Arterial Vasodilation In Cirrhosis Research Articles

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.

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.

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

Increased nitric oxide synthase expression in arterial vessels of cirrhotic rats with ascites

Arterial vasodilatation is thought to play a major role in the pathogenesis of systemic hemodynamics and renal disturbances occurring in cirrhotic patients. Recent investigations suggest that an increased vascular nitric oxide (NO) production could be implicated in this abnormality. The current study assessed whether increased expression of inducible and/or endothelial nitric oxide synthase (iNOS and eNOS, respectively) occurs in arterial vessels of cirrhotic rats. The investigation was performed in thoracic and abdominal aortas and mesenteric arteries of 10 control rats and 16 cirrhotic rats with ascites. iNOS and eNOS messenger RNA (mRNA) expression were evaluated by polymerase chain reaction and ribonuclease protection assay, respectively. Endothelial NOS protein expression was assessed by Western blot. No iNOS mRNA was detected in arterial vessels of control rats. In contrast iNOS mRNA was consistently detected in all arteries of cirrhotic rats with ascites, the weakest signal being observed in the thoracic aorta and the strongest in the mesenteric artery. Enhanced eNOS mRNA abundance was found in the aorta of cirrhotic animals as compared with controls. Higher eNOS protein expression was noted in the thoracic aorta of cirrhotic rats. These results indicate the existence of increased eNOS and iNOS expression in arterial vessels of cirrhotic rats, suggesting that transcriptional activation of vascular NOSs and the associated nitric oxide hyperproduction may be of major importance in the pathogenesis of arterial vasodilation in cirrhosis.

Increased nitric oxide synthase expression in arterial vessels of cirrhotic rats with ascites

Arterial vasodilatation is thought to play a major role in the pathogenesis of systemic hemodynamics and renal disturbances occurring in cirrhotic patients. Recent investigations suggest that an increased vascular nitric oxide (NO) production could be implicated in this abnormality. The current study assessed whether increased expression of inducible and/or endothelial nitric oxide synthase (iNOS and eNOS, respectively) occurs in arterial vessels of cirrhotic rats. The investigation was performed in thoracic and abdominal aortas and mesenteric arteries of 10 control rats and 16 cirrhotic rats with ascites. iNOS and eNOS messenger RNA (mRNA) expression were evaluated by polymerase chain reaction and ribonuclease protection assay, respectively. Endothelial NOS protein expression was assessed by Western blot. No iNOS mRNA was detected in arterial vessels of control rats. In contrast iNOS mRNA was consistently detected in all arteries of cirrhotic rats with ascites, the weakest signal being observed in the thoracic aorta and the strongest in the mesenteric artery. Enhanced eNOS mRNA abundance was found in the aorta of cirrhotic animals as compared with controls. Higher eNOS protein expression was noted in the thoracic aorta of cirrhotic rats. These results indicate the existence of increased eNOS and iNOS expression in arterial vessels of cirrhotic rats, suggesting that transcriptional activation of vascular NOSs and the associated nitric oxide hyperproduction may be of major importance in the pathogenesis of arterial vasodilation in cirrhosis. (Hepatology 1996 Dec;24(6):1481-6)

Upregulation of endothelial constitutive NOS: a major role in the increased NO production in cirrhotic rats.

Nitric oxide (NO) is postulated to mediate the peripheral arterial vasodilation in cirrhosis. However, it is not known which isoform of the nitric oxide synthase (NOS) is involved in the increased production of NO. This study was therefore undertaken to examine the expression of the NOS isoforms in arteries of cirrhotic rats compared with controls. Cirrhosis was induced by CCl4, and vessels were harvested for immunoblots using antibodies against inducible NOS (iNOS) and endothelial constitutive NOS (ecNOS). Endothelial cells were used as controls for ecNOS, and vascular smooth muscle cells treated with lipopolysaccharide or septic rats were used for iNOS controls. The results demonstrated an upregulation of ecNOS in both the aortas and mesenteric arteries of cirrhotic compared with control rats. Chronic inhibition of NOS decreased ecNOS in cirrhotic vessels. Although iNOS mRNA was found by reverse transcription-polymerase chain reaction in arteries of cirrhotic rats, iNOS protein was not detectable by immunoblotting compared with septic rats, suggesting a low vascular level of this isoform. In conclusion, the ecNOS seems to play a major role in the increased NO production in cirrhotic rats, whereas the role of iNOS remains elusive.

