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Copyright ©2010 Baishideng. All rights reserved.
World J Hepatol. Jun 27, 2010; 2(6): 208-220
Published online Jun 27, 2010. doi: 10.4254/wjh.v2.i6.208
Physiopathology of splanchnic vasodilation in portal hypertension
María Martell, Mar Coll, Nahia Ezkurdia, Imma Raurell, Joan Genescà
María Martell, Mar Coll, Nahia Ezkurdia, Imma Raurell, Joan Genescà, Liver Diseases Laboratory, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
Author contributions: Martell M, Coll M, Ezkurdia N and Raurell I drafted the various sections of the manuscript and made figures and illustrations; and Genescà J did the original design and approved the final version of the paper.
Supported by the Grants from the Ministerio de Educación y Ciencia, No. SAF2006-0314, and from the Ministerio de Ciencia e Innovación, No. SAF2009-08354
Correspondence to: Maria Martell, PhD, Liver Diseases Laboratory p006, Institut de Recerca Hospital Vall d’Hebron, Pg Vall d’Hebron 119-129, Barcelona 08035, Spain.
Telephone: +34-93-4894034 Fax: +34-93-4894032
Received: January 14, 2010
Revised: June 9, 2010
Accepted: June 16, 2010
Published online: June 27, 2010


In liver cirrhosis, the circulatory hemodynamic alterations of portal hypertension significantly contribute to many of the clinical manifestations of the disease. In the physiopathology of this vascular alteration, mesenteric splanchnic vasodilation plays an essential role by initiating the hemodynamic process. Numerous studies performed in cirrhotic patients and animal models have shown that this splanchnic vasodilation is the result of an important increase in local and systemic vasodilators and the presence of a splanchnic vascular hyporesponsiveness to vasoconstrictors. Among the molecules and factors known to be potentially involved in this arterial vasodilation, nitric oxide seems to have a crucial role in the physiopathology of this vascular alteration. However, none of the wide variety of mediators can be described as solely responsible, since this phenomenon is multifactorial in origin. Moreover, angiogenesis and vascular remodeling processes also seem to play a role. Finally, the sympathetic nervous system is thought to be involved in the pathogenesis of the hyperdynamic circulation associated with portal hypertension, although the nature and extent of its role is not completely understood. In this review, we discuss the different mechanisms known to contribute to this complex phenomenon.

Key Words: Liver cirrhosis, Portal hypertension, Splanchnic vasodilation, Hyperdynamic circulation, Sympathetic nervous system


Portal hypertension is defined as a pathological increase in portal vein pressure and it is diagnosed when the hepatic venous pressure gradient (HVPG) is above the normal range (1-5 mm Hg). HVPG is assessed by a hepatic hemodynamic study through a suprahepatic vein catheterization and estimates the difference of pressure between the portal vein and the inferior cava vein. Liver cirrhosis is the most frequent cause of portal hypertension in western countries. When HVPG increases to 10 mm Hg or more, portal hypertension of cirrhosis results in severe complications including ascites, hepatorenal syndrome, hepatic encephalopathy and haemorrhage from esophageal varices[1,2]. Two main factors contribute to establish and maintain portal hypertension: the vascular resistance due to difficult outflow of portal blood to the hepatic veins and the increased splanchnic blood flow (hyperdynamic syndrome). Portal hypertension is also associated with the formation of porto-systemic venous collaterals in an attempt to decompress the portal venous system[3,4]. However, this collateral circulation leads to the generation of varices which contribute to the morbidity and mortality of the disease.


Applying the Ohm’s law in the portal venous system: ΔP = Q × R, then the portal pressure gradient (ΔP), is the result of the product of the blood flow within the entire portal venous system (Q) and the vascular resistance of the same vascular system (R), including the hepatic vascular bed and the porto-systemic collaterals. Thus, portal hypertension is caused by an increase in blood flow, an increase in resistance or a combination of both. The initial mechanism that leads to portal hypertension in liver cirrhosis is an increase in hepatic resistance, mainly as a result of a mechanical occlusion. In later stages, an increase in splanchnic blood flow leads to the hyperdynamic circulation state, which in turn contributes to the maintenance and aggravation of many of the complications of cirrhosis and portal hypertension (Figure 1)[5].

Figure 1
Figure 1 Physiopathology of portal hypertension. In cirrhosis, the initiating factor leading to portal hypertension is an increase in intrahepatic vascular resistance (R), whereas the increase in portal blood flow (F) is a secondary phenomenon that maintains and worsens the increased portal pressure, giving rise to the hyperdynamic circulation syndrome. The different factors implicated in the distinct mechanisms of portal hypertension are shown. AII: angiotensin II; AEA: anandamide; AM: adrenomedullin; CGRP: calcitonine gene related peptide; CO: carbon monoxide; ET: endothelin; H2S: hydrogen sulfide; LT: leukotrienes; NE: norepinephrine; NO: nitric oxide; PGI2: prostacyclin; SP: substance P; TXA2: thromboxane A2.

The vascular resistance to portal blood flow is dependent on two factors: the intrahepatic resistance and the resistance generated by the collateral circulation. The increased intrahepatic vasculature resistance (IHVR) to portal blood flow is the main and primary factor of portal hypertension secondary to liver cirrhosis (Figure 1).

Intrahepatic resistance

Classically, structural distortion of the intrahepatic vasculature, as a consequence of fibrosis, scaring and vascular thrombosis, has been considered the only cause of the increased IHVR. The cellular mechanisms involved in fibrosis formation and cirrhosis are well known. In response to hepatocellular injury, hepatic stellate cells are activated and their phenotype changes from a quiescent one to a myofibroblast-like cell. As a result of hepatic stellate cell activation, collagenization (capillarization) of the Space of Disse occurs, and the injured liver becomes cirrhotic[6,7]. The pioneering work by Bathal and Groszmann[8], based on a perfused rat liver model, demonstrated that in addition to the structural changes, a dynamic component, represented by contractile elements of the hepatic vascular bed, might contribute to the increased intrahepatic vascular tone. It has been suggested that this modifiable component represents 40% of the total IHVR[9]. In cirrhosis, an increased production of vasoconstrictors and a deficient release of vasodilators, in combination to an exaggerate response to vasoconstrictors and an impaired vasodilatory response of the hepatic vascular bed, are the mechanisms responsible for the increased dynamic component of IHVR[10].

Among all overexpressed vasoconstrictors[11-14], endothelin (ET) seems to play a particularly important role in the enhanced vascular tone in liver cirrhosis. Patients with liver cirrhosis present elevated ET-1 and ET-3 plasma concentrations[15]. Moreover, not only hepatic ET-1 levels, but also ET receptor density are increased in the cirrhotic rat liver[16]. The ETA receptor, found on vascular smooth muscle cells, causes vasoconstriction, whereas the ETB receptor subtype located on endothelial cells induces vasorelaxation by stimulating endothelial nitric oxide synthase (eNOS)[17]. Several studies have been focused on ET blockade therapies. However, in contrast to what might be expected, ETB receptor stimulation by ETB agonist administration, resulted in an increased portal pressure in cirrhotic rats[18]. The effect of ETA antagonists in reducing portal pressure of cirrhotic rats remains controversial[18,19]. In addition to endothelin, other contributing factors to the increased IHVR are the products of S-lipoxygenase (cysteinyl-leukotriene) and the cyclooxygenase pathways (thromboxane A2), angiotensin II and the sympathetic system[11,12,14].

In addition to the exaggerated production of vasoconstrictors, the intrahepatic production of vasodilators, mainly nitric oxide (NO), remains insufficient in the cirrhotic liver[20,21]. NO is a potent vasodilator produced from L-arginine by different NOS. Although in the liver both eNOS and inducible NOS (iNOS) isoforms can be active, the insufficient hepatic NO production observed in cirrhosis has been attributed to the endothelial isoform[22,23]. Because mRNA and protein levels of eNOS are found in equal amounts in cirrhotic and normal livers, this NO-deficient production has been attributed to a post-translational dysfunction in eNOS activity[20,24,25]. On one hand, an increased expression of caveolin (an eNOS inhibitory protein)[24], and on the other hand, a decrease in eNOS phosphorilation due to abnormal Akt (protein kinase B) signalling[26], are the mechanisms that might explain the reduced eNOS activity in liver cirrhosis. In addition to a decreased NOS activity, an increased NO degradation has also been suggested to be responsible for the diminished NO bioavailability. Since superoxide (O2-) is able to react with NO to generate peroxinitrite (ONOO-), NO bioavailability can be substantially reduced if the O2- levels are increased as a consequence of a decrease in superoxide dismutase activity. Indeed, a portal injection of adenovirus containing superoxide dismutase encoding gene reduces portal pressure by increasing NO bioavailability in cirrhotic rats[27].

