Vasodilation In Cirrhosis Research Articles

English

BACKGROUND The increased propensity for acute kidney injury (AKI) in patients with cirrhosis stems from haemodynamic abnormalities typical for patients with cirrhosis and ascites. 15 which is due to development of portal hypertension and portosystemic collaterals with splanchnic and systemic vasodilatation, resulting in decrease in effective arterial blood volume with increase in renin angiotensin-aldosterone system (RAAS), sympathetic nervous system and non-osmotic release of antidiuretic hormone causing sodium retention, increased intravascular volume, and a hyperdynamic circulatory state, 16 complemented with increased production of nitric oxide which is considered the main cause of vasodilatation in cirrhosis. Mechanism of renal dysfunction in cirrhosis includes portal hypertension & its accompanying haemodynamic abnormalities15 leading to increased synthesis of endogenous vasodilatory compounds such as nitric oxide leading to vasodilatation in splanchnic & systemic arterial systems ultimately leading to activation of reninangiotensinogen–aldosterone system causing compensatory renal vasoconstriction & hypo-perfusion resulting into renal failure. We wanted to study the clinical profile of patients with AKI who presented to a tertiary care hospital in Bangalore. METHODS Ninety-four patients of either gender admitted in the department of gastroenterology at a tertiary care hospital with age > 18 years with either diagnosed or newly diagnosed case of cirrhosis of liver (including both compensated & decompensated cases) admitted with acute kidney injury diagnosed according to International Club of Ascites Classification were enrolled in this study. The sample size was based on number of eligible patients admitted to tertiary care hospital during the study period. Details of the study were explained to them and consent was taken either from the patient or their attender. RESULTS Most patients were in the age group > 60 yrs. with 32 male patients (45.07 %) in the age group of 40 - 60 years & 13 female patients (56.52 %) in the age group of > 60 yrs. 78.7 % of patients developed AKI before hospital admission i.e., at community level; whereas 21.3 % of patients developed AKI after hospital admission i.e., they had normal creatinine level on admission. CONCLUSIONS Pre renal AKI was the most common cause of AKI followed by hepatorenal syndrome & acute tubular necrosis (ATN) comprising 52.1 %, 28.7 % & 19.1 % respectively. KEYWORDS AKI, Cirrhosis, ATN

Blockade of Mas Receptor or Mas-Related G-Protein Coupled Receptor Type D Reduces Portal Pressure in Cirrhotic but Not in Non-cirrhotic Portal Hypertensive Rats.

Portal hypertension (PHT) resulting from splanchnic vasodilatation is a major cause of morbidity and mortality in patients with cirrhosis. The renin-angiotensin system (RAS) plays an important role in splanchnic vasodilatation in cirrhosis. This study investigated whether acute blockade of the vasodilatory receptors of the alternate RAS, Mas (MasR), Mas-related G-protein coupled receptor type D (MrgD), and angiotensin II type-2 receptor (AT2R) improves PHT in cirrhotic and non-cirrhotic portal hypertensive rats and counteracts systemic hypotension associated with angiotensin II type 1 receptor (AT1R) blockade. Cirrhotic bile duct ligated (BDL) or carbon tetrachloride (CCl4) injected and non-cirrhotic partial portal vein ligated (PPVL) rats were used for measurement of portal pressure (PP) and mean arterial pressure before and after an intravenous bolus injection of the MasR, MrgD, and AT2R blockers, A779, D-Pro7-Ang-(1-7) (D-Pro) and PD123319, respectively. Separate groups of rats received a combined treatment with A779 or D-Pro given 20 min after AT1R blocker losartan. Mesenteric expression of MasR, MrgD, and AT2R and circulating levels of peptide blockers were also measured. Treatment with A779 and D-Pro significantly reduced PP in cirrhotic rat models. Despite rapid degradation of A779 and D-Pro in the rat circulation, the PP lowering effect of the blockers lasted for up to 25 min. We also found that PD123319 reduced PP in CCl4 rats, possibly by blocking the MasR and/or MrgD since AT2R expression in cirrhotic mesenteric vessels was undetectable, whereas the expression of MasR and MrgD was markedly elevated. While losartan resulted in a marked reduction in PP, its profound systemic hypotensive effect was not counteracted by the combination therapy with A779 or D-Pro. In marked contrast, none of the receptor blockers had any effect on PP in non-cirrhotic PPVL rats whose mesenteric expression of MasR and MrgD was unchanged. We conclude that in addition to MasR, MrgD, a newly discovered receptor for Angiotensin-(1-7), plays a key role in splanchnic vasodilatation in cirrhosis. This implies that both MasR and MrgD are potential therapeutic targets to treat PHT in cirrhotic patients. We also conclude that the alternate RAS may not contribute to the development of splanchnic vasodilatation in non-cirrhotic PHT.

