Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of antinatriuretic systems such as the renin-angiotensin system, is of major importance in the pathogenesis of sodium retention in cirrhosis. In this study, we studied the intrarenal renin-angiotensin system by measuring renin and angiotensinogen mRNA expression in the kidney of rats subjected to long-term bile duct ligation in a phase before the development of ascites, when sodium retention is already present. Experiments were performed in sham-operated and bile duct-ligated rats 3 wk after surgery. Balance studies showed lower sodium excretion and greater sodium retention in the bile duct-ligated rats compared with the control animals. Plasma renin activity (4.41 +/- 1.01 ng Angiotensin I/ml/hr in the bile duct-ligated group vs. 4.20 +/- 0.74 in the controls) and plasma renin concentration were not different between the two groups. However, plasma renin substrate was significantly decreased in bile duct-ligated animals. Total kidney renin mRNA was significantly higher in the bile duct-ligated animals (0.83 +/- 0.14 densitometric units vs. 0.44 +/- 0.04 in the controls), as determined on Northern-blot analysis and densitometric quantitation. Angiotensinogen mRNA expression in the kidneys of bile duct-ligated rats was significantly decreased (0.09 +/- 0.01 densitometric units) compared with that of the controls (0.21 +/- 0.03). These results indicate that sodium-retaining, nonascitic bile duct-ligated rats show abnormalities of the intrarenal renin angiotensin system that precede changes in plasma renin activity. Our data suggest that the intrarenal renin angiotensin system may participate in the initiation of the renal pathophysiological abnormalities present in bile duct-ligated rats.
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PMID:Renin and angiotensinogen mRNA expression in the kidneys of rats subjected to long-term bile duct ligation. 818 73

Resistance to the natriuretic action of atrial natriuretic factor (ANF) in cirrhosis with ascites has been correlated with rising levels of antinatriuretic factors, such as renin, angiotensin II (AII), and aldosterone, as well as increased sympathetic nerve activity. To determine whether AII can serve as a mediator rather than only as a marker of the antinatriuresis, a nonpressor dose of AII (5 ng/kg/min) was given during an ANF infusion in eight patients with cirrhosis and ascites who responded to ANF infusion with a natriuresis. Patients were maintained in metabolic balance and measurements of para-aminohippuric acid, inulin, and lithium clearance were taken before and during infusion of ANF with or without AII. Atrial natriuretic factor infusion was associated with a natriuretic response accompanied by an increase in glomerular filtration rate, filtration fraction, and lithium clearance compared with baseline. The addition of AII was associated with a return of the glomerular filtration rate to baseline, with no change in filtration fraction. This was reversible on withdrawal of AII infusion. Natriuresis induced by ANF occurred despite baseline elevations of the renin angiotensin aldosterone system and was associated with an increase in distal delivery of sodium and a decrease in fractional reabsorption of distally delivered sodium as estimated by lithium clearance parameters. Angiotensin II infusion exerted effects on both proximal and distal nephron sites to abrogate ANF-induced natriuresis. These results suggest that AII may serve as a mediator as well as a marker of resistance to the natriuretic effect of ANF in patients with cirrhosis and ascites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II modulates atrial natriuretic factor-induced natriuresis in cirrhosis with ascites. 848 14

1. Decreased pressor sensitivity to angiotensin II occurs in cirrhosis, but the mechanism remains unclear. 2. Angiotensin II dose-response studies were performed in conscious, chronically instrumented cirrhotic and control rats, and angiotensin II concentration-response studies were performed in isolated blood vessels obtained from similar groups of animals. 3. Cirrhotic rats demonstrated a significantly decreased pressor response to angiotensin II (5-80 ng/kg intravenously). However, angiotensin II-generated tension in thoracic aortic rings isolated from cirrhotic rats and studied in vitro was not impaired. These findings are consistent with the concept that circulating vasodilator substances in cirrhosis rather than an abnormality intrinsic to vascular smooth muscle cells are responsible for the decreased pressor sensitivity to angiotensin II in vivo. 4. Pretreatment with the cyclo-oxygenase inhibitor indomethacin (3 mg/kg intravenously) restored pressor sensitivity to angiotensin II to normal, suggesting that cyclo-oxygenase products, possibly vasodilator prostaglandins, may be involved in mediating pressor resistance to this hormone in vivo.
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PMID:Dissociation between pressor sensitivity in vivo and contractile reactivity in vitro to angiotensin II in rats with experimental cirrhosis. 850 29