Collateral circulation

The increase in portal pressure leads to the appearance of direct connections between the portal blood vessels and the general circulation. This attempt to decompress the portal venous system leads to severe complications, such as hepatic encephalopathy and the formation of esophageal varices. Taking into account that porto-systemic shunting diverts a large quantity of portal blood flow away from the liver, the vascular resistance of these vessels might contribute importantly to increasing vascular resistance of the portal venous system. Porto-systemic collaterals formation, which involves both neovascularisation and opening existing vessels[28,29], has been suggested to be angiogenic-dependent. Angiogenesis is mediated mainly by the vascular endothelial growth factor (VEGF). Fernandez et al demonstrated that anti-VEGF receptor-2 monoclonal antibody prevented porto-systemic collateral vessel formation in portal hypertensive mice[30,31]. Furthermore, since NAD(P)H is required for VEGF-induced angiogenesis, NAD(P)H oxidase blockade significantly reduced porto-systemic collateral formation[32]. The same authors have demonstrated that portal hypertensive rats treated with signalling inhibitors of VEGF and platelet derived growth factor (PDGF) significantly reduce their porto-systemic collaterization[33]. Also, the use, in experimental rat models of portal hypertension, of Sorafenib, a potent inhibitor of proangiogenic VEGF receptor-2 and PDGF receptor-β, induced an important decrease in splanchnic neovascularisation and in the extent of porto-systemic collaterals, along with a marked attenuation of hyperdynamic splanchnic and systemic circulations[34].


The splanchnic circulation is the main vascular bed responsible for the reduction in vascular resistance in the portal hypertensive state. An increase in splanchnic blood flow in portal hypertension is the result of a marked vasodilation of arterioles in splanchnic organs, which drain blood into the portal venous system[35]. The increase in blood flow in splanchnic organs and the subsequent increase in portal venous inflow, together with an increased resistance to portal inflow, maintains and aggravates the portal hypertensive syndrome[9]. An increased production or activation of vasodilatory mediators and systems, and a decreased vascular reactivity to vasoconstrictors (Figure 1), are probably responsible for this splanchnic hyperaemia (vasodilation). In addition, increased angiogenesis probably collaborates in increasing the splanchnic blood inflow[30,31].

Hyperdynamic circulation

The hyperdynamic circulatory state of portal hypertension is characterized by splanchnic and peripheral vasodilation, increased plasma volume and increased cardiac output[5]. The hyperdynamic splanchnic circulation is mediated in part by arterial vasodilation, but this vasodilation alone is not sufficient to cause the circulation to become hyperdynamic. It is the combination of arterial vasodilation and blood volume expansion that produces optimal conditions for maintaining the hyperdynamic circulatory state in portal hypertension[35,36] (Figure 1). The arterial vasodilation in the peripheral and splanchnic circulation leads to a decrease in central blood volume. This relative arterial hypovolemia leads to the stimulation of cardiopulmonary volume receptors and arterial baroreceptors, activating the sympathetic nervous system, the renin-angiotensin-aldostern system and arginin-vasopresin (antidiuretic hormone). Mediators from these systems result in sodium and water retention by the kidneys, and consequently, plasma volume expansion. Sodium retention is due to increased tubular reabsorption of sodium, mediated by receptors for aldosterone, angiotensin and alpha-adrenergic stimuli. The decrease in water excretion is due to increased secretion of antidiuretic hormone[37].

The harmful effects of hyperdynamic circulation are not restricted to the hepatosplanchnic circulation. The hyperdynamic circulation also affects the cardiac (increase cardiac output), the pulmonary (hepatopulmonary syndrome) and the cerebral circulation (acute hepatic coma)[38,39]. Other organs such as the kidney and the brain (chronic encephalopathy) appear to be indirectly affected by the vasodilation in the other circulatory beds[5].

Animal models

The development of experimental models to study the hemodynamic alterations of portal hypertension has been of critical importance for the understanding of this syndrome. The pioneering work of Chojkier and Groszmann in establishing the partial portal-vein ligated (PVL) model has been a basic element in understanding portal hypertension pathophysiology[3,40]. In this model, the portal vein is isolated and a stenosis is created by a single ligature around a 20-gauge blunt-tipped needle lying along the portal vein. Subsequent removal of the needle yields a calibrate stenosis of the portal vein.

The PVL model reproduces all systemic and hemodynamic abnormalities detected in portal hypertension and the circulatory hyperdynamic state: portal pressure and portal flow increase, appearance of porto-systemic shunts, splanchnic vasodilation with splanchnic arteriolar resistance reduction and splanchnic flow increase, systemic vasodilation with arterial hypotension, total peripheral resistance reduction and cardiac output increase[40]. This model is extraordinarily homogenous, reproducible and has highly predictable chronobiology that permits the elucidation of the sequence of events involved in the generation of the hyperdynamic syndrome[41,42]. Porto-systemic shunting is detectable at two days after PVL surgery and the percentage of portal blood inflow diverted to collaterals approaches 100% after 1 wk[42]. Circulation becomes hyperdynamic 4-5 d after PVL, and 1 wk after portal vein ligation, rats present the complete range of portal hypertensive alterations with hyperdynamic circulatory syndrome and porto-systemic shunting formation.

Although the PVL model is easy to use and reproducible, the experimental rat models of cirrhosis generated by different mechanisms (basically by carbon tetrachloride administration and bile duct ligation) are probably more similar to human cirrhosis, since in addition to displaying all the hemodynamic alterations of portal hypertension, they present the metabolic, infectious and other complications of advanced liver disease[36,43]. Results obtained in PVL rats are usually tested in these models of cirrhosis.


The arterial vascular tone is determined by the balance between the effects of vasoactive molecules acting on the vascular smooth muscle. As mentioned, an increased concentration of circulatory vasodilators and an enhanced endothelial production of local vasodilators, as well as a decreased vascular responsiveness to endogenous vasoconstrictors have been observed in splanchnic vessels in portal hypertension[36] (Figure 1). Among the molecules and factors known to be potentially involved in this arterial vasodilation, none of them can be described as solely responsible, since this phenomenon is multifactorial in origin[44].

Nitric oxide

NO, an endothelial-derived relaxing factor, has been recognized as the most important vasodilator molecule that mediates the excessive arterial vasodilation observed in portal hypertension[45]. Its involvement, initially suggested by Vallance and Moncada[46], has been confirmed by a number of studies. In cirrhotic patients, increased levels of nitrates and nitrites, degradation products of NO oxidation[47], have been observed. In the splanchnic vascular bed of rats with portal hypertension an overproduction of NO responsible for vasopressor hyposensitivity has been clearly demonstrated[48]. Furthermore, inhibition of NO production reduces porto-systemic shunting and largely prevents the development of the hyperdynamic circulation[49]. NO is produced from L-arginine by the family of NOS enzymes, forming the free radical NO and citrulline as byproducts[50]. NO has a short life and is rapidly oxidized to the stable, inactive end-products, nitrite and nitrate[51]. The mechanism by which NO causes vasodilation is through the stimulation of soluble guanylyl cyclase (sGC) to generate cyclic guanosine monophosphate (cGMP) in vascular smooth muscle[52] (Figure 2). Three isoforms are known to produce NO: constitutively expressed isoforms, eNOS[53] and neuronal NOS (nNOS)[54], and iNOS[55] which, surprisingly, does not appear to be involved in the increased NO production in cirrhosis[56]. The major enzymatic source of the vascular NO overproduction has been shown to be eNOS[57]. In animal models (PVL rats) at least, it has been observed that eNOS upregulation precedes the hyperdynamic circulatory changes[45]. More recent evidence suggests that nNOS is also upregulated in aorta[58] and mesenteric arteries[59], playing a role in the development/maintenance of the hyperdynamic splanchnic circulation in experimental cirrhosis.

Figure 2
Figure 2 Molecular pathways associated to splanchnic vasodilation. Vasoactive molecules involved in the regulation of vascular tone in the arteries of the splanchnic circulation. Nitric oxide (NO), carbon monoxide (CO), prostacyclin (PGl2) or hydrogen sulfide (H2S), generated through different pathways in endothelial cells, cause vasodilation in vascular smooth muscle cells by either activating soluble guanylate cyclase (sGC) to generate cyclic guanosine monophosphate (cGMP), by stimulating adenylate cyclase (AC) and generation of cyclic adenosine monophosphate (cAMP) or through the opening of KATP channels. Also, anandamide activates endothelial cannabinoid 1 receptors (CB1R) provoking vasodilation. AA: arachidonic acid; AC: adenylyl cyclase; Akt: protein kinase B; BH4: tetrahydrobiopterin; CaM: calmodulin; CSE: cystathionine-γ-lyase; COX: cyclooxygenase; eNOS: endothelial nitric oxide synthase; HSP90: heat shock protein 90; IP3: inositol triphosphate; TNFα: tumor necrosis factor α; VEGF: vascular endothelial growth factor.