Increased aortic cyclic guanosine monophosphate concentration in experimental cirrhosis in rats: Evidence for a role of nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis

Arterial vasodilation is considered to be the key factor in the development of sodium and water retention leading to ascites formation in cirrhosis. To determine if nitric oxide (NO) is involved in the pathogenesis of arterial vasodilation in cirrhosis, we measured the concentration of cyclic guanosine monophosphate (cGMP), the second messenger of NO, in arterial tissue from rats with carbon tetrachloride-induced cirrhosis. Aortic cGMP concentration was markedly increased in cirrhotic rats, particularly in those with ascites (ascites, 826 ± 70; no ascites, 597 ± 48; controls, 331 ± 25 fmol/mg, ANOVA F = 23.1, P < .0001), and correlated inversely with arterial pressure (r = −.56, P < .0001) and systemic vascular resistance ( r = −.69, P = .014) and directly with cardiac index ( r = .74, P < .01). The chronic administration of the NO synthesis inhibitor N G- nitro- l- arginine- methylester ( l-NAME) (10 mg/kg/day for 7 days) induced a marked reduction in aortic cGMP concentration in cirrhotic rats with ascites to similar values obtained in l-NAME-treated control rats (86 ± 14 vs. 89 ± 8 fmol/mg, respectively, NS), indicating that the high-aortic cGMP content in cirrhotic rats was caused by an increased NO synthesis. Mean arterial pressure after l-NAME treatment increased to similar values in both groups of animals. These results suggest that in cirrhosis there is an increased vascular production of NO that may play a role in the pathogenesis of arterial vasodilation.

Increased aortic cyclic guanosine monophosphate concentration in experimental cirrhosis in rats: Evidence for a role of nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis

Arterial vasodilation is considered to be the key factor in the development of sodium and water retention leading to ascites formation in cirrhosis. To determine if nitric oxide (NO) is involved in the pathogenesis of arterial vasodilation in cirrhosis, we measured the concentration of cyclic guanosine monophosphate (cGMP), the second messenger of NO, in arterial tissue from rats with carbon tetrachloride-induced cirrhosis. Aortic cGMP concentration was markedly increased in cirrhotic rats, particularly in those with ascites (ascites, 826 +/- 70; no ascites, 597 +/- 48; controls, 331 +/- 25 fmol/mg, ANOVA F = 23.1, P < .0001), and correlated inversely with arterial pressure (r = -.56, P < .0001) and systemic vascular resistance (r = -.69, P = .014) and directly with cardiac index (r = .74, P < .01). The chronic administration of the NO synthesis inhibitor NG-nitro-L-arginine-methyl-ester (L-NAME) (10 mg/kg/day for 7 days) induced a marked reduction in aortic cGMP concentration in cirrhotic rats with ascites to similar values obtained in L-NAME-treated control rats (86 +/- 14 vs. 89 +/- 8 fmol/mg, respectively, NS), indicating that the high-aortic cGMP content in cirrhotic rats was caused by an increased NO synthesis. Mean arterial pressure after L-NAME treatment increased to similar values in both groups of animals. These results suggest that in cirrhosis there is an increased vascular production of NO that may play a role in the pathogenesis of arterial vasodilation.

Nitric oxide production in arterial vessels of cirrhotic rats

Indirect evidence exists implicating vascular nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis. In the current study, a coincubation assay to estimate the vascular nitric oxide production was developed and the nitric oxide production by arterial segments of cirrhotic and control rats was assessed. In the assay, measurement of reporter monolayer cell-associated cGMP levels allows the influence of nitric oxide released by arterial segments to be determined. RFL-6 cells served as reporter cells. Nitric oxide production was determined in thoracic aorta and mesenteric arteries of 22 control rats, 10 cirrhotic rats without ascites, and 12 cirrhotic rats with ascites. Basal and bradykinin-stimulated (10(-6) mol/L) intracellular content of nitric oxide-dependent cGMP was significantly higher in RFL-6 cells coincubated with aortic segments of cirrhotic rats with (21.3 +/- 3.6 pmol/10(5) cells, P < .05 and 44.7 +/- 7.0 pmol/10(5) cells, P < .025) and without ascites (15.3 +/- 3.0 pmol/10(5) cells, P < .05 and 43.2 +/- 7.6 pmol/10(5) cells, P < .05) than in those incubated with aortic segments of control rats (9.7 +/- 1.3 and 19.5 +/- 2.5 pmol/10(5) cells). RFL-6 cells exposed to bradykinin-stimulated mesenteric arterial segments of cirrhotic rats also showed increased cGMP content (ascitic: 2.73 +/- 0.31 pmol/10(5) cells, P < .005; nonascitic: 2.58 +/- 0.51 pmol/10(5) cells, P < .025) compared with cells exposed to control mesenteric arterial segments (1.28 +/- 0.15 pmol/10(5) cells). No differences between cirrhotic and control vessels were observed after endothelium denudation.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitric oxide production in arterial vessels of cirrhotic rats