New therapeutic paradigm and concepts for patients with cirrhotic refractory ascites

The activation of renin-angiotensin-aldosterone-vasopressin system is a key factor in the formation of ascites due to splanchnic vasodilation in cirrhosis. In theory, aldosterone antagonists, contraction of blood vessels, vasopressin V2 receptor, and angiotensin receptor antagonists are important targets for the prevention and treatment of cirrhotic ascites. The 15%-20% of patients with cirrhotic ascites that show no response to at least one week's treatment with potent diuretics (spironolactone 160 mg/d combined with furosemide 80 mg/d) are considered to have refractory ascites. At present, effective treatments for refractory ascites include tolvaptan, large-volume paracentesis (4000-6000 ml/time/day) combined with albumin (4 g/L ascites), ascites ultrafiltration and reinfusion, transjugular intrahepatic portosystemic shunt, and liver transplantation. In the future, with the development of vasoactive drugs, rifaximin, ascites drainage pump, and other new therapies, the treatment of refractory ascites may be more effective to reduce the need for liver transplantation.

Hormones and hemodynamics in pregnancy.

Context:Normal pregnancy is associated with sodium and water retention, which results in plasma volume expansion prior to placental implantation. The explanation offered for these events is that pregnancy ‘resets’ both volume and osmoreceptors.Evidence Acquisition:The mechanisms for such an enigmatic ‘resetting’ in pregnancy have not previously been explained. However, recent human pregnancy studies have demonstrated that the earliest hemodynamic change in pregnancy is primary systemic arterial vasodilation. This arterial underfilling is associated with a secondary increase in cardiac output and activation of the neurohumoral axis, including stimulation of the renin-angiotensin-aldosterone, sympathetic, and non-osmotic vasopressin systems. Resistance to the pressor effects of angiotensin and sympathetic stimulation in pregnancy is compatible with an increase in endothelial nitric oxide synthase activity.Results:In contrast to the sodium and water retention which occur secondary to the primary arterial vasodilation in cirrhosis, glomerular filtration and renal blood flow are significantly increased in normal pregnancy. A possible explanation for this difference in arterial vasodilation states is that relaxin, an arterial vasodilator which increases during pregnancy, has a potent effect on both systemic and renal circulation. Endothelial damage in pregnancy is pivotal in the pathogenesis of preeclampsia in pregnancy.Conclusions:Against a background of the primary arterial vasodilation hypothesis, it is obvious that reversal of the systemic vasodilatation in pregnancy, without subsequent activation of the renin-angiotensin-aldosterone system (78), will evoke a reversal of all the links in the chain of events in normal pregnancy adaptation, thus, it may cause preeclampsia. Namely, a decrease of renal vasodilation will decrease glomerular filtration rate.

Activation of the Mas Receptor by Angiotensin-(1–7) in the Renin–Angiotensin System Mediates Mesenteric Vasodilatation in Cirrhosis

