angiotensinogen and Liver-Cirrhosis

The renin-angiotensin system is an important regulator of vascular resistance in many patients with hypertension and congestive heart failure. To quantitatively evaluate this contribution requires correlation of markers of the renin-angiotensin system with haemodynamic parameters, notably blood pressure, cardiac output, and calculated systemic vascular resistance. In addition, to determine ventricular loading properties, assessment of cardiac filling pressures is also required. The availability of specific pharmacological inhibitors of the renin-angiotensin system greatly enhances such correlation, as the haemodynamic consequence of blocking the renin-angiotensin system can then more fully identify its contribution. In the last decade, highly specific pharmacological inhibitors have become available to serve such a purpose. Renin inhibitory peptides, and renin-specific antibodies can block the rate-limiting step of the renin-angiotensin cascade: namely, the cleavage of 4 amino acids from the angiotensinogen substrate by renin. However, this method of blockade is still at the early stages of investigation. More readily available are converting enzyme inhibitors which block the formation of angiotensin II, the potent vasoconstrictor which mediates increased systemic vascular resistance, and angiotensin II analogues which compete with endogenous angiotensin II for vascular and adrenal receptors. Although hypertension and chronic congestive heart failure are clinically distinct entities in many respects, their common bond is the fact that both pathological mechanisms are mediated by an increase of systemic vascular resistance. The implications of blocking the resulting vasoconstriction in both entities are therefore quite similar. This review summarises our present knowledge of the contribution of the renin-angiotensin system to the vasoconstriction of hypertension and congestive heart failure, and also summarises the haemodynamic consequences of such inhibition. The implications of the response to these specific pharmacological probes, as well as their limitations, are discussed. Their importance rests not only in their therapeutic application, but also in their contribution as probes for pathophysiological mechanisms of vasoconstriction in cardiovascular disease.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Captopril; Dipeptides; Enalapril; Heart Failure; Hemodynamics; Humans; Hypertension; Hypertension, Pulmonary; Kinetics; Liver Cirrhosis; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Renin; Renin-Angiotensin System; Teprotide

The aim of this work was to establish a potential correlation between specific polymorphisms and presence of hepatic fibrosis in Mexican patients with established liver fibrosis (ELF). Second, necroinflammatory index improvement was correlated with Pirfenidone (PFD) treatment response and the same polymorphisms.. We analyzed TGF-beta polymorphisms in codon 25, a single basepair guanine insertion-deletion polymorphism (4G/5G) for PAI-1 and angiotensin AT-6 single nucleotide polymorphism located in -6 promoter region. Twenty patients infected with either hepatitis C virus (HCV) (n = 13) or affected by alcohol consumption (n= 7) were included. Thirty subjects with no hepatic damage were included in control group. Blood samples for genomic DNA were obtained and plasminogen activator inhibitor-1 polymorphisms were done by polymerase chain reaction-artificial introduction of a restriction site, TGF-beta by polymerase chain reaction-amplification refractory mutation system and AT by polymerase chain reaction-restriction fragment length polymorphisms. Liver biopsies were obtained at baseline and after 12 months of PFD treatment.. Established liver fibrosis patients had the homozygote G/G TGF-beta genotype, which has been associated with increased development of fibrosis. None of our patients had the G/C genotype. All pure HCV and pure alcohol abuse subjects carried G/G TGF-beta genotype (100% vs 37% control) (P = 0.0006). The odds of having TGF-beta G/G genotype was 19.5 for HCV patients and 10.83 for alcohol consumption patients as compared with healthy subjects (P < 0.001). Established liver fibrosis patients had an improvement in necroinflammatory index after PFD treatment when correlated with plasminogen activator inhibitor-1 and angiotensinogen-6 genotypes.. Our data suggested that a combination of inherited polymorphisms increased the risk of advanced fibrosis in ELF patients. Pure HCV and pure alcohol consumption patients which were homozygous G/G carriers had 19.5- and 10.8-fold higher risk to develop advanced fibrosis respectively.