In endothelial cells, eNOS is activated by calcium/calmodulin (Ca2+/CaM) in response to an elevation of cytosolic Ca2+ and by phosphorilation of eNOS at several sites[60,61]. Initial up-regulation of eNOS starts at the post-translational level by Akt-mediated eNOS phosphorilation[62], which increases its activity at any Ca2+ concentration[63]. During early cirrhosis, this pathway is stimulated by different forms of stimuli such as vascular endothelial growth factor (VEGF), inflammatory cytokines, and mechanical forces by shear stress[63-65]. This latter mechanism involves an increased interaction of eNOS with the positive regulator molecular chaperone heat shock protein 90 (Hsp90)[66]. Later, in advanced stages of portal hypertension, bacterial translocation activates eNOS through a tumor necrosis factor-α dependent increase in tetrahydrobiopterine, an essential cofactor of eNOS[67,68] (Figure 2). It is worth remarking that, according to several studies, other mechanisms such as changes in subcellular localization of eNOS[69], S-nitrosilation[70,71] or asymmetric dimethylarginine degrading enzyme might be involved in the regulation of eNOS activity[72].

In summary, different mechanisms such as complex protein-protein interactions and posttranslational modifications have been reported to up-regulate eNOS in portal hypertension[73].

Other paracrine vasodilators

In addition to NO, other local paracrine/autocrine vasodilators have been described as possibly being involved in the pathogenesis of the hyperdynamic circulation associated with portal hypertension (Figures 1 and 2).

Carbon monoxide: Carbon monoxide (CO) is a gaseous molecule produced by heme oxygenase (HO) during heme metabolism to biliberdin IX[74]. CO, in a similar manner to NO in cirrhosis, is believed to relax smooth muscle cells through the activation of NO-dependent sGC, resulting in an increased production of cGMP. Although CO is a far less potent mediator than NO[75], a role in vasodilation of portal hypertension has been suggested[76]. CO-induced vasodilation can also occur via Ca2+-activated potassium channels[77]. In portal hypertension, an inducible isoform of HO, HO-1, has been shown to be up-regulated in systemic and splanchnic arterial circulation[78], although the mechanisms of activation remain to be fully understood.

Prostacyclin (PGI2): Prostacyclin is synthesized by cyclooxygenase and released from the endothelium to promote smooth muscle relaxation by activating adenylyl cyclase and augmenting the intracellular level of cyclic adenosine monophosphate[79]. Increased levels of circulating PGI2 have been observed in patients with cirrhosis[80] and in portal hypertensive rabbits[81], supporting a role for prostaglandins in the pathogenesis of the hyperdynamic circulatory syndrome.

Hydrogen sulfide (H2S): Recent evidence has suggested a role for H2S, a potent vasodilator, in the development of hyperdynamic circulation in cirrhosis[82]. This is based on the observation that in cirrhosis, endotoxaemia leads to upregulation of the enzyme cystathionine-γ-lyase, responsible for H2S production, which causes vasodilation through the opening of KATP channels[83].

Circulating vasodilators

Early studies in the physiopathology of portal hypertension focused on the role of circulating vasodilator substances of splanchnic origin accumulated as a consequence of reduced hepatic metabolism and/or increased porto-systemic shunting. The strongest evidence is for glucagon, whereas other substances described here have not been extensively investigated[84,85].

Glucagon: Numerous studies have demonstrated elevated plasma glucagon levels in patients with cirrhosis and in portal hypertensive rat models. Glucagon seems to promote vasodilation by relaxing the vascular smooth muscle and decreasing its sensitivity to endogenous vasoconstrictors, although the exact mechanism remains to be elucidated[86].

Endocannabinoid: The contribution of the endocannabinoid system in the development of splanchnic vasodilation has been described in several studies proposing various mechanisms. The main endocannabinoid mediator is anandamide, a product of arachinoid acid metabolism. Endocannabinoids activate endothelial cannabinoid 1 receptors and vanilloid receptor 1 causing pronounced vasodilation in BDL rats[87]. Anandamide levels are increased in monocytes in cirrhosis and over-activation of cannabinoid 1 receptors induce mesenteric NO production by eNOS in mesenteric vessels from portal hypertensive rats[87,88].

Adrenomedullin: In a similar way to endocannabinoids, increased peptide adrenomedullin levels have been found in plasma of cirrhotic rats[89] and patients[90]. Adrenomedullin is a vasoactive peptide known to contribute to enhancement of eNOS activity causing vasodilation. This peptide phosphorylates and activates Akt and increases cGMP production in rat aorta, probably promoting vasorelaxation through production of NO[91].

Endothelium-derived hyperpolarizing factor: Endothelium-derived hyperpolarizing factor (EDHF) has been shown to be an important endothelium-dependent vasodilator in resistance vessels of eNOS knockout mice[92]. Its role becomes more significant when the production of NO is inhibited, because NO seems to inhibit the release of EDHF[93].

Other endogenous humoral vasodilators including atrial-natriuretic peptide, whose levels tend to increase in advanced stages of liver cirrhosis with ascites[94], adenosine, histamine, bile salts, calcitinin gene related protein (CGRP) and substance P, have been proposed to play a role in the arterial vasodilation in portal hypertension[95] (Figure 1).

Contracting signalling alterations

In cirrhosis and portal hypertension, the majority of the vessels are dilated despite systemic activation of vasoconstrictors[96-98]. This splanchnic resistance to vasoconstrictor agents can be attributed to vascular hyporesponsiveness[99,100], explaining why the hyperdynamic circulation increases with progression of the disease despite the stimulation of renin-angiotensin, sympathetic nervous system and vasopressin release. Impaired responsiveness to vasoconstrictors is involved both in the increased vasodilation of splanchnic territories and in vasoconstriction of essential end-organs, triggering the severe complications of cirrhosis.

The contractile state of vascular smooth muscle depends essentially on myosin light chain (MLC) phosphorylation and is regulated via activation of MLC kinase or inhibition of MLC phosphatase[101,102] (Figure 3). In contrast, pathways leading to vasorelaxation decrease MLC phosphorylation via deactivation of MLC kinase or activation of MLC phosphatases[103-106]. All vasoconstrictor receptors belong to the superfamily of guanine nucleotide-binding protein (G-protein)-coupled receptors (GPCR). Stimulation of GPCR on the vascular smooth muscle cell activates G proteins and consequently their down stream effectors, phospholipase C β (PLCβ) and the small GTPase, RhoA. PLCβ hydrolyzes phosphatidylinositol 4,5-biphosphate into inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 diffuses in the cytosol and DAG remains in the plasma membrane activating protein kinase C. Both products cause an increase in intracellular calcium in vascular smooth muscle cells. The released calcium initiates a cascade of intracellular events, causing MLC phosphorilation and resulting in cross-bridging of actin and myosin, leading to contraction[101,102]. In addition, the parallel cascade of G-protein-induced RhoA activation subsequently activates Rho kinase causing inhibition of MLC phosphatase, enhanced MLC phosphorilation and eventually vascular contraction.

Figure 3
Figure 3 Vasodilation/contractile signaling in vascular smooth muscle cells. The contractile state of vascular smooth muscle depends on the phosphorilation state of myosin light chains (MLCs). Under normal conditions, contractile agonists activate G protein couple receptors (GPCR). These receptors subsequently activate downstream effectors such as phospholipase C (PLC) and GTPase RhoA, leading to the increase of MLC phosphorilation via the activation of MLC kinase or the inhibition of MLC phosphatase. DAG: diacylglycerol; IP3: inositol triphosphate; PIP2: Phosphatidylinositol 4,5-bisphosphate; PKC: protein kinase C.

In several studies both in animal models and human tissues the diminished contractile response to α1-adrenergic agonists or other vasoconstrictors persisted after removal of the endothelium or pharmacological inhibition of endogenous NO production. It is also known that vascular hyporeactivity is not caused by a down regulation of receptors to most relevant endogenous vasoconstrictors or by a decrease in their affinity. These vasoconstrictor receptors are actually increased in the hepatic artery. Therefore, the defective contractile signalling should be at the subreceptor level[107,108]. Recent evidence suggests that during portal hypertension these contracting signalling pathways are altered early after receptor stimulation, most probably at the level of Gα effectors. In rats with secondary biliary cirrhosis induced by bile duct ligation, it has been observed that impaired response to α-adrenoreceptor stimulation involves a reduced activation of PLCβ and consequently, a diminished formation of inositol phosphates[109], as well as reduced activation of RhoA with subsequently defective Rho kinase activation[110]. Moreover, this impairment in PLCβ and RhoA activation is resistant to endothelium denudation or pharmacological NOS inhibition[109,110], supporting the existence of defects in receptor-mediated activation of contraction.