Splanchnic vascular hypocontractility with subsequent increased portal venous inflow leads to portal hypertension. Although the renin-angiotensin system contributes to fibrogenesis and increased hepatic resistance in patients with cirrhosis, little is known about its effects in the splanchnic vasculature, particularly those of the alternate system in which angiotensin (Ang) II is cleaved by the Ang-converting enzyme-2 (ACE2) to Ang-(1-7), which activates the G-protein-coupled Mas receptor (MasR). We investigated whether this system contributes to splanchnic vasodilatation and portal hypertension in cirrhosis. We measured levels of renin-angiotensin system messenger RNA and proteins in splanchnic vessels from patients and rats with cirrhosis. Production of Ang-(1-7) and splanchnic vascular reactivity to Ang-(1-7) was measured in perfused mesenteric vascular beds from rats after bile-duct ligation. Ang-(1-7) and MasR were blocked in rats with cirrhosis to examine splanchnic vascular hemodynamics and portal pressure response. Levels of ACE2 and MasR were increased in splanchnic vessels from cirrhotic patients and rats compared with healthy controls. We also observed an ACE2-dependent increase in Ang-(1-7) production. Ang-(1-7) mediated splanchnic vascular hypocontractility in ex vivo splanchnic vessels from rats with cirrhosis (but not control rats) via MasR stimulation. Identical effects were observed in the splanchnic circulation in vivo. MasR blockade reduced portal pressure, indicating that activation of this receptor in splanchnic vasculature promotes portal inflow to contribute to development of portal hypertension. In addition, the splanchnic effects of MasR required nitric oxide. Interestingly, Ang-(1-7) also decreased hepatic resistance. In the splanchnic vessels of patients and rats with cirrhosis, increased levels of ACE2 appear to increase production of Ang-(1-7), which leads to activation of MasR and splanchnic vasodilatation in rats. This mechanism could cause vascular hypocontractility in patients with cirrhosis, and might be a therapeutic target for portal hypertension.

Sodium Retention in Heart Failure and Cirrhosis

Patients with cirrhosis and heart failure (HF) share the pathophysiology of decreased effective arterial blood volume because of splanchnic vasodilatation in cirrhosis and decreased cardiac output in HF, with resultant stimulation of the renin-angiotensin-aldosterone system. Hyperaldosteronism plays a major role in the pathogenesis of ascites and contributes to resistance to loop diuretics. Therefore, the use of high doses of aldosterone antagonist (spironolactone up to 400 mg/day) is the main therapy to produce a negative sodium balance in cirrhotic patients with ascites. Hyperaldosteronism also has increasingly been recognized as a risk factor for myocardial and vascular fibrosis. Therefore, low-dose aldosterone antagonists are being used in patients with HF for cardioprotective action. However, the doses (25 to 50 mg/day) at which they are being used in cardiac patients as reported in the Randomized Aldactone Evaluation Study are not natriuretic. It is likely, therefore, that the mortality benefit relates primarily from their effect on cardiac and vascular fibrosis. Resistance to commonly used loop diuretics is frequently present in patients with advanced HF. In patients with decompensated HF with volume overload who are loop diuretic resistant, ultrafiltration may be the only available option. This is, however, an invasive procedure. For these patients, natriuretic doses of aldosterone antagonists (spironolactone >50 mg/day) may be a potential option. The competitive natriuretic response of aldosterone antagonists is related to activity of the renin-angiotensin-aldosterone system: the higher the renin-angiotensin-aldosterone system activity, the higher the dose of aldosterone antagonist required to produce natriuresis. This article will discuss the potential use of natriuretic doses of aldosterone antagonists in patients with HF, including the potential side effect of hyperkalemia.

Hemodynamic effects of substance P and its receptor antagonist RP67580 in anesthetized rats with carbon tetrachloride-induced cirrhosis

Objective. Substance P (SP) is a vasodilator that may contribute to systemic and splanchnic vasodilatation in cirrhosis. The aim of this study was to determine the effects of SP (dose –13 pg/kg) and its specific inhibitor, RP67580 (dose – 300 µg/kg) on mean arterial pressure (MAP) and portal pressure (PP) in cirrhotic rats and controls. Material and methods. MAP and PP were measured before and after administering SP and RP67580. Additionally, a small group of cirrhotic rats were pretreated with L-NAME to block the effects of nitric oxide (NO) before measurements. Results. SP produced transient systemic hypotension in both groups. SP caused a significant increase in PP in cirrhotic rats and a decrease in PP in controls. RP67580 reduced the hypotensive effect of SP, but not completely. RP67580 decreased PP in the cirrhotic group but not in controls. In cirrhotic rats pretreated with L-NAME, SP administration caused a significant decrease in MAP but no significant change in PP. Conclusions. Exogenous SP increases PP and decreases MAP in cirrhotic rats. RP687580 decreases PP and reduces SP-induced hypotension in cirrhotic rats. NO blockade abolishes the effect of SP on PP. SP contributes to splanchnic vasodilatation in cirrhosis and this effect may be mediated by NO.