Topics: Adult; Aged; Angiotensinogen; Anti-Inflammatory Agents, Non-Steroidal; Base Sequence; DNA Primers; Female; Hepatitis C; Humans; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Mexico; Middle Aged; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic; Pyridones; Transforming Growth Factor beta

Decompensated liver cirrhosis is characterized by activation of the renin-angiotensin-aldosterone system (RAAS). We investigated whether compartmentalization of these components occurs in ascitic fluid.. In 26 patients with cirrhosis RAAS components and albumin were quantified in simultaneously obtained plasma and ascitic fluid samples. Renin degradation was determined in vitro in plasma and ascites.. Plasma angiotensinogen was below normal reference values in all but two patients and correlated inversely with plasma renin (r = -0.73, P < 0.001). Plasma renin activity was elevated in most subjects. The plasma and ascites concentrations of renin, prorenin, angiotensinogen and aldosterone were closely (P < 0.001) correlated. Expressed as a percentage of plasma levels, the angiotensinogen level (18 +/- 11%) was slightly lower than the albumin level (23 +/- 8%), whereas the aldosterone level (43 +/- 18%) was considerably higher (P < 0.0001). For renin and prorenin these percentages were much lower (P < 0.0001), despite the fact that their molecular weight is lower than that of albumin and angiotensinogen. This was not due to a more rapid degradation of renin in ascites fluid, since the in-vitro degradation rates of renin in plasma and ascitic fluid were identical.. In hepatic cirrhosis ascites can be regarded as an ultrafiltrate of plasma RAAS components. Since differences in molecular weight or metabolic rate cannot explain the low ascites-to-plasma ratio of renin and prorenin, either their transcapillary transport is impaired and/or they selectively bind to (pro)renin binding sites.

Topics: Aged; Aldosterone; Angiotensinogen; Angiotensins; Ascites; Ascitic Fluid; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Plasma; Renin; Renin-Angiotensin System

It is known that the renin-angiotensin system (RAS) regulates fibrosis. Polymorphisms in the genes of the RAS may contribute to the outcome of liver cirrhosis. Angiotensinogen (AGT), mainly produced in the liver, is the substrate of renin. The aim of this study was to determine whether polymorphisms in the promoter region of the AGT gene are associated with liver cirrhosis in patients with chronic hepatitis B.. Restriction fragment length polymorphism PCR was used to study polymorphisms in the promoter region of the AGT gene in patients with liver cirrhosis and in a control population. Four polymorphisms were assayed: G-217A, G-152A, A-20C and A-6G.. A statistically significant relationship was seen between polymorphisms of the AGT core promoter region and liver cirrhosis in patients with chronic hepatitis B (A-20C, P = 0.007; A-6G, P = 0.042). However, the distributions of the AGT-217 and AGT-152 genotypes were not significantly different from the control population (P = 0.615 and P = 0.170, respectively).. Polymorphisms of the core promoter region of the AGT gene (AGT-20 and AGT-6) were associated with liver cirrhosis in patients with chronic hepatitis B.

Topics: Alleles; Angiotensinogen; Genetic Predisposition to Disease; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Polymorphism, Genetic; Promoter Regions, Genetic

Topics: Adult; Angiotensinogen; DNA Mutational Analysis; Female; Genome; Humans; Liver Cirrhosis; Male; Middle Aged; Mutation; Promoter Regions, Genetic