The impaired response to contractile agonists occurring in portal hypertension has been also explained by desensitization of GPCRs by receptor-desensitising proteins, namely G-protein-coupled receptor kinase 2 (GRK-2) and β-arrestin 2. These receptor-desensitising proteins have been found to be up-regulated in aortas from BDL rats as well as in hepatic arteries from patients with cirrhosis, inducing desensitisation of angiotensin II receptor[111]. Moreover, it is known that the GRK-2/β-arrestin 2 system also induces desensitization of a variety of different receptors and that GRK-2/β-arrestin 2 mediated receptor desensitisation is initiated in response to exaggerated receptor stimulation[112,113]. It seems possible that elevated plasma levels of angiotensin II and catecholamines, which are well established in cirrhosis, are responsible for the onset of these processes in hypocontractile vessels[114,115].

Another observation contributing to the understanding of the dysregulation of contractile signalling in portal hypertension has come from the recent studies on increased release and enhanced effect of neuropeptide Y (NPY) on adrenergic mesenteric contraction in PVL rats[116]. By itself, NPY mediates no direct vasoconstriction, but potentiates NE-evoked vasoconstriction in the mesenteric vasculature through the Y1 specific receptor. Enhanced release of NPY may represent a compensatory mechanism to counterbalance arterial vasodilation by restoring the efficacy of endogenous catecholamines, especially in states of high alpha1-adrenergic activity.

Nervous system and portal hypertension

Histological studies have revealed that vascular smooth muscle is innervated by neurons containing NOS immunoreactivity[54], as well as by those containing tyrosine hydroxylase and choline acetyltransferase[117]. These efferent post-ganglionic neurons, identified as nitrergic, noradrenergic and cholinergic, control vasoconstriction of vascular smooth muscle cells from blood vessels. Functionally, nitrergic nerves are more important in vascular tone control than cholinergic nerves, which only play a role in modulating adrenergic and nitrergic nerve functions[118].

In the mesenteric circulation, both in humans and rodents, vasoconstriction induced by the sympathetic nervous system (SNS) is mainly mediated by post-synaptic α1-adrenoreceptors[119]. Indeed, α1-adrenoreceptor stimulation is the major mechanism through which the SNS regulates vascular tone. It has been shown that stimulation of perivascular nerves in blood vessels evokes vasoconstriction. This vasoconstriction is blocked by tetrodotoxin (neurotoxin), prazosin (α1-adrenoceptor antagonist), guanethidine (adrenergic neuron blocker) or 6-hydroxydopamine (neurotoxin that destroys adrenergic neurons)[120,121]. Thus, the vascular tone of peripheral blood vessels might be controlled mainly by sympathetic adrenergic nerves through the release of the neurotransmitter norepinephrine (NE). Moreover, different investigations have also shown that other agents like NPY and adenosine triphosphate are also released in the SNS, acting as co-transmitters of NE and potentiating its action[122].

There are a large number of publications evaluating the role of SNS in human cirrhosis. Increased systemic levels of catecholamines have been found in many studies, tending to increase when liver disease worsens[114,115]. These elevated levels are a result of an increased production of NE (increased plasma levels of NE, spillover of NE from the neuroeffector junctions and muscle sympathetic nervous activity), rather than a decreased clearance[123,124]. However, the origin of this SNS-hyperactivity is not homogeneous, since there are organs or tissues in which increased NE production has not been found. One of the main sites of NE overproduction is the kidney[124,125]. Another important site of NE production is muscle, with many studies showing increased muscle sympathetic nerve traffic[126,127]. There are also regional differences, the upper limb seems to release increased amounts of NE, but the lower limb does not[125,128]. Also, in contrast to the increased sympathetic nerve traffic found in muscles, the skin seems to present a normal level of sympathetic activity[127].

It seems quite clear that the adrenergic system plays a role in the cardiovascular, homeostatic and metabolic dysfunction present in advanced liver disease and that in cirrhosis and portal hypertension there is a global overactivity of this system. What is more questionable is whether this SNS-hyperactivity takes place everywhere and especially in mesenteric vessels. In this regard, our group has recently demonstrated an important down-regulation, both at the transcriptional and translational level, of many proteins implicated in adrenergic neurotransmission in the superior mesenteric artery from PVL and cirrhotic rats[129]. This adrenergic inhibition is accompanied by a remarkable regression/atrophy of the sympathetic innervation in the whole mesenteric vascular bed. However, this nervous atrophy is not present in other vascular territories such as the renal arteries[130]. The down-regulation of the mesenteric adrenergic system has been interpreted as a local consequence of portal hypertension that might contribute to aggravating splanchnic vasodilation, which is responsible for a generalized sympathetic overactivity, especially in muscles and kidneys. The observation that alpha-adrenergic agonists, such as norepinephrine and midodrine, are effective in the treatment of hepatorenal syndrome[131,132], the ultimate consequence of arterial vasodilation in cirrhosis, suggests that, at least in some areas, the adrenergic activity rather than overactivated, might be suppressed. The recent observation that NPY restores adrenergic superior mesenteric artery hyporeactivity in PVL rats[116], would also point to a deficient local adrenergic tone in portal hypertension. Also, Joh and co-workers[133] have demonstrated that using antagonists to α-adrenergic receptors, the response to vasoconstrictor blockade in portal hypertensive animals differed drastically from normal rats. Unlike the response of normal rats, α-adrenergic blockade produced essentially no change in intestinal microvascular dimensions, while vasopressin or angiotensin II blockade was associated with arteriolar dilation. These data suggest that loss of adrenergic vascular tone could be a very important functional vasoconstrictor defect in portal hypertension.

The neural pathway controlling the cardiovascular system includes the primary afferent innervation (sensory neurons), the brain stem medullary cardiovascular nuclei, and the effector arm composed of sympathetic and parasympathetic efferent nerves[134,135]. Considering this system, the signal responsible for the post-ganglionic sympathetic nerve regression suggested by our studies probably originates in preganglionic neurons or other neurons with a synaptic connection to post-ganglionic neurons. The afferent stimulus originating from pressure increases in portal or mesenteric vessels or microvasculature would reach the central nuclei through the afferent nerves and from there to the sympathetic ganglia[136,137] (Figure 4). In this context, it is important to mention that several studies suggest that by pharmacologically eliminating the primary afferent nerves by capsaicin administration, the development of hemodynamic alterations is prevented as well as ascites formation, in PVL and cirrhotic rats[138-141]. In addition, these afferent sensory nerves once activated by peripheral stimuli can also release the transmitter content (the vasodilator peptides substance P and CGRP) from their peripheral terminals in innervated tissue to elicit functional responses[142]. It has been described that periarterial nerve stimulation in rat mesenteric resistance arteries produces neurogenic vasodilation mediated by CGRP[143], and that CGRP release suppresses sympathetic nerve mediated vasoconstriction[143]. Finally, different studies showing high levels of substance P and CGRP in patients with cirrhosis and liver failure have suggested that these neuronally generated vasodilators could play a role in splanchnic vasodilation of portal hypertension[144,145].

Figure 4
Figure 4 Hypothesis regarding the mechanisms and effects of the sympathetic post-ganglionic atrophy in splanchnic vasodilation. The afferent stimulus of portal hypertension, originating from pressure increases in portal or mesenteric vessels or microvasculature, reaches the brain stem cardiovascular nuclei through the afferent nerves. From there, post-ganglionic sympathetic nerve regression are mediated by efferent sympathetic nerves, leading to neurotransmission inhibition and vasoconstriction impairment mediated by norepinephrine (NE).

Perivascular presence of nNOS–containing nerves, so called nitrergic nerves, has been demonstrated in numerous vascular beds and multiple species. These nNOS immunoreactive fibers play an important role in regulating vascular tone, mediating neurogenic vasodilation by releasing NO. Up-regulation of n-NOS has been recently demonstrated in mesenteric arteries of PVL rats[58,146]. This nNOS activation seems to mediate an increased neural NO-mediated vasodilatation and might be an additional pathway for mesenteric smooth muscle relaxation in portal hypertension. Moreover, the non-selective NOS inhibition by L-NAME (N-(G)-nitro-L-arginine methyl ester) and the selective inhibition of nNOS by L-VNIO (vinyl-L-N-5-(1-imino-3-butenyl)-L-ornithine), increase the induced adrenergic vasoconstriction in rat mesenteric arteries in response to periarterial nerve stimulation[147]. These findings strongly suggest that endogenous NO also modulates the neurogenic release of NE from adrenergic nerve terminals.


The increase in splanchnic flow that contributes to portal hypertention results from persistent mesenteric vasodilation together with angiogenesis. Studies in animal models and in patients have shown that splanchnic arterial vasodilation is a multifactorial phenomenon. In addition to overproduction of vasodilators (especially nitric oxide), defects in the contractile signalling pathways in smooth muscle cells in response to vasoconstrictor stimulation contribute to vascular hyporesponsiveness to endogenous vasoconstrictors. In addition, sympathetic atrophy seems to participate in the late stages of portal hypertension. It is reasonable to suggest that mesenteric sympathetic atrophy decreases the vascular tone of the mesenteric tree, allowing an increased activity of vasodilatory mediators (humoral and nervous). However, little is known about possible interactions between participating pathways and mechanisms, and further efforts are needed to clarify this essential component of portal hypertension.