In order to evaluate the activation of the sympathetic nervous and renin-angiotensin systems and antidiuretic hormone release in the setting of chronic liver disease, we studied 30 patients with cirrhosis who presented normal renal function. The cirrhotic patients were divided into two groups according to Child's score: 20 were Child A and 10 Child B. The control group consisted of 10 normal subjects. Blood samples were collected for determination of norepinephrine (NE), dopamine (DA), angiotensin I and II (AI and AII), and antidiuretic hormone (ADH), using the method of high-performance liquid chromatography (HPLC). No significant differences (p < 0.05) were found in the plasma levels of NE, DA, AI, and AII between the cirrhotic patients and the controls, although the absolute values observed in both groups of cirrhotics were clearly higher than in controls. The ADH levels were higher in Child B in comparison to Child A patients and controls, though this difference was not significant as well. Our results suggest a hormonal activation in cirrhotic patients, even in the early stages of hepatic disease (without ascites). We also noted an increase in ADH levels in Child B patients in relation to Child A and controls, although there was no difference in osmolality, suggesting a non-osmotic ADH release.
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PMID:Neurohumoral systems in patients with cirrhosis. 910 13

Renal sodium retention on standing is one aspect of the abnormal renal sodium handling in preascitic, well-compensated patients with cirrhosis. Recently, it has been shown that low doses (7.5 mg) of the angiotensin II (Ang II) receptor antagonist, losartan, can reverse renal sodium retention on high, 200-mmol sodium/d diet in these patients and restore them to sodium balance. Therefore, the effect of 7.5 mg of losartan on sodium excretion, when changing from supine to erect posture for 2 hours, was examined in 10 well-compensated patients with cirrhosis and 9 age- and sex-matched controls on the same sodium diet, under strictly controlled metabolic conditions. In contrast to control subjects, in whom sodium excretion was unaffected, single 7.5-mg doses of losartan again restored the preascitic patients with cirrhosis to sodium balance. In addition, it blunted the fall in erect posture- induced renal sodium excretion by a reduction in proximal and distal tubular reabsorption of sodium. These changes occurred without any significant changes in blood volumes, systemic and renal hemodynamics, or glomerular filtration rate (GFR) and filtered sodium load compared with controls, and despite activation of the systemic renin-angiotensin-aldosterone system, which was still within normal levels. In conclusion, the beneficial natriuretic effects of low-dose losartan on erect posture - induced sodium retention in preascitic cirrhosis supports the suggestion that the pathophysiology of sodium retention in preascites is in part caused by an intrarenal tubular effect of Ang II in that posture.
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PMID:The mechanism of improved sodium homeostasis of low-dose losartan in preascitic cirrhosis. 1277 29