To investigate the expression of local angiotensinogen mRNA and activation of local nuclear factor-kappaB in vasculopathy of portal hypertension and to discuss their role in the pathogenesis of portal hypertensive vasculopathy.. RT-PCR was used to detect the expression of local angiotensinogen mRNA in 28 specimens of splenic artery and vein obtained during operation of elective separation and amputation on 28 portal hypertension (PH) patients, 20 males and 8 females, aged 51.7 +/- 10 (30 - 65), and in 12 specimens of normal vessel from 12 patients undergoing splenectomy due to traumatic rupture of spleen. Chemiluminescent electrophoretic mobility shift assay (EMSA) was used to detect the activation of NF-kappaB in splenic artery and vein.. The levels of local angiotensinogen mRNA in the splenic artery and vein of PH group were 0.48 +/- 0.21 and 0.43 +/- 0.16 respectively, both significantly higher than those in the control group (0.23 +/- 0.12 and 0.18 +/- 0.10, both P < 0.05). There was no significant difference between the splenic artery and vein in the expression of local angiotensinogen mRNA in PH group. The activation levels of NF-kappaB in splenic artery and vein of the PH patients were 1.44 +/- 0.23 and 1.38 +/- 0.18 respectively, both significantly higher than those of the control group (0.19 +/- 0.20 and 0.25 +/- 0.16 respectively, both P < 0.05). However, there was no significant difference in the activation levels of NF-kappaB between the splenic artery and vein in the PH patients (P > 0.05).. Local angiotensinogen and activation of NF-kappaB maybe one of the factors in the pathogenesis of portal hypertensive vasculopathy, which can cause and advance portal hypertensive vasculopathy.

Topics: Adult; Aged; Angiotensinogen; Female; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; NF-kappa B; RNA, Messenger; Splenic Artery; Splenic Vein

Angiotensin II contributes to the post-glomerular arteriolar vasoconstriction which maintains the glomerular filtration rate (GFR) in renal hypoperfusion. To explore whether depressed angiotensin II generation, due to reduced angiotensinogen production or low angiotensin-converting enzyme (ACE) levels, could impair kidney function in advanced cirrhosis.. We studied and prospectively followed up 21 diuretic-free ascitic cirrhotic patients, through these determinations: plasma levels of active renin (AR), renin activity (PRA), angiotensin II, ACE and aldosterone; renal clearances of sodium, inulin and para-aminohippurate; antipyrine clearance. Fifteen healthy subjects were also studied.. GFR distribution was bimodal, 10 patients had low GFR values (l-GFR group) and 11 had normal-GFR values (n-GFR group) (below and above 105 ml/min per 1.73 m(2) body surface area). Antipyrine clearance and Child-Pugh score did not differ in the two patient groups. l-GFR group had higher AR and PRA values, lower ACE levels and a significantly higher AR/Angiotensin II ratio than n-GFR group (all P<0.01). All 21 patients showed increased values of the AR/PRA ratio, i.e. subnormal angiotensinogen levels (P<0.03). The 18-month survival rates of l-GFR and n-GFR groups were 20 and 81% (P<0.02).. Low-GFR cirrhotic patients had a worse survival rate associated with more severe contraction of the effective arterial blood volume, higher AR/Angiotensin II ratio and lower ACE levels.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin II; Angiotensinogen; Blood Volume; Case-Control Studies; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney; Liver; Liver Cirrhosis; Male; Middle Aged; Peptidyl-Dipeptidase A; Prospective Studies; Renal Circulation; Renin; Survival Analysis

To investigate the expression of local renin and angiotensinogen mRNA in cirrhotic portal hypertensive patients.. The expression of local renin and angiotensinogen mRNA in the liver, splenic artery and vein of PH patients was detected by RT-PCR analysis.. Expression of local renin mRNA in the liver of control group was (0.19+/-0.11), significantly lower than that in splenic artery (0.45+/-0.17) or splenic vein(0.39+/-0.12) respectively, (P<0.05). Expression of local angiotensinogen mRNA in the liver was (0.64+/-0.21), significantly higher than that in splenic artery(0.41+/-0.15) or in splenic vein (0.35+/-0.18) respectively, (P<0.05). Expression of local renin mRNA in the liver, splenic artery and vein of PH group was (0.78+/-0.28), (0.86+/-0.35) and (0.81+/-0.22) respectively, significantly higher than that in the control group, (P<0.05). Expression of local angiotensinogen mRNA in the liver, splenic artery and vein of PH group was (0.96+/-0.25), (0.83+/-0.18) and (0.79+/-0.23) respectively, significantly higher than that in the control group, (P<0.05). There was no significant difference between the liver, splenic artery and vein in the expression of local renin or local angiotensinogen mRNA in PH group, (P<0.05).. In normal subjects the expression of local renin and angiotensinogen mRNA was organ specific, but with increase of the expression of LRAS, the organ-specificity became lost in cirrhotic patients. LRAS may contribute to increased resistance of portal vein with liver and formation of splanchnic vasculopathy.