Peer reviewer: Radha Krishan Dhiman, MD, DM, FACG, Professor, Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India

S- Editor Zhang HN L- Editor Roemmele A E- Editor Liu N

1.  Casado M, Bosch J, García-Pagán JC, Bru C, Bañares R, Bandi JC, Escorsell A, Rodríguez-Láiz JM, Gilabert R, Feu F. Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings. Gastroenterology. 1998;114:1296-1303.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology. 1985;5:419-424.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Chojkier M, Groszmann RJ. Measurement of portal-systemic shunting in the rat by using gamma-labeled microspheres. Am J Physiol. 1981;240:G371-G375.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Moreau R, Lebrec D. Molecular and structural basis of portal hypertension. Clin Liver Dis. 2006;10:445-457, vii.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology. 2006;43:S121-S131.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Mallat A. Hepatic stellate cells and intrahepatic modulation of portal pressure. Digestion. 1998;59:416-419.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Reeves HL, Friedman SL. Activation of hepatic stellate cells--a key issue in liver fibrosis. Front Biosci. 2002;7:d808-d826.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol. 1985;1:325-337.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Rodríguez-Vilarrupla A, Fernández M, Bosch J, García-Pagán JC. Current concepts on the pathophysiology of portal hypertension. Ann Hepatol. 2007;6:28-36.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Bosch J, García-Pagán JC. Complications of cirrhosis. I. Portal hypertension. J Hepatol. 2000;32:141-156.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Graupera M, García-Pagán JC, Titos E, Claria J, Massaguer A, Bosch J, Rodés J. 5-lipoxygenase inhibition reduces intrahepatic vascular resistance of cirrhotic rat livers: a possible role of cysteinyl-leukotrienes. Gastroenterology. 2002;122:387-393.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Graupera M, García-Pagán JC, Abraldes JG, Peralta C, Bragulat M, Corominola H, Bosch J, Rodés J. Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers. Hepatology. 2003;37:172-181.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Rockey DC, Weisiger RA. Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance. Hepatology. 1996;24:233-240.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Lautt WW, Greenway CV, Legare DJ. Effect of hepatic nerves, norepinephrine, angiotensin, and elevated central venous pressure on postsinusoidal resistance sites and intrahepatic pressures in cats. Microvasc Res. 1987;33:50-61.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Møller S, Gülberg V, Henriksen JH, Gerbes AL. Endothelin-1 and endothelin-3 in cirrhosis: relations to systemic and splanchnic haemodynamics. J Hepatol. 1995;23:135-144.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Gandhi CR, Sproat LA, Subbotin VM. Increased hepatic endothelin-1 levels and endothelin receptor density in cirrhotic rats. Life Sci. 1996;58:55-62.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Webb DJ, Monge JC, Rabelink TJ, Yanagisawa M. Endothelin: new discoveries and rapid progress in the clinic. Trends Pharmacol Sci. 1998;19:5-8.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Kojima H, Sakurai S, Kuriyama S, Yoshiji H, Imazu H, Uemura M, Nakatani Y, Yamao J, Fukui H. Endothelin-1 plays a major role in portal hypertension of biliary cirrhotic rats through endothelin receptor subtype B together with subtype A in vivo. J Hepatol. 2001;34:805-811.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Cho JJ, Hocher B, Herbst H, Jia JD, Ruehl M, Hahn EG, Riecken EO, Schuppan D. An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis. Gastroenterology. 2000;118:1169-1178.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Gupta TK, Toruner M, Chung MK, Groszmann RJ. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology. 1998;28:926-931.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Loureiro-Silva MR, Cadelina GW, Groszmann RJ. Deficit in nitric oxide production in cirrhotic rat livers is located in the sinusoidal and postsinusoidal areas. Am J Physiol Gastrointest Liver Physiol. 2003;284:G567-G574.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Rockey DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology. 1998;114:344-351.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Van de Casteele M, Omasta A, Janssens S, Roskams T, Desmet V, Nevens F, Fevery J. In vivo gene transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetised carbon tetrachloride cirrhotic rats. Gut. 2002;51:440-445.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Shah V, Toruner M, Haddad F, Cadelina G, Papapetropoulos A, Choo K, Sessa WC, Groszmann RJ. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology. 1999;117:1222-1228.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Mittal MK, Gupta TK, Lee FY, Sieber CC, Groszmann RJ. Nitric oxide modulates hepatic vascular tone in normal rat liver. Am J Physiol. 1994;267:G416-G422.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Morales-Ruiz M, Cejudo-Martín P, Fernández-Varo G, Tugues S, Ros J, Angeli P, Rivera F, Arroyo V, Rodés J, Sessa WC. Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats. Gastroenterology. 2003;125:522-531.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Laviña B, Gracia-Sancho J, Rodríguez-Vilarrupla A, Chu Y, Heistad DD, Bosch J, García-Pagán JC. Superoxide dismutase gene transfer reduces portal pressure in CCl4 cirrhotic rats with portal hypertension. Gut. 2009;58:118-125.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Lee FY, Colombato LA, Albillos A, Groszmann RJ. Administration of N omega-nitro-L-arginine ameliorates portal-systemic shunting in portal-hypertensive rats. Gastroenterology. 1993;105:1464-1470.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Sumanovski LT, Battegay E, Stumm M, van der Kooij M, Sieber CC. Increased angiogenesis in portal hypertensive rats: role of nitric oxide. Hepatology. 1999;29:1044-1049.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Fernandez M, Vizzutti F, Garcia-Pagan JC, Rodes J, Bosch J. Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology. 2004;126:886-894.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Fernandez M, Mejias M, Angermayr B, Garcia-Pagan JC, Rodés J, Bosch J. Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats. J Hepatol. 2005;43:98-103.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Angermayr B, Fernandez M, Mejias M, Gracia-Sancho J, Garcia-Pagan JC, Bosch J. NAD(P)H oxidase modulates angiogenesis and the development of portosystemic collaterals and splanchnic hyperaemia in portal hypertensive rats. Gut. 2007;56:560-564.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Fernandez M, Mejias M, Garcia-Pras E, Mendez R, Garcia-Pagan JC, Bosch J. Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats. Hepatology. 2007;46:1208-1217.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Mejias M, Garcia-Pras E, Tiani C, Miquel R, Bosch J, Fernandez M. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology. 2009;49:1245-1256.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Tsai MH. Splanchnic and systemic vasodilatation: the patient. J Clin Gastroenterol. 2007;41 Suppl 3:S266-S271.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Wiest R. Splanchnic and systemic vasodilation: the experimental models. J Clin Gastroenterol. 2007;41 Suppl 3:S272-S287.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Ginès P, Martin PY, Niederberger M. Prognostic significance of renal dysfunction in cirrhosis. Kidney Int Suppl. 1997;61:S77-S82.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Lockwood AH, Yap EW, Rhoades HM, Wong WH. Altered cerebral blood flow and glucose metabolism in patients with liver disease and minimal encephalopathy. J Cereb Blood Flow Metab. 1991;11:331-336.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Palma DT, Fallon MB. The hepatopulmonary syndrome. J Hepatol. 2006;45:617-625.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Vorobioff J, Bredfeldt JE, Groszmann RJ. