adrenomedullin and Ascites

Plasma levels of adrenomedullin, a potent vasodilator peptide, are increased in cirrhotic patients, whereas its role in vascular hyporeactivity in cirrhosis has not been clarified.. Adrenomedullin expression was evaluated by radioimmunoassay and reverse-transcription polymerase chain reaction. Vascular reactivity to phenylephrine, alpha-adrenoceptor agonist, was investigated in the aortic rings from control rats and CCl-induced cirrhotic rats with ascites in the presence of the neutralizing antibody against adrenomedullin, human adrenomedullin and/or N-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor.. Plasma adrenomedullin levels were significantly higher in cirrhotic rats than in controls (16.3 +/- 2.9 versus 7.4 +/- 1.7 fmol/mL, P < 0.05) and correlated negatively with systemic arterial pressure (r = -0.62, P < 0.05). Gene expression of adrenomedullin in various organs (liver, kidney, lung) and vessels (portal vein, aorta) was enhanced in cirrhotic rats compared with controls. Neutralizing antibody against adrenomedullin ameliorated the blunted contractile response to phenylephrine in cirrhotic aorta (Rmax: 1.5 +/- 0.1 versus 1.0 +/- 0.1 g/mg tissue, P < 0.05), whereas contraction remained unchanged in control aorta (Rmax: 1.9 +/- 0.2 versus 1.9 +/- 0.2 g/mg tissue). Intravenous infusion of human adrenomedullin induced a reduction of mean arterial pressure together with an increase of serum nitrate levels, which was abolished by neutralizing antibody against adrenomedullin. Human adrenomedullin caused a blunted contractile response to phenylephrine in both control and cirrhotic aortas, which was not observed in the presence of N-nitro-L-arginine methyl ester.. These findings indicate that the overproduction of adrenomedullin may contribute to vascular hyporeactivity in cirrhosis via a release of nitric oxide.

Topics: Adrenergic alpha-Agonists; Adrenomedullin; Animals; Aorta, Thoracic; Ascites; Kidney; Liver; Liver Cirrhosis; Lung; Male; Nitric Oxide; Peptides; Phenylephrine; Rats; Rats, Sprague-Dawley; RNA, Messenger; Vasodilation

This prospective cohort study was aimed at investigating the role of adrenomedullin, a potent vasodilator peptide, in liver cirrhosis and its relationship with nitric oxide and cytokines. Overall, 66 consecutive patients with liver cirrhosis and 15 controls matched for age and sex distribution were included. Adrenomedullin levels in patients with cirrhosis were higher than in controls [28.1 (23.5-34.8) vs 21.9 (21.1-26.4) pmol/liter, P = 0.002]. Child class A patients had adrenomedullin levels similar to those of controls, but lower than patients in class B and C, respectively (P = 0.01). Patients with ascites showed more elevated adrenomedullin levels than patients without (P = 0.001). Adrenomedullin levels had significant correlations with aldosterone (r = 0.55; P < 0.001), plasma renin activity (r = 0.49; P < 0.001) and nitrates-nitrites levels (r = 0.52; P < 0.001). Weak correlations were found with tumor necrosis factor-alpha and interleukin-6. This study shows that high levels of adrenomedullin in liver cirrhosis correlate with features associated with plasma volume expansion, and suggests that, in late stages of cirrhosis, adrenomedullin might contribute to vasodilatation by increasing the generation of nitric oxide.

Topics: Adrenomedullin; Aged; Ascites; Cohort Studies; Female; Hemodynamics; Humans; Interleukin-6; Liver Cirrhosis; Male; Middle Aged; Nitric Oxide; Peptides; Prospective Studies; Tumor Necrosis Factor-alpha; Vasodilator Agents

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.. 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.. 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.. 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.