Topics: Adult; Aged; Angiotensinogen; Endothelium, Vascular; Female; Gene Expression; Humans; Hypertension, Portal; Immunohistochemistry; Liver Cirrhosis; Male; Microscopy, Electron, Scanning; Middle Aged; Organ Specificity; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Splenic Vein

Progressive hepatic fibrosis and cirrhosis develops in 20% to 30% of patients with chronic hepatitis C virus (HCV). We propose that host genetic factors influencing fibrogenesis may account for some of the variability in progression of this disease. In progressive fibrosis of other organs, particularly heart and kidney, production of the profibrogenic cytokine, transforming growth factor beta1 (TGF-beta1), may be enhanced by angiotensin II, the principal effector molecule of the renin-angiotensin system. The inheritance of polymorphisms in TGF-beta1, interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha), and genes of the renin-angiotensin system was examined in 128 patients with chronic HCV. The influence of genotypes on the stage of hepatic fibrosis was tested after adjustment for potential confounders (age, gender, alcohol consumption, portal inflammation, and steatosis), which may have independent effects on histological severity. The stage of fibrosis was 0 in 30 (23.4%), 1 in 44 (34.4%), 2 in 27 (21.1%), and 3 or 4 in 27 (21.1%). A statistically significant relationship was seen between inheritance of high TGF-beta1- and angiotensinogen (AT)-producing genotypes and the development of progressive hepatic fibrosis. This association persisted after correcting for potential confounders. Patients who inherited neither of the profibrogenic genotypes had no or only minimal fibrosis. Knowledge of these polymorphisms may have prognostic significance in patients with chronic HCV and may direct more aggressive therapy towards those patients with an increased risk of disease progression. The documentation of a significant relationship between AT genotype and fibrosis raises the novel suggestion that angiotensin II may be another mediator of extracellular matrix production in the liver.

Topics: Adult; Aged; Angiotensinogen; Female; Genes, ras; Hepatitis C, Chronic; Humans; Interleukin-10; Liver Cirrhosis; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

We compared the determination of plasma renin activity (PRA) and the direct immunoradiometric measurement of active renin (AR) as ways of assessing the activity of the renin-angiotensin system in normal volunteers and in patients with hypertension, heart failure, or liver failure. The levels of plasma renin substrate, angiotensinogen, and the ratio of PRA to AR concentration did not differ in the normal volunteers and the patients with essential or renovascular hypertension. However, compared to the volunteers, patients with severe heart or liver failure had markedly reduced plasma renin substrate levels, which led to a considerable underestimation of AR concentration when it was measured by PRA.

Topics: Adult; Angiotensinogen; Female; Heart Failure; Humans; Hypertension; Immunoradiometric Assay; Liver Cirrhosis; Male; Middle Aged; Pregnancy; Renin