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Am J Physiol. 1983;244:G52-G57.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Colombato LA, Albillos A, Groszmann RJ. Temporal relationship of peripheral vasodilatation, plasma volume expansion and the hyperdynamic circulatory state in portal-hypertensive rats. Hepatology. 1992;15:323-328.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Sikuler E, Kravetz D, Groszmann RJ. Evolution of portal hypertension and mechanisms involved in its maintenance in a rat model. Am J Physiol. 1985;248:G618-G625.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Abraldes JG, Pasarín M, García-Pagán JC. Animal models of portal hypertension. World J Gastroenterol. 2006;12:6577-6584.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Hennenberg M, Trebicka J, Sauerbruch T, Heller J. Mechanisms of extrahepatic vasodilation in portal hypertension. Gut. 2008;57:1300-1314.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Wiest R, Shah V, Sessa WC, Groszmann RJ. NO overproduction by eNOS precedes hyperdynamic splanchnic circulation in portal hypertensive rats. Am J Physiol. 1999;276:G1043-G1051.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide? Lancet. 1991;337:776-778.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Genesca J, Gonzalez A, Segura R, Catalan R, Marti R, Varela E, Cadelina G, Martinez M, Lopez-Talavera JC, Esteban R. Interleukin-6, nitric oxide, and the clinical and hemodynamic alterations of patients with liver cirrhosis. Am J Gastroenterol. 1999;94:169-177.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Hori N, Wiest R, Groszmann RJ. Enhanced release of nitric oxide in response to changes in flow and shear stress in the superior mesenteric arteries of portal hypertensive rats. Hepatology. 1998;28:1467-1473.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  García-Pagán JC, Fernández M, Bernadich C, Pizcueta P, Piqué JM, Bosch J, Rodés J. Effects of continued NO inhibition on portal hypertensive syndrome after portal vein stenosis in rat. Am J Physiol. 1994;267:G984-G990.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992;6:3051-3064.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Geller DA, Billiar TR. Molecular biology of nitric oxide synthases. Cancer Metastasis Rev. 1998;17:7-23.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Ignarro LJ, Byrns RE, Wood KS. Endothelium-dependent modulation of cGMP levels and intrinsic smooth muscle tone in isolated bovine intrapulmonary artery and vein. Circ Res. 1987;60:82-92.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Marsden PA, Heng HH, Scherer SW, Stewart RJ, Hall AV, Shi XM, Tsui LC, Schappert KT. Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. J Biol Chem. 1993;268:17478-17488.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Bredt DS, Hwang PM, Snyder SH. Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature. 1990;347:768-770.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Xie QW, Cho HJ, Calaycay J, Mumford RA, Swiderek KM, Lee TD, Ding A, Troso T, Nathan C. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science. 1992;256:225-228.  [PubMed]  [DOI]  [Cited in This Article: ]
56.  Weigert AL, Martin PY, Niederberger M, Higa EM, McMurtry IF, Gines P, Schrier RW. Endothelium-dependent vascular hyporesponsiveness without detection of nitric oxide synthase induction in aortas of cirrhotic rats. Hepatology. 1995;22:1856-1862.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Cahill PA, Redmond EM, Hodges R, Zhang S, Sitzmann JV. Increased endothelial nitric oxide synthase activity in the hyperemic vessels of portal hypertensive rats. J Hepatol. 1996;25:370-378.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  Jurzik L, Froh M, Straub RH, Schölmerich J, Wiest R. Up-regulation of nNOS and associated increase in nitrergic vasodilation in superior mesenteric arteries in pre-hepatic portal hypertension. J Hepatol. 2005;43:258-265.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Xu L, Carter EP, Ohara M, Martin PY, Rogachev B, Morris K, Cadnapaphornchai M, Knotek M, Schrier RW. Neuronal nitric oxide synthase and systemic vasodilation in rats with cirrhosis. Am J Physiol Renal Physiol. 2000;279:F1110-F1115.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol. 2003;284:R1-R12.  [PubMed]  [DOI]  [Cited in This Article: ]
61.  Fulton D, Gratton JP, Sessa WC. Post-translational control of endothelial nitric oxide synthase: why isn’t calcium/calmodulin enough? J Pharmacol Exp Ther. 2001;299:818-824.  [PubMed]  [DOI]  [Cited in This Article: ]
62.  Iwakiri Y, Tsai MH, McCabe TJ, Gratton JP, Fulton D, Groszmann RJ, Sessa WC. Phosphorylation of eNOS initiates excessive NO production in early phases of portal hypertension. Am J Physiol Heart Circ Physiol. 2002;282:H2084-H2090.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399:601-605.  [PubMed]  [DOI]  [Cited in This Article: ]
64.  Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999;399:597-601.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Michell BJ, Griffiths JE, Mitchelhill KI, Rodriguez-Crespo I, Tiganis T, Bozinovski S, de Montellano PR, Kemp BE, Pearson RB. The Akt kinase signals directly to endothelial nitric oxide synthase. Curr Biol. 1999;9:845-848.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Shah V, Wiest R, Garcia-Cardena G, Cadelina G, Groszmann RJ, Sessa WC. Hsp90 regulation of endothelial nitric oxide synthase contributes to vascular control in portal hypertension. Am J Physiol. 1999;277:G463-G468.  [PubMed]  [DOI]  [Cited in This Article: ]
67.  Wiest R, Das S, Cadelina G, Garcia-Tsao G, Milstien S, Groszmann RJ. Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility. J Clin Invest. 1999;104:1223-1233.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Wiest R, Cadelina G, Milstien S, McCuskey RS, Garcia-Tsao G, Groszmann RJ. Bacterial translocation up-regulates GTP-cyclohydrolase I in mesenteric vasculature of cirrhotic rats. Hepatology. 2003;38:1508-1515.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Fulton D, Babbitt R, Zoellner S, Fontana J, Acevedo L, McCabe TJ, Iwakiri Y, Sessa WC. Targeting of endothelial nitric-oxide synthase to the cytoplasmic face of the Golgi complex or plasma membrane regulates Akt- versus calcium-dependent mechanisms for nitric oxide release. J Biol Chem. 2004;279:30349-30357.  [PubMed]  [DOI]  [Cited in This Article: ]
70.  Erwin PA, Lin AJ, Golan DE, Michel T. Receptor-regulated dynamic S-nitrosylation of endothelial nitric-oxide synthase in vascular endothelial cells. J Biol Chem. 2005;280:19888-19894.  [PubMed]  [DOI]  [Cited in This Article: ]
71.  Erwin PA, Mitchell DA, Sartoretto J, Marletta MA, Michel T. Subcellular targeting and differential S-nitrosylation of endothelial nitric-oxide synthase. J Biol Chem. 2006;281:151-157.  [PubMed]  [DOI]  [Cited in This Article: ]
72.  Laleman W, Omasta A, Van de Casteele M, Zeegers M, Vander Elst I, Van Landeghem L, Severi T, van Pelt J, Roskams T, Fevery J. A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis. Hepatology. 2005;42:1382-1390.  [PubMed]  [DOI]  [Cited in This Article: ]
73.  Sessa WC. eNOS at a glance. J Cell Sci. 2004;117:2427-2429.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997;37:517-554.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  Suematsu M, Wakabayashi Y, Ishimura Y. Gaseous monoxides: a new class of microvascular regulator in the liver. Cardiovasc Res. 1996;32:679-686.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  De las Heras D, Fernández J, Ginès P, Cárdenas A, Ortega R, Navasa M, Barberá JA, Calahorra B, Guevara M, Bataller R. Increased carbon monoxide production in patients with cirrhosis with and without spontaneous bacterial peritonitis. Hepatology. 2003;38:452-459.  [PubMed]  [DOI]  [Cited in This Article: ]
77.  Wang R, Wu L, Wang Z. The direct effect of carbon monoxide on KCa channels in vascular smooth muscle cells. Pflugers Arch. 1997;434:285-291.  [PubMed]  [DOI]  [Cited in This Article: ]
78.  Fernandez M, Lambrecht RW, Bonkovsky HL. Increased heme oxygenase activity in splanchnic organs from portal hypertensive rats: role in modulating mesenteric vascular reactivity. J Hepatol. 2001;34:812-817.  [PubMed]  [DOI]  [Cited in This Article: ]