Role of Ca2+‐dependent potassium channels in in vitro anandamide‐mediated mesenteric vasorelaxation in rats with biliary cirrhosis

Anandamide can activate potassium (K(+)) channels to induce an endothelium-dependent vasorelaxation in normal rat mesenteric arteries. Cannabinoids contribute partly to the splanchnic vasodilation in cirrhosis. This study investigated the roles of vascular K(+) channels in anandamide-induced mesenteric vasorelaxation in isolated rat cirrhotic vessels. The effects of the pretreatment of AM251, a specific CB(1) receptor antagonist, were assessed on the vascular reactivity to phenylephrine (PE), potassium chloride (KCl), acetylcholine (ACh) and sodium nitroprusside (SNP). Additionally, cannabinoid (CB(1) and CB(2)) receptors' protein expression and the effects of different K(+) channel blockers on vascular reactivity to anandamide were also studied. Cirrhotic mesenteric arteries showed an overexpression of CB(1) receptor associated with hyporeactivity to PE and KCl, and hyper-response to ACh, SNP and anandamide. Pretreatment with AM251 significantly improved the hyporeactivity to KCl and ameliorated the hyper-response to ACh in cirrhotic vessels. Increased relaxation response to anandamide was suppressed by combinations of vascular Ca(2+)-dependent K(+) channel blockers (including apamin+charybdotoxin+iberiotoxin or apamin+TRAM-34+iberiotoxin) (TRAM-34, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole). In cirrhotic mesenteric arteries, vascular CB(1) receptor and anandamide contribute to the in vitro hyporeactivity to KCl. In addition, hyper-response to ACh may probably act through the modulation of vascular Ca(2+)-dependent K(+) channels.

Nitric oxide is a mediator of the adenosine-induced vasodilatation of the hepatic artery in CCl4-cirrhotic rats

Background and aim: In normal livers, hepatic arterial vasodilatation produced by adenosine is mediated by the adenosine receptor A2a and this response is nitric oxide independent. It has been shown that muscle hypoxia leads to an increase in tissue adenosine and vasodilatation. This effect is modulated by the A1 receptor and mediated by nitric oxide. Additionally, we have previously reported that hepatic arterial vasodilatation in cirrhosis is mediated by nitric oxide. The aim of this study was to evaluate the role of adenosine in hepatic arterial vasodilatation in cirrhosis and its relationship to nitric oxide if any.

Roles of anandamide in the hepatic microcirculation in cirrhotic rats

Cannabinoids have been reported to participate in the pathogenesis of peripheral vasodilatation in cirrhosis. However, their roles in increased intrahepatic resistance (IHR) in cirrhotic livers are unknown. We aimed to investigate the effects of cannabinoids in the hepatic microcirculation of cirrhotic rats produced by bile duct ligation. In isolated liver perfusion, portal perfusion pressure (PPP) and the production of eicosanoids in the perfusate were measured. In addition, various hepatic protein levels [cyclooxygenase (COX) isoform and 5-lipoxygenase (5-LOX)] were also determined. Finally, concentration-response curves for PPP and the corresponding production of eicosanoids in response to anandamide (1.44 x 10(-10)-1.44 x 10(-3) M) after indomethacin (COX inhibitor), piriprost (5-LOX inhibitor), or furegrelate (thromboxane A(2) synthase inhibitor) preincubation were obtained. The study showed that cirrhotic livers had significantly higher levels of PPP, COX-2 and 5-LOX protein expression, and production of thromboxane B(2) (TXB(2)) and cysteinyl leukotrienes (Cys-LTs) than normal livers. Anandamide induced a dose-dependent increase in PPP in both normal and cirrhotic livers. The anandamide-induced increase in PPP was found concomitantly with a significant increase in TXB(2) and Cys-LT production in the perfusate. In response to anandamide administration, cirrhotic livers exhibited a significantly greater increase in IHR and production of TXB(2) and Cys-LTs than normal livers. Indomethacin and furegrelate, but not piriprost, significantly ameliorated the anandamide-induced increase in IHR in cirrhotic livers. In conclusion, anandamide plays, in part, an important role in increased IHR of cirrhotic livers. The anandamide-induced increase in IHR in cirrhotic livers may be mediated by increased COX-derived eicosanoid (mainly thromboxane A(2)) production.