Topics: Adrenomedullin; Ascites; Biomarkers; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney; Liver Cirrhosis; Male; Middle Aged; Peptides; Renal Insufficiency; Vasoconstriction

Adrenomedullin recently discovered in human pheochromocytoma is a potent vasodilatory peptide mainly derived from vascular endothelial and smooth muscle cells. Hyperdynamic circulation, ultimately leading to ascites formation, has been attributed to peripheral vasodilatation in liver cirrhosis. However, little is known about the role of adrenomedullin in this condition.. Plasma adrenomedullin concentrations were measured by radioimmunoassay after extraction and purification in 28 cirrhotic patients without ascites, 12 cirrhotic patients with ascites and 10 healthy subjects.. Plasma adrenomedullin concentrations in cirrhotic patients with ascites (12.7+/-4.5 fmol/ml) were significantly higher than those in cirrhotic patients without ascites (8.2+/-2.3 fmol/ml, p<0.005) and healthy subjects (5.8+/-0.8 fmol/ml, p<0.005). Interestingly, plasma adrenomedullin concentrations were highest in patients with refractory ascites (n=5, 15.8+/-3.0 fmol/ml) and were positively correlated with the Child-Pugh score (r=0.44, p<0.01). Moreover, plasma adrenomedullin concentrations were positively correlated with plasma renin activity (r=0.63, p<0.0001), plasma aldosterone (r=0.60, p<0.0001) and plasma norepinephrine concentrations (r=0.60, p<0.0001), and negatively correlated with creatinine clearance (r=-0.61, p<0.0005) and urinary sodium excretion (r=-0.44, p<0.02). Stepwise multiple regression analysis using certain independent variables, including Pugh's score, vasoactive substances, renal function and hemodynamic parameters, showed that the adjusted R square was highest when plasma renin activity and creatinine clearance (standard coefficient=0.53, -0.49, respectively) were considered (adjusted R square=0.61, p<0.0001).. Plasma adrenomedullin concentrations increased with the progression of liver cirrhosis and were highest in cirrhotic patients with refractory ascites. In addition, elevated adrenomedullin was associated with activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, and with functional renal impairment in cirrhosis. Considering the potent vasodilatory action of adrenomedullin, increased adrenomedullin may participate in the hyperdynamic circulation, ultimately leading to ascites formation, in patients with liver cirrhosis.

Topics: Adrenomedullin; Aged; Ascites; Bilirubin; Biomarkers; Blood Pressure; Creatinine; Female; Heart Rate; Humans; Liver Cirrhosis; Male; Middle Aged; Norepinephrine; Peptides; Radioimmunoassay; Reference Values; Regression Analysis; Renin; Severity of Illness Index; Vascular Resistance

The role of adrenomedullin in cirrhosis is at present unknown. The aim of this study was to investigate plasma levels of adrenomedullin in cirrhosis.. We measured plasma adrenomedullin concentrations using radioimmunoassay in 43 patients with cirrhosis (17 in Child-Pugh's class A, 13 in Child-Pugh's class B, and 13 in Child-Pugh's class C) and compared these values with those in 24 age-matched healthy subjects. Renal function, plasma cyclic adenosine monophosphate (cAMP) concentration, plasma renin activity, and plasma aldosterone concentration were measured in each patient.. Plasma adrenomedullin levels were increased significantly in patients with cirrhosis compared with healthy subjects. In addition, plasma adrenomedullin values were higher in patients with cirrhosis and ascites than in those without ascites. Moreover, plasma adrenomedullin levels increased in relation to the severity of cirrhosis. Significant positive correlations also were found between adrenomedullin and cAMP concentrations and plasma renin activity or plasma aldosterone concentrations.. Plasma adrenomedullin is increased in patients with cirrhosis compared with healthy subjects. The increase in plasma adrenomedullin levels is related at least in part to the severity of cirrhosis and may contribute to the arteriolar vasodilation in patients with cirrhosis. These effects are related in part to a cAMP-dependent pathway.

Topics: Adrenomedullin; Adult; Aged; Aldosterone; Ascites; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Peptides; Radioimmunoassay; Renin; Serum Albumin