79.  Smith WL. The eicosanoids and their biochemical mechanisms of action. Biochem J. 1989;259:315-324.  [PubMed]  [DOI]  [Cited in This Article: ]
80.  Guarner C, Soriano G, Such J, Teixidó M, Ramis I, Bulbena O, Roselló J, Guarner F, Gelpi E, Balanzó J. Systemic prostacyclin in cirrhotic patients. Relationship with portal hypertension and changes after intestinal decontamination. Gastroenterology. 1992;102:303-309.  [PubMed]  [DOI]  [Cited in This Article: ]
81.  Sitzmann JV, Campbell K, Wu Y, St Clair C. Prostacyclin production in acute, chronic, and long-term experimental portal hypertension. Surgery. 1994;115:290-294.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Ebrahimkhani MR, Mani AR, Moore K. Hydrogen sulphide and the hyperdynamic circulation in cirrhosis: a hypothesis. Gut. 2005;54:1668-1671.  [PubMed]  [DOI]  [Cited in This Article: ]
83.  Cheng Y, Ndisang JF, Tang G, Cao K, Wang R. Hydrogen sulfide-induced relaxation of resistance mesenteric artery beds of rats. Am J Physiol Heart Circ Physiol. 2004;287:H2316-H2323.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Møller S, Bendtsen F, Henriksen JH. Vasoactive substances in the circulatory dysfunction of cirrhosis. Scand J Clin Lab Invest. 2001;61:421-429.  [PubMed]  [DOI]  [Cited in This Article: ]
85.  Silva G, Navasa M, Bosch J, Chesta J, Pilar Pizcueta M, Casamitjana R, Rivera F, Rodés J. Hemodynamic effects of glucagon in portal hypertension. Hepatology. 1990;11:668-673.  [PubMed]  [DOI]  [Cited in This Article: ]
86.  Pizcueta MP, García-Pagán JC, Fernández M, Casamitjana R, Bosch J, Rodés J. Glucagon hinders the effects of somatostatin on portal hypertension. A study in rats with partial portal vein ligation. Gastroenterology. 1991;101:1710-1715.  [PubMed]  [DOI]  [Cited in This Article: ]
87.  Moezi L, Gaskari SA, Liu H, Baik SK, Dehpour AR, Lee SS. Anandamide mediates hyperdynamic circulation in cirrhotic rats via CB(1) and VR(1) receptors. Br J Pharmacol. 2006;149:898-908.  [PubMed]  [DOI]  [Cited in This Article: ]
88.  Domenicali M, Ros J, Fernández-Varo G, Cejudo-Martín P, Crespo M, Morales-Ruiz M, Briones AM, Campistol JM, Arroyo V, Vila E. Increased anandamide induced relaxation in mesenteric arteries of cirrhotic rats: role of cannabinoid and vanilloid receptors. Gut. 2005;54:522-527.  [PubMed]  [DOI]  [Cited in This Article: ]
89.  Sakurai S, Kojima H, Uemura M, Satoh H, Fukui H. Local regulator adrenomedullin contributes to the circulatory disturbance in cirrhotic rats. World J Gastroenterol. 2006;12:2095-2102.  [PubMed]  [DOI]  [Cited in This Article: ]
90.  Genesca J, Gonzalez A, Catalan R, Segura R, Martinez M, Esteban R, Groszmann RJ, Guardia J. Adrenomedullin, a vasodilator peptide implicated in hemodynamic alterations of liver cirrhosis: relationship to nitric oxide. Dig Dis Sci. 1999;44:372-376.  [PubMed]  [DOI]  [Cited in This Article: ]
91.  Nishimatsu H, Suzuki E, Nagata D, Moriyama N, Satonaka H, Walsh K, Sata M, Kangawa K, Matsuo H, Goto A. Adrenomedullin induces endothelium-dependent vasorelaxation via the phosphatidylinositol 3-kinase/Akt-dependent pathway in rat aorta. Circ Res. 2001;89:63-70.  [PubMed]  [DOI]  [Cited in This Article: ]
92.  Scotland RS, Chauhan S, Vallance PJ, Ahluwalia A. An endothelium-derived hyperpolarizing factor-like factor moderates myogenic constriction of mesenteric resistance arteries in the absence of endothelial nitric oxide synthase-derived nitric oxide. Hypertension. 2001;38:833-839.  [PubMed]  [DOI]  [Cited in This Article: ]
93.  Bauersachs J, Popp R, Hecker M, Sauer E, Fleming I, Busse R. Nitric oxide attenuates the release of endothelium-derived hyperpolarizing factor. Circulation. 1996;94:3341-3347.  [PubMed]  [DOI]  [Cited in This Article: ]
94.  Warner L, Skorecki K, Blendis LM, Epstein M. Atrial natriuretic factor and liver disease. Hepatology. 1993;17:500-513.  [PubMed]  [DOI]  [Cited in This Article: ]
95.  Groszmann RJ, de Francis R. Portal Hypertension. Shiff’s Diseases of the Liver. Philadelphia: Loppincott Williams and Wilkins 1999; .  [PubMed]  [DOI]  [Cited in This Article: ]
96.  Barrière E, Tazi KA, Pessione F, Heller J, Poirel O, Lebrec D, Moreau R. Role of small-conductance Ca2+-dependent K+ channels in in vitro nitric oxide-mediated aortic hyporeactivity to alpha-adrenergic vasoconstriction in rats with cirrhosis. J Hepatol. 2001;35:350-357.  [PubMed]  [DOI]  [Cited in This Article: ]
97.  Atucha NM, Shah V, García-Cardeña G, Sessa WE, Groszmann RJ. Role of endothelium in the abnormal response of mesenteric vessels in rats with portal hypertension and liver cirrhosis. Gastroenterology. 1996;111:1627-1632.  [PubMed]  [DOI]  [Cited in This Article: ]
98.  Heinemann A, Wachter CH, Holzer P, Fickert P, Stauber RE. Nitric oxide-dependent and -independent vascular hyporeactivity in mesenteric arteries of portal hypertensive rats. Br J Pharmacol. 1997;121:1031-1037.  [PubMed]  [DOI]  [Cited in This Article: ]
99.  Sieber CC, Lopez-Talavera JC, Groszmann RJ. Role of nitric oxide in the in vitro splanchnic vascular hyporeactivity in ascitic cirrhotic rats. Gastroenterology. 1993;104:1750-1754.  [PubMed]  [DOI]  [Cited in This Article: ]
100.  Groszmann RJ, Abraldes JG. Portal hypertension: from bedside to bench. J Clin Gastroenterol. 2005;39:S125-S130.  [PubMed]  [DOI]  [Cited in This Article: ]
101.  Somlyo AP, Wu X, Walker LA, Somlyo AV. Pharmacomechanical coupling: the role of calcium, G-proteins, kinases and phosphatases. Rev Physiol Biochem Pharmacol. 1999;134:201-234.  [PubMed]  [DOI]  [Cited in This Article: ]
102.  Pfitzer G. Invited review: regulation of myosin phosphorylation in smooth muscle. J Appl Physiol. 2001;91:497-503.  [PubMed]  [DOI]  [Cited in This Article: ]
103.  Feil R, Lohmann SM, de Jonge H, Walter U, Hofmann F. Cyclic GMP-dependent protein kinases and the cardiovascular system: insights from genetically modified mice. Circ Res. 2003;93:907-916.  [PubMed]  [DOI]  [Cited in This Article: ]
104.  Hofmann F, Ammendola A, Schlossmann J. Rising behind NO: cGMP-dependent protein kinases. J Cell Sci. 2000;113:1671-1676.  [PubMed]  [DOI]  [Cited in This Article: ]
105.  Münzel T, Feil R, Mülsch A, Lohmann SM, Hofmann F, Walter U. Physiology and pathophysiology of vascular signaling controlled by guanosine 3’,5’-cyclic monophosphate-dependent protein kinase [corrected]. Circulation. 2003;108:2172-2183.  [PubMed]  [DOI]  [Cited in This Article: ]
106.  Sausbier M, Schubert R, Voigt V, Hirneiss C, Pfeifer A, Korth M, Kleppisch T, Ruth P, Hofmann F. Mechanisms of NO/cGMP-dependent vasorelaxation. Circ Res. 2000;87:825-830.  [PubMed]  [DOI]  [Cited in This Article: ]
107.  Neef M, Biecker E, Heller J, Schepke M, Nischalke HD, Wolff M, Spengler U, Reichen J, Sauerbruch T. Portal hypertension is associated with increased mRNA levels of vasopressor G-protein-coupled receptors in human hepatic arteries. Eur J Clin Invest. 2003;33:249-255.  [PubMed]  [DOI]  [Cited in This Article: ]
108.  Schepke M, Heller J, Paschke S, Thomas J, Wolff M, Neef M, Malago M, Molderings GJ, Spengler U, Sauerbruch T. Contractile hyporesponsiveness of hepatic arteries in humans with cirrhosis: evidence for a receptor-specific mechanism. Hepatology. 2001;34:884-888.  [PubMed]  [DOI]  [Cited in This Article: ]
109.  Lin HC, Yang YY, Huang YT, Lee TY, Hou MC, Lee FY, Lee SD. Vascular contractile response and signal transduction in endothelium-denuded aorta from cirrhotic rats. World J Gastroenterol. 2005;11:2306-2312.  [PubMed]  [DOI]  [Cited in This Article: ]
110.  Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997;389:990-994.  [PubMed]  [DOI]  [Cited in This Article: ]
111.  Hennenberg M, Trebicka J, Biecker E, Schepke M, Sauerbruch T, Heller J. Vascular dysfunction in human and rat cirrhosis: role of receptor-desensitizing and calcium-sensitizing proteins. Hepatology. 2007;45:495-506.  [PubMed]  [DOI]  [Cited in This Article: ]
112.  Ferguson SS. Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev. 2001;53:1-24.  [PubMed]  [DOI]  [Cited in This Article: ]
113.  Bünemann M, Hosey MM. G-protein coupled receptor kinases as modulators of G-protein signalling. J Physiol. 1999;517:5-23.  [PubMed]  [DOI]  [Cited in This Article: ]