Cirrhotic cardiomyopathy: an endocannabinoid connection?

British Journal of Pharmacology (2005) 146, 313–314. doi:10.1038/sj.bjp.0706332

Vasoconstrictor responses are normal but prostanoid‐mediated vasodilatation is enhanced in human cirrhotic mesenteric arteries

The mechanisms responsible for mesenteric vasodilatation in cirrhosis have not been fully elucidated. The aim of the present study was to examine whether there is altered intrinsic vascular reactivity of human mesenteric vessels in cirrhosis, which might contribute to vasodilatation in vivo. Ten mesenteric arteries from six cirrhosis patients undergoing liver transplantation were compared with 11 arteries from six control patients. Vasoconstrictor responses to potassium, norepinephrine and methoxamine were determined. Endothelium-dependent vasodilatation responses to acetylcholine and substance P were determined both before and after inhibition of nitric oxide (NO) and prostanoid synthesis. Cirrhotic vessels responded normally to potassium depolarization and did not differ to control vessels with respect to sensitivity and maximal response to norepinephrine. In cirrhotic vessels, inhibition of NO synthesis had significantly less effect on substance P-induced vasorelaxation than in controls (% Relaxation: cirrhosis 70.3 +/- 9.6; control 34.9 +/- 9.5; P = 0.03). However, after inhibition of both NO and prostanoid synthesis, vasodilatory responses were eliminated in both groups. The findings of the present study indicate that intrinsic hyporesponsiveness to vasoconstrictors does not play a pathogenetic role in the mesenteric vasodilatation in human cirrhosis. Furthermore, vasodilator prostanoids might make a significant contribution in mediating enhanced endothelium-dependent vasorelaxation in the mesenteric circulation.

Nitric oxide and the hyperdynamic circulation in cirrhosis: is there a role for selective intestinal decontamination?

Abnormal vascular tone is responsible for many of the complications seen in cirrhosis making the identification of the pathophysiology of abnormal dilatation a major focus in hepatology research. The study of abnormal vascular tone is complicated by the multiple vascular beds involved (hepatic, splanchnic, peripheral, renal and pulmonary), the differences in the underlying cause of portal hypertension (hepatic versus pre-hepatic) and the slow evolution of the hyperdynamic state. The autonomic nervous system, circulating vasodilators and abnormalities in vascular smooth muscle cells (receptors, ion channels, signalling systems and contraction) have all been implicated. There is overwhelming evidence for an overproduction of NO (nitric oxide) contributing to the peripheral dilatation in both animal models of, and in humans with, cirrhosis and portal hypertension. This review focuses on the proposal that endotoxaemia, possibly from gut-derived bacterial translocation, causes induction of NOS (NO synthase) leading to increased vascular NO production, which is the primary stimulus for the development of vasodilatation in cirrhosis and its accompanying clinical manifestations. The current controversy lies not in whether NO production is elevated, but in which isoform of NOS is responsible. We review the evidence for endotoxaemia in cirrhosis and the factors contributing to gut-derived bacterial translocation, including intestinal motility and permeability, and finally discuss the possible role of selective intestinal decontamination in the management of circulatory abnormalities in cirrhosis.

Increased vascular heme oxygenase-1 expression contributes to arterial vasodilation in experimental cirrhosis in rats.