Angiotensin II (ANG-II) and its receptor (AT1) have been potential targets of therapy for liver cirrhosis. However, AT1 expression in human cirrhotic livers has not been clarified. We studied AT1 and ANG-II generating enzymes in human autopsy (20 cirrhotics and 20 normal controls) and biopsy (10 cirrhotics) livers. AT1 immunoreactivity in tissue sections was quantified by computer-aided morphometry. AT1 protein and mRNA levels were assessed by Western blotting and real-time polymerase chain reaction. Concerning ANG-II generating system, angiotensin-converting enzyme (ACE) and mast cell chymase were examined. AT1 expression was seen not only in vascular smooth muscle cells, but also in activated stellate cells/myofibroblasts and liver parenchymal cells. AT1-positive vessels and myofibroblasts were significantly increased in fibrous septa of cirrhosis, although overall hepatic AT1 expression was reduced in the cirrhotic livers compared with the controls. Augmentation of AT1-positive vessels was related to severity of portal hypertension. Expressions of ACE and chymase were enhanced in the cirrhotic livers. These results suggest that hepatic AT1 expression is shifted to and concentrated in vessels and myofibroblasts in cirrhotic settings, and increased ANG-II generation by ACE and chymase contributes to portal hypertension and liver fibrosis via binding to AT1 expressed on vessels and myofibroblasts.
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PMID:Expression of angiotensin II type 1 receptor in human cirrhotic livers: Its relation to fibrosis and portal hypertension. 1590 19

Morbidity and mortality of chronic liver disease are primarily caused by liver cirrhosis and portal hypertension, both of them secondary disorders of progressive liver fibrosis. The main fibrogenic cell type in the liver, the hepatic stellate cell (HSC), is activated and stimulated by several factors, among which the renin-angiotensin-aldosterone system (RAAS) plays a major role. Angiotensin II induces various profibrotic pathways via the angiotensin II receptor type 1 (AT(1) receptor) not only in heart and kidney, but also in liver tissue. Stimulation of the AT(1) receptor promotes the transformation of the quiescent HSC into the myofibroblast like activated HSC and the synthesis of transforming growth factor-beta1 (TGF-beta), the major profibrotic cytokine in the liver. In addition, aldosterone has been suggested to induce profibrotic effects in chronic heart and liver disease. This review focuses on the concept that inhibitors of the RAAS retard or even reverse liver fibrosis and reduce portal hypertension. Angiotensin converting enzyme (ACE) inhibitors, AT(1) receptor antagonists, and aldosterone antagonists have been demonstrated to reduce the proliferation of HSC, to decrease the synthesis of profibrotic molecules, and to have the potential to improve liver fibrosis. However, side-effects such as systemic hypotension may impair the clinical application of RAAS inhibitors in patients with liver cirrhosis and portal hypertension. Also, efficacy may be limited by the downregulation of AT(1) receptors in advanced fibrosis, which has been observed in animal and human studies. Randomized clinical studies are essential to evaluate, whether this approach is beneficial in patients with chronic liver disease and progressive fibrosis.
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PMID:Impact of inhibitors of the Renin-Angiotensin-aldosterone system on liver fibrosis and portal hypertension. 1716 28

Angiotensin converting enzyme (ACE) 2 activity and angiotensin-(1-7) [Ang-(1-7)] levels are increased in experimental cirrhosis; however, the pathways of hepatic Ang-(1-7) production have not been studied. This study investigated the role of ACE2, ACE, and neutral endopeptidase (NEP) in the hepatic formation of Ang-(1-7) from angiotensin I (Ang I) and Ang II and their effects on portal resistance. Ang I or Ang II were administered to rat bile duct ligated (BDL) and control livers alone and in combination with the ACE inhibitor lisinopril, the ACE and NEP inhibitor omapatrilat, or the ACE2 inhibitor MLN4760 (n = 5 per group). BDL markedly upregulated ACE, ACE2, and NEP. Ang-(1-7) was produced from Ang II in healthy and in BDL livers and was increased following ACE inhibition and decreased by ACE2 inhibition. In contrast, Ang-(1-7) production from Ang I was minimal and not affected by ACE or NEP inhibition. Surprisingly, ACE2 inhibition in BDLs dramatically increased Ang-(1-7) production from Ang I, an effect abolished by ACE2/NEP inhibition. Ang II and Ang I induced greater portal pressure increases in BDL livers than controls. The effects of Ang I were closely correlated with Ang II production and were strongly attenuated by both ACE and ACE/NEP inhibition. These findings show that the major substrate for hepatic production of Ang-(1-7) is Ang II and this is catalyzed by ACE2. Ang I is largely converted to Ang II by ACE, and net conversion of Ang I to Ang-(1-7) is small. NEP has the ability to generate large amounts of Ang-(1-7) in the BDL liver from Ang I only when ACE2 activity is greatly decreased or inhibited.
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PMID:Portal pressure responses and angiotensin peptide production in rat liver are determined by relative activity of ACE and ACE2. 1938 7