Indirect evidence exists implicating vascular nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis. In the current study, a coincubation assay to estimate the vascular nitric oxide production was developed and the nitric oxide production by arterial segments of cirrhotic and control rats was assessed. In the assay, measurement of reporter monolayer cell-associated cGMP levels allows the influence of nitric oxide released by arterial segments to be determined. RFL-6 cells served as reporter cells. Nitric oxide production was determined in thoracic aorta and mesenteric arteries of 22 control rats, 10 cirrhotic rats without ascites, and 12 cirrhotic rats with ascites. Basal and bradykinin-stimulated (10 −6 mol/L) intracellular content of nitric oxide-dependent cGMP was significantly higher in RFL-6 cells coincubated with aortic segments of cirrhotic rats with (21.3 ± 3.6 pmol/10 5 cells, P < .05 and 44.7 ± 7.0 pmol/10 5cells, P < .025) and without ascites (15.3 ± 3.0 pmol/10 5cells, P < .05 and 43.2 ± 7.6 pmol/10 5cells, P < .05) than in those incubated with aortic segments of control rats (9.7 ±1.3 and 19.5 ± 2.5 pmol/10 5cells). RFL-6 cells exposed to bradykinin-stimulated mesenteric arterial segments of cirrhotic rats also showed increased cGMP content (ascitic: 2.73 ± 0.31 pmol/10 5cells, P < .005; nonascitic: 2.58 ± 0.51 pmol/10 5cells, P < .025) compared with cells exposed to control mesenteric arterial segments (1.28 ± 0.15 pmol/10 5cells). No differences between cirrhotic and control vessels were observed after endothelium denudation. These results indicate that basal and bradykinin-stimulated vascular nitric oxide production is higher in cirrhotic rats with and without ascites than in control rats in and that the endothelial lining is the site where vascular L-arginine nitric oxide pathway activation takes place in experimental cirrhosis.

Increased aortic c-GMP concentration in experimental cirrhosis in rats. Evidence for a role of nitric oxide (NO) in the pathogenesis of arterial vasodilation in cirrhosis

Increased aortic c-GMP concentration in experimental cirrhosis in rats. Evidence for a role of nitric oxide (NO) in the pathogenesis of arterial vasodilation in cirrhosis

Abnormal sympathetic and renal response to sodium restriction in compensated cirrhosis

It has been proposed that in liver cirrhosis portal hypertension causes splanchnic vasodilation and this induces blood volume expansion to maintain blood pressure. The current study was designed to explore the homeostatic response to sodium restriction, a maneuver aiming to contract blood volume, in compensated cirrhosis. Mean blood pressure, sympathetic nervous activity, and proximal sodium reabsorption were evaluated in 16 healthy control and 21 nonazotemic cirrhotic patients (11 without ascites and 10 with ascites) under two experimental conditions: after 4 days on a free sodium diet (basal condition) and after 4 days on a restricted sodium diet (40 mmol/day). No differences were observed in basal conditions in the above parameters between control and cirrhotic patients without ascites. However, cirrhotic patients with ascites showed lower basal values of mean blood pressure and higher basal levels of both plasma norepinephrine and fractional proximal sodium reabsorption than controls. Neither control nor cirrhotic patients with ascites showed significant changes in the measured parameters after sodium restriction. In contrast, in nonascitic patients, this maneuver induced an elevation in plasma norepinephrine concentration (164.4 ± 24.6 vs. 270.1 ± 24.9 pg/mL; mean ± SEM; P < 0.005) and in fractional proximal sodium reabsorption (86.4 ± 2.1 vs. 91.8% ± 0.5%; P < 0.01). In addition, the nonascitic cirrhotic patients became hypotensive compared with controls (80.9 ± 1.6 vs. 88.5 ± 4.8 mm Hg; P < 0.05) when subjected to the low-sodium diet. In patients without ascites, under conditions of sodium restriction, the decrease in mean arterial pressure correlated inversely with the increase in plasma norepinephrine concentration (r = −0.713; P < 0.05), whereas the levels of plasma norepinephrine correlated directly with fractional proximal sodium reabsorption (r = 0.893; P < 0.01). These findings suggest that ineffective circulatory volume is detected in nonascitic cirrhotic patients only under conditions of sodium restriction, but it is always present in cirrhotic patients with ascites, irrespectively of the amount of sodium in the diet. These results are compatible with the existence of fixed arterial vasodilation in cirrhosis.