Vascular heme oxygenase (HO) regulates vascular tone in normal conditions and in some pathologic circumstances (e.g., sepsis). However, its possible role in the pathogenesis of arterial vasodilation in cirrhosis is unknown. To address this question, the expression and activity of HO in arterial vessels was studied in rats at 1, 2, and 4 weeks after bile duct ligation (BDL) or sham operation. A progressively increased expression of HO-1 was found in aorta and mesenteric arteries of BDL rats in a close chronologic relationship with the progression from acute cholestatic liver injury (1 week) to the fully developed cirrhosis with intense systemic arterial vasodilation (4 weeks). No changes were found in the expression of the constitutive isoform HO-2. HO-1 was mainly located in vascular smooth muscle cells of the arterial wall. Aortic HO activity increased in parallel with the expression of HO-1 (up to 600% in rats with cirrhosis compared with sham rats) and correlated with hemodynamic parameters. Increased expression of HO-1 and HO activity were also found in other organs, such as liver and spleen, though to a lesser extent compared with vascular tissue. The acute administration of an inhibitor of HO to cirrhotic rats, at a dose that normalized aortic HO activity, was associated with significantly greater effects on arterial pressure, total peripheral vascular resistance, and cardiac index, compared with effects in sham rats. In conclusion, these findings are consistent with a role for HO in the pathogenesis of arterial vasodilation in cirrhosis.

Plasma erythropoietin level in patients with cirrhosis and its relationship to the severity of cirrhosis and renal function.

The level of plasma erythropoietin (EPO) in patients with cirrhosis is controversial. It is known that overproduction of nitric oxide (NO) plays, in part, a role for the development of peripheral arterial vasodilatation in cirrhosis with portal hypertension. It has also been hypothesized that a possible interaction is noted between endogenous EPO and NO production. The current study was undertaken to evaluate the relationship between plasma EPO levels and the severity of liver disease, hemodynamic values, renal functions, and plasma nitrate/nitrite levels in patients with cirrhosis. The authors measured the biochemistry, plasma EPO and nitrate/nitrite levels in 67 patients with cirrhosis (Child-Pugh class A in 23 and Child-Pugh class B and C in 44) and compared their values with those in 34 healthy subjects. Systemic and splanchnic hemodynamic measurements and effective renal plasma flow were obtained from cirrhotic patients. Plasma EPO and nitrate/nitrite levels were significantly increased in patients with cirrhosis compared with healthy subjects. Additionally, plasma EPO values were higher in cirrhotic patients with ascites or with anemia than in those without ascites or without anemia, respectively. Plasma EPO levels were positively correlated to the hepatic venous pressure gradient (HVPG) and Child-Pugh score, negatively correlated to the renal and hepatic blood flows, but were not correlated to nitrate/nitrite level and systemic vascular resistance in cirrhotic patients. Multiple regression analysis showed that HVPG and renal plasma flow were independent predictors for the elevated EPO level in cirrhotic patients. Plasma EPO levels were increased in patients with cirrhosis compared with those in healthy subjects. The increase in plasma EPO levels is related to the degree of portal hypertension, the severity of cirrhosis and the renal plasma flow. In contrast, the EPO levels had no correlation to the nitrate/nitrite levels and systemic vascular resistance in patients with cirrhosis.

Sodium in preascitic cirrhosis: please pass the salt

See article on page 847 The relationship between sodium retention, hyperactivity of the neurohumoral vasoactive systems, and ascites formation in cirrhosis is intriguing and still remains a subject of interest...

Relationship of asymmetric dimethylarginine to dialysis treatment and atherosclerotic disease

The pathogenesis of renal sodium and water retention in cirrhosis involves extrarenal mechanisms because when kidneys from cirrhotic patients are transplanted into persons with normal livers, renal sodium and water retention no longer occurs. Cirrhosis is accompanied by portal hypertension, which leads to a hyperdynamic circulatory state. The Peripheral Arterial Vasodilation Hypothesis incriminates a relative underfilling of the arterial vascular compartment, which leads to the same neurohumoral responses that occurs in low cardiac output. Activation of the renain-angiotensin-aldosterone axis and the sympathetic system as well as non-osmotic release of vasopressin are well documented in cirrhosis. This sequence of events results in renal water and sodium retention, failure to escape from the sodium-retaining effect of aldosterone, and renal resistance to atrial natriuretic peptide. Dilutional hyponatremia is the strongest predictor of the occurrence of hepatorenal syndrome. The pathogenesis of the peripheral arterial vasodilation is not completely elucidated, but there is evidence for a major role of nitric oxide (NO). Increased vascular NO production has been demonstrated in cirrhosis. In the rat model of cirrhosis, normalization of vascular NO production with a NOS inhibitor corrects the hyperdynamic circulation, improves sodium and water excretion, and decreases neurohumoral activation. This insight into the mechanism(s) of the peripheral arterial vasodilation in cirrhosis should provide new tools in the treatment of edema and ascites, a major cause of morbidity and mortality in cirrhosis.