Plasma renin activity, angiotensinogen, active renin and aldosterone concentrations and, 1 hour after addition of trypsin 1 mg per ml of plasma at -4 degrees C, prorenin and total renin concentrations were measured in 49 normotensive volunteers. Renin activity and active renin concentration were correlated (n = 98, r = 0.902, p less than 0.01) and their ratio was not dependent on the angiotensinogen concentration. Prorenin accounted for 90 per cent of total renin and was 40 per cent higher in males than in females in both supine and upright positions (p = 0.02 and p = 0.01). The change in position markedly increased plasma renin activity as well as active renin and aldosterone concentrations and, to a lesser degree, prorenin concentration, thereby raising the active/total renin ratio. Plasma renin activity, active renin concentration and plasma aldosterone concentration were significantly and negatively correlated with age, but not with urinary sodium excretion. Plasma renin activity and active renin and angiotensinogen concentrations were also measured in 14 patients with high angiotensinogen concentration (pregnant women and oestrogen users) and in 14 patients with cirrhosis and subnormal angiotensinogen concentration. In these patients the ratio of plasma renin activity to active renin concentration was correlated with the angiotensinogen concentration (n = 28, r = 0.643, p less than 0.01). The slope of the regression line between renin activity and active renin concentration was significantly different in patients with cirrhosis and in healthy volunteers, the measurement of renin activity leading to a ten-fold underestimation of active renin concentration. In clinical investigations of the renin system, plasma samples should be handled at room temperature to avoid cryoactivation of prorenin. The determination of active renin concentration should be preferred to that of plasma renin activity because it is not influenced by physiological or pathological variations in angiotensinogen.

Topics: Adolescent; Adult; Age Factors; Aged; Aldosterone; Angiotensinogen; Enzyme Precursors; Estrogens; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Posture; Pregnancy; Reference Values; Renin; Renin-Angiotensin System; Sex Characteristics

Topics: Adult; Aged; Angiotensinogen; Captopril; Cushing Syndrome; Female; Furosemide; Humans; Hyperaldosteronism; Hypertension; Liver Cirrhosis; Male; Middle Aged; Sodium Chloride

We have altered the method for measuring plasma renin concentration (P.R.C.) originated by Haas, et al (7) by using radioimmunoassay of angiotensin I and avoiding the addition of extrinsic renin substrate. Thus modified, the method gives values for P.R.A. (plasma renin activity), P.R.C. (plasma renin concentration), and also P.R.R. (plasma renin reactivity), which is the rate of reaction of renin substrate in the plasma with added extrinsic renin. By applying this modified method to a wide variety of plasma samples and independently measuring plasma renin substrate concentration (P.R.S.) in the same samples, we found a good correlation between P.R.R. and P.R.S. Our results indicate that the rate of the renin - renin substrate reaction in human plasma is proportional to renin substrate concentration over a wide range of values up to 5000 ng angiotensin I/ml or higher. Thus, first order reaction kinetics with respect to substrate concentration is followed even at high substrate levels and the Km must be high. An additional finding was that pregnant women have elevated P.R.C. levels in contrast with women taking oral contraceptives who have P.R.C. levels lower than normal.

Topics: Alcoholism; Angiotensin I; Angiotensinogen; Contraceptives, Oral; Depression, Chemical; Diabetes Mellitus; Female; Humans; Liver Cirrhosis; Male; Pregnancy; Radioimmunoassay; Renin; Sex Factors

Topics: Angiotensinogen; Angiotensins; Contraceptives, Oral; Cushing Syndrome; Diuretics; Electrophoresis, Polyacrylamide Gel; Female; Humans; Hypertension; Isoelectric Focusing; Kinetics; Liver Cirrhosis; Molecular Weight; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Regression Analysis; Uremia

Oestrogen stimulation of plasma renin substrate (PRS) was studied in men with alcoholic cirrhosis. PRS values, before and 1, 2, 4 and 6 days after a single oral administration of 100 microgram of an oestrogen derivative, 11beta-methoxy-17-ethynyl-1,3,5(10)-estratriene-3,17beta-diol (Moxestrol), were measured by radioimmunoassay of generated angiotensin I in five men with normal liver function and five men with alcoholic cirrhosis. Basal PRS was 0.93 +/- 0.22 nmol/ml (mean +/- 1 SD) in the normal men and significantly lower (P less than 0.01) in the men with cirrhosis (0.33 +/- 0.14 nmol/ml). Two days after administration of Moxestrol, PRS rose significantly but transiently (P less than 0.05) to 1.41 +/- 0.42 nmol/ml in the normal men and to 0.47 +/- 0.15 in the cirrhotic men, the relative increase (approximately 50%) being similar in both groups. A study of the plasma kinetics and urinary excretion of Moxestrol was also performed to evaluate its metabolic clearance rate and absorption. Since the intestinal absorption of [14C] Moxestrol was not depressed in cirrhotic men, the low PRS values recorded are probably the consequence of hepatocyte dysfunction.