114.  Henriksen JH, Ring-Larsen H. Hepatorenal disorders: role of the sympathetic nervous system. Semin Liver Dis. 1994;14:35-43.  [PubMed]  [DOI]  [Cited in This Article: ]
115.  Henriksen JH, Ring-Larsen H, Christensen NJ. Aspects of sympathetic nervous system regulation in patients with cirrhosis: a 10-year experience. Clin Physiol. 1991;11:293-306.  [PubMed]  [DOI]  [Cited in This Article: ]
116.  Wiest R, Jurzik L, Herold T, Straub RH, Schölmerich J. Role of NPY for vasoregulation in the splanchnic circulation during portal hypertension. Peptides. 2007;28:396-404.  [PubMed]  [DOI]  [Cited in This Article: ]
117.  Burnstock G, Gannon B, Iwayama T. Sympathetic innervation of vascular smooth muscle in normal and hypertensive animals. Circ Res. 1970;27 Suppl 2:5-23.  [PubMed]  [DOI]  [Cited in This Article: ]
118.  Toda N, Okamura T. The pharmacology of nitric oxide in the peripheral nervous system of blood vessels. Pharmacol Rev. 2003;55:271-324.  [PubMed]  [DOI]  [Cited in This Article: ]
119.  Piascik MT, Soltis EE, Piascik MM, Macmillan LB. Alpha-adrenoceptors and vascular regulation: molecular, pharmacologic and clinical correlates. Pharmacol Ther. 1996;72:215-241.  [PubMed]  [DOI]  [Cited in This Article: ]
120.  Kawasaki H, Takasaki K. Vasoconstrictor response induced by 5-hydroxytryptamine released from vascular adrenergic nerves by periarterial nerve stimulation. J Pharmacol Exp Ther. 1984;229:816-822.  [PubMed]  [DOI]  [Cited in This Article: ]
121.  Kawasaki H, Urabe M, Takasaki K. Enhanced 5-hydroxytryptamine release from vascular adrenergic nerves in spontaneously hypertensive rats. Hypertension. 1987;10:321-327.  [PubMed]  [DOI]  [Cited in This Article: ]
122.  Pablo Huidobro-Toro J, Verónica Donoso M. Sympathetic co-transmission: the coordinated action of ATP and noradrenaline and their modulation by neuropeptide Y in human vascular neuroeffector junctions. Eur J Pharmacol. 2004;500:27-35.  [PubMed]  [DOI]  [Cited in This Article: ]
123.  Nicholls KM, Shapiro MD, Van Putten VJ, Kluge R, Chung HM, Bichet DG, Schrier RW. Elevated plasma norepinephrine concentrations in decompensated cirrhosis. Association with increased secretion rates, normal clearance rates, and suppressibility by central blood volume expansion. Circ Res. 1985;56:457-461.  [PubMed]  [DOI]  [Cited in This Article: ]
124.  Henriksen JH, Ring-Larsen H, Kanstrup IL, Christensen NJ. Splanchnic and renal elimination and release of catecholamines in cirrhosis. Evidence of enhanced sympathetic nervous activity in patients with decompensated cirrhosis. Gut. 1984;25:1034-1043.  [PubMed]  [DOI]  [Cited in This Article: ]
125.  Henriksen JH, Ring-Larsen H, Christensen NJ. Kidney, lower limb and whole-body uptake and release of catecholamines in alcoholic liver disease. Clin Physiol. 1988;8:203-213.  [PubMed]  [DOI]  [Cited in This Article: ]
126.  Pozzi M, Grassi G, Pecci V, Turri C, Boari G, Bolla GB, Dell’Oro R, Massironi S, Roffi L, Mancia G. Early effects of total paracentesis and albumin infusion on muscle sympathetic nerve activity in cirrhotic patients with tense ascites. J Hepatol. 1999;30:95-100.  [PubMed]  [DOI]  [Cited in This Article: ]
127.  Pozzi M, Grassi G, Redaelli E, Dell’oro R, Ratti L, Redaelli A, Foglia G, Di Lelio A, Mancia G. Patterns of regional sympathetic nerve traffic in preascitic and ascitic cirrhosis. Hepatology. 2001;34:1113-1118.  [PubMed]  [DOI]  [Cited in This Article: ]
128.  Henriksen JH, Ring-Larsen H, Christensen NJ. Catecholamines in plasma from artery, cubital vein, and femoral vein in patients with cirrhosis. Significance of sampling site. Scand J Clin Lab Invest. 1986;46:39-44.  [PubMed]  [DOI]  [Cited in This Article: ]
129.  Coll M, Genescà J, Raurell I, Rodríguez-Vilarrupla A, Mejías M, Otero T, Oria M, Esteban R, Guardia J, Bosch J. Down-regulation of genes related to the adrenergic system may contribute to splanchnic vasodilation in rat portal hypertension. J Hepatol. 2008;49:43-51.  [PubMed]  [DOI]  [Cited in This Article: ]
130.  Coll M, Martell M, Raurell I, Ezkurdia N, Cuenca S, Hernández-Losa J, Esteban R, Guardia J, Bosch J, Genescà J. Atrophy of mesenteric sympathetic innervation may contribute to splanchnic vasodilation in rat portal hypertension. Liver Int. 2010;30:593-602.  [PubMed]  [DOI]  [Cited in This Article: ]
131.  Duvoux C, Zanditenas D, Hézode C, Chauvat A, Monin JL, Roudot-Thoraval F, Mallat A, Dhumeaux D. Effects of noradrenalin and albumin in patients with type I hepatorenal syndrome: a pilot study. Hepatology. 2002;36:374-380.  [PubMed]  [DOI]  [Cited in This Article: ]
132.  Wong F, Pantea L, Sniderman K. Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology. 2004;40:55-64.  [PubMed]  [DOI]  [Cited in This Article: ]
133.  Joh T, Granger DN, Benoit JN. Endogenous vasoconstrictor tone in intestine of normal and portal hypertensive rats. Am J Physiol. 1993;264:H171-H177.  [PubMed]  [DOI]  [Cited in This Article: ]
134.  Gibbins IL, Jobling P, Morris JL. Functional organization of peripheral vasomotor pathways. Acta Physiol Scand. 2003;177:237-245.  [PubMed]  [DOI]  [Cited in This Article: ]
135.  Holzer P. Peptidergic sensory neurons in the control of vascular functions: mechanisms and significance in the cutaneous and splanchnic vascular beds. Rev Physiol Biochem Pharmacol. 1992;121:49-146.  [PubMed]  [DOI]  [Cited in This Article: ]
136.  Stein RD, Genovesi S, Demarest KT, Weaver LC. Capsaicin treatment attenuates the reflex excitation of sympathetic activity caused by chemical stimulation of intestinal afferent nerves. Brain Res. 1986;397:145-151.  [PubMed]  [DOI]  [Cited in This Article: ]
137.  Keef KD, Kreulen DL. Venous mechanoreceptor input to neurones in the inferior mesenteric ganglion of the guinea-pig. J Physiol. 1986;377:49-59.  [PubMed]  [DOI]  [Cited in This Article: ]
138.  Lee SS, Sharkey KA. Capsaicin treatment blocks development of hyperkinetic circulation in portal hypertensive and cirrhotic rats. Am J Physiol. 1993;264:G868-G873.  [PubMed]  [DOI]  [Cited in This Article: ]
139.  Li Y, Song D, Zhang Y, Lee SS. Effect of neonatal capsaicin treatment on haemodynamics and renal function in cirrhotic rats. Gut. 2003;52:293-299.  [PubMed]  [DOI]  [Cited in This Article: ]
140.  Song D, Sharkey KA, Breitman DR, Zhang Y, Lee SS. Disordered central cardiovascular regulation in portal hypertensive and cirrhotic rats. Am J Physiol Gastrointest Liver Physiol. 2001;280:G420-G430.  [PubMed]  [DOI]  [Cited in This Article: ]
141.  Song D, Liu H, Sharkey KA, Lee SS. Hyperdynamic circulation in portal-hypertensive rats is dependent on central c-fos gene expression. Hepatology. 2002;35:159-166.  [PubMed]  [DOI]  [Cited in This Article: ]
142.  Rubino A, Burnstock G. Capsaicin-sensitive sensory-motor neurotransmission in the peripheral control of cardiovascular function. Cardiovasc Res. 1996;31:467-479.  [PubMed]  [DOI]  [Cited in This Article: ]
143.  Kawasaki H, Takasaki K, Saito A, Goto K. Calcitonin gene-related peptide acts as a novel vasodilator neurotransmitter in mesenteric resistance vessels of the rat. Nature. 1988;335:164-167.  [PubMed]  [DOI]  [Cited in This Article: ]
144.  Bendtsen F, Schifter S, Henriksen JH. Increased circulating calcitonin gene-related peptide (CGRP) in cirrhosis. J Hepatol. 1991;12:118-123.  [PubMed]  [DOI]  [Cited in This Article: ]
145.  Fernández-Rodriguez CM, Prieto J, Quiroga J, Zozoya JM, Andrade A, Núñez M, Sangro B, Penas J. Plasma levels of substance P in liver cirrhosis: relationship to the activation of vasopressor systems and urinary sodium excretion. Hepatology. 1995;21:35-40.  [PubMed]  [DOI]  [Cited in This Article: ]
146.  Kwon SY, Groszmann RJ, Iwakiri Y. Increased neuronal nitric oxide synthase interaction with soluble guanylate cyclase contributes to the splanchnic arterial vasodilation in portal hypertensive rats. Hepatol Res. 2007;37:58-67.  [PubMed]  [DOI]  [Cited in This Article: ]
147.  Hatanaka Y, Hobara N, Honghua J, Akiyama S, Nawa H, Kobayashi Y, Takayama F, Gomita Y, Kawasaki H. Neuronal nitric-oxide synthase inhibition facilitates adrenergic neurotransmission in rat mesenteric resistance arteries. J Pharmacol Exp Ther. 2006;316:490-497.  [PubMed]  [DOI]  [Cited in This Article: ]