Update on peripheral arterial vasodilation, ascites and hepatorenal syndrome in cirrhosis.

In cirrhosis of the liver, according to the peripheral arterial vasodilation hypothesis, relative underfilling of the arterial tree triggers a neurohumoral response (activation of renin-angiotensin-aldosterone system, sympathetic nervous system, nonosmotic release of vasopressin) aimed at restoring circulatory integrity by promoting renal sodium and water retention. Evidence has accumulated for a major role of increased vascular production of nitric oxide as the primary cause of arterial vasodilation in cirrhosis. Ascites is a common complication in cirrhosis. Treatment of ascites consists of a low salt diet with diuretics, and paracentesis together with plasma volume expanders in diuretic-resistant patients. Progression of cirrhosis may result in hepatorenal syndrome, a state of functional renal failure that carries an ominous prognosis. Orthotopic liver transplantation has remained the only curative treatment for patients with advanced liver disease; other modalities such as transjugular intrahepatic portosystemic shunt or vasopressin analogues may serve as a bridge to transplantation. Another complication of decompensated cirrhosis is spontaneous bacterial peritonitis, the incidence of which can be reduced by primary or secondary antibiotic prophylaxis by using orally active antibiotics.

Increased adrenomedullin levels in cirrhosis: Relationship with hemodynamic abnormalities and vasoconstrictor systems

Background & Aims: Arterial vasodilation in cirrhosis may be related to increased circulating levels of vasodilators. This study was designed to assess the circulating levels of adrenomedullin, a recently described vasodilator peptide, in cirrhosis. Methods: Plasma adrenomedullin levels were measured in 17 healthy subjects and 34 cirrhotic patients. Hemodynamic parameters, renal function, and levels of vasoactive substances were also assessed. Results: Patients with ascites had increased adrenomedullin levels (289 ± 47 pg/mL) compared with healthy subjects and patients without ascites (135 ± 17 and 142 ± 32 pg/mL, respectively; P < 0.05). Adrenomedullin levels correlated inversely with arterial pressure, glomerular filtration rate, and renal plasma flow and correlated directly with pulse rate, endothelin levels, and aldosterone and plasma renin activity. In cirrhotic patients, no significant differences in adrenomedullin levels were found between samples obtained from hepatic vein, renal vein, pulmonary artery, and femoral artery. Plasma expansion with albumin suppressed the renin-angiotensin system but did not affect adrenomedullin levels. Conclusions: Circulating levels of adrenomedullin are increased in patients with ascites and correlate with hemodynamic and renal abnormalities and activation of vasoconstrictor systems. These increased levels seem to result from a generalized increase in adrenomedullin production from vascular tissue and are not suppressed by plasma expansion. Adrenomedullin may participate in the pathogenesis of arterial vasodilation in cirrhosis. GASTROENTEROLOGY 1998;114:336-343

Time Course-dependent Evolution of Nitric Oxide-mediated Arterial Hyporeactivity to Phenylephrine in Rats with Ligated Bile Duct

Background: Nitric oxide (NO) may be heavily involved the phenomenon of arterial vasodilation in cirrhosis. However, the subject is still controversial. Aim: This study therefore characterizes the dynamic role of the NO system during development of experimental cirrhosis. Methods: The contractile response to phenylephrine of thoracic rat aortic rings was studied in vitro before and after nitric oxide blockade. Experiments were performed 1, 2, 3, and 4 weeks after induction of cirrhosis via bile duct ligation with an appropriate control group. Results