal hypertensive model.
Hepatology, 5 (1985), pp. 97-101
Colombato L.A., Albillos A., Groszmann R.J..
The role of central blood volume in the development of sodium retention in portal hypertensive rats.
Gastroenterology, 110 (1996), pp. 193-198
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