Angiotensin II (AT-II) is a peptide that plays an important role in the renin-angiotensin-aldosterone (RAA) system. Traditionally, the RAA system has been related with states of systemic hypertension and hypoperfusion as a counterbalance mechanism. Recently, AT-II has been studied for its properties in the process of fibrosis in several organs, especially in the liver. AT-II is capable to stimulate the activated hepatic stellate cells, which increase expression of profibrogenic molecules like tumor growth factor-beta, tissue inhibitor of metalloproteinase-1 and collagen I, among others. At the same time, AT-II is implied in the hemodynamic balance of cirrhosis and portal hypertension. Due to its profibrogenic and vasoactive properties, blockade of AT-II actions constitutes an important therapeutic target to inhibit fibrotic processes and reduction of risk of complications of portal hypertension as well. Some drugs like angiotensin-converting enzyme inhibitors or the angiotensin II receptor blockers have been studied as alternatives for the treatment of patients with cirrhosis with promising results. Nonetheless, additional research is required in order to consider these drugs as a part of the integral treatment of the patient with cirrhosis and portal hypertension.
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PMID:Role of angiotensin II in liver fibrosis-induced portal hypertension and therapeutic implications. 1973 16

Recent studies have shown that, in cirrhosis, portal angiotensin-(1-7) [Ang-(1-7)] levels are increased and hepatic expression of angiotensin converting enzyme 2 (ACE2) and the Mas receptor are upregulated, but the effects of Ang-(1-7) on hepatic hemodynamics in cirrhosis have not been studied. This study investigated the effects of Ang-(1-7) on vasoconstrictor-induced perfusion pressure increases in cirrhotic rat livers. Ang II or the alpha 1 agonist methoxamine (MTX) were injected in the presence or absence of Ang-(1-7), and the perfusion pressure response was recorded. Denudation of vascular endothelial cells with sodium deoxycholate was used to investigate the contribution of endothelium to the effects of Ang-(1-7). Ang-(1-7) alone had no effect on perfusion pressure. However, it reduced the maximal vasoconstriction response and area under the pressure response curve to Ang II and MTX by >50% (P < 0.05). This effect of Ang-(1-7) was not blocked by Mas receptor inhibition with A779 or by Ang II type 1 and type 2 receptor and bradykinin B(2) receptor blockade and was not reproduced by the Mas receptor agonist AVE0991. D-Pro(7)-Ang-(1-7), a novel Ang-(1-7) receptor antagonist, completely abolished the vasodilatory effects of Ang-(1-7), as did inhibition of endothelial nitric oxide synthase (eNOS) with N(G)-nitro-L-arginine methyl-ester, guanylate cyclase blockade with ODQ and endothelium denudation. The functional inhibition by D-Pro(7)-Ang-(1-7) was accompanied by significant (P < 0.05) inhibition of eNOS phosphorylation. This study shows that Ang-(1-7) significantly inhibits intrahepatic vasoconstriction in response to key mediators of increased vascular and sinusoidal tone in cirrhosis via a receptor population present on the vascular endothelium that is sensitive to D-Pro(7)-Ang-(1-7) and causes activation of eNOS and guanylate cyclase-dependent NO signaling pathways.
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PMID:Angiotensin-(1-7) reduces the perfusion pressure response to angiotensin II and methoxamine via an endothelial nitric oxide-mediated pathway in cirrhotic rat liver. 2308 15


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