Topics: Adult; Aged; Angiotensinogen; Angiotensins; Estradiol; Estrogens; Humans; Kinetics; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged

Plasma renin activity (PRA), plasma renin concentration (PRC), angiotensinogen, angiotensin II (AT II) and plasma aldosterone were determined by radioimmunoassay in 77 patients with cirrhosis of the liver [group I: with ascites, untreated (n=23); group II: patients with ascites during treatment (n=32); group III: after removal of fluids, but under further spironolactone therapy (n=10); group IV: untreated subjects without ascites (n=12)]. With the exception of decreased angiotensinogen values in all groups ranging between 39% (group IV) and 73% (group III) no significant changes of the other parameters of the RAAS were found in untreated patients. A highly significant increase of PRA, PRC, AT II and plasma aldosterone was observed in treated cirrhotics with (group II) or without (group III) ascites. In the total series of patients AT II was closely related to PRA, PRC and aldosterone emphasizing aldosterone secretion. Plasma sodium was inversely correlated to PRA, PRC, AT II and aldosterone, but no relationship was detected between these parameters of the RAAS and plasma potassium. Our results indicate that hyperaldosteronism in cirrhosis appears unlikely to be the major determinant of avid renal sodium retention and ascites formation. An increased activity of the RAAS is most often initiated by therapeutic factors and/or markedly altered electrolyte metabolism. Therefore, basal conditions of the patients to be studied must be well defined to exclude any artificially induced stimulation of the RAAS.

Topics: Adult; Aged; Aldosterone; Angiotensin II; Angiotensinogen; Ascites; Diuretics; Humans; Liver Cirrhosis; Middle Aged; Renin

The electrophoretic mobility of renin substrate in human plasma was determined by electrophoresis of the plasma on a cylinder of polyacrylamide gel, followed by slicing the gel, incubation of each slice with human renin, EDTA, and BAL in saline, and determination of the angiotensin formed by radioimmunoassay. With this modified technique 5, and possibly 8, electrophoretically dissimilar renin substrates have been found in human plasma. Significant variations in the patterns of renin substrates in the blood plasma of pregnant women and of those taking oral contraceptives were shown. In normal plasma from male or female subjects there was a single large peak of renin substrate with a mobility slightly less than that of albumin, and there were a series of very small peaks of renin substrate with lesser mobilities than the major peak. Increasing the sample size and prolonging the period of incubation with renin made the smaller peaks more apparent. In women using oral contraceptives, a distinctly different pattern of renin substrates was found. Early smaller peaks were increased. The major peak was sometimes increased also. Pregnancy produced a strikingly different pattern of renin substrates. There was an increase in all slow-moving peaks and their bases ran together without a return to the baseline. The absence of peaks when renin was omitted indicated that they were renin substrates. In 2 of 4 patients having cirrhosis of the liver with ascites, the amount of major substrate peak was greatly diminished and minor peaks were somewhat reduced. In 3 bilaterally nephrectomized patients, the major peak was not increased and the pattern of minor peaks was normal.

Topics: Angiotensin II; Angiotensinogen; Contraceptives, Oral; Electrophoresis, Polyacrylamide Gel; Female; Humans; Liver Cirrhosis; Male; Nephrectomy; Pregnancy

Topics: Aldosterone; Angiotensin II; Angiotensinogen; Corticosterone; Hepatic Encephalopathy; Hepatitis; Humans; Hydrocortisone; Hyperaldosteronism; Liver Cirrhosis; Liver Diseases; Renin