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)

The role of nitric oxide (NO) in portal hypertension is poorly understood. The role of NO upon hepatic arterial and portal venous vasoconstrictor responses to noradrenaline and ATP in rats with secondary biliary cirrhosis was evaluated. Cirrhosis was induced by bile duct ligation after which livers were excised and dual-perfused in vitro. Concentration-dependent dose-response curves were then constructed to hepatic arterial and portal venous noradrenaline and ATP. Hepatic arterial responses to noradrenaline and ATP were significantly attenuated in cirrhotic rats. 100 microM N(G)-nitro-L-arginine methyl ester (L-NAME) restored attenuated hepatic arterial responses to noradrenaline and ATP in cirrhotic rats. Portal venous responses to noradrenaline in cirrhotic rats were significantly increased compared to controls and were not affected by L-NAME. However, portal venous responses to ATP were significantly attenuated in cirrhotic rats and were also not restored by L-NAME. Hepatic arterial or portal venous responses to noradrenaline did not change after infusion of L-NAME. Hepatic arterial responses to noradrenaline and ATP were significantly attenuated in cirrhotic rats, possibly due to increased production of NO. However, portal venous responses in cirrhotic rats were increased to noradrenaline and attenuated to ATP, and were not related to increased NO production.
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PMID:The action of nitric oxide on hepatic haemodynamics during secondary biliary cirrhosis in the rat. 1256 14

The mechanisms initiating and perpetuating the fibrogenic response in the injured liver are not well understood. Hepatic stellate cells are activated by liver injury to become proliferative and fibrogenic myofibroblasts. Emerging evidence suggests that the sympathetic nervous system may play a role in the development of cirrhosis. It is not known, however, whether this requires a direct interaction between sympathetic neurotransmitters and stellate cell receptors, or results indirectly, from sympathetic effects on the vasculature. Using cultured hepatic stellate cells, we show that the sympathetic neurotransmitters, norepinephrine and neuropeptide Y, markedly stimulate the proliferation of activated, myofibroblastic, hepatic stellate cells. Norepinephrine, but not neuropeptide Y, also induces collagen gene expression. In conclusion, physiologically relevant concentrations of sympathetic neurotransmitters directly modulate the phenotype of hepatic stellate cells. This suggests that targeted interruption of sympathetic nervous system signaling in hepatic stellate cells may be useful in constraining the fibrogenic response to liver injury.
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PMID:Norepinephrine and neuropeptide Y promote proliferation and collagen gene expression of hepatic myofibroblastic stellate cells. 1264 23

Hepatorenal syndrome is a life-threatening complication occurring commonly in cirrhosis liver and rarely in acute liver failure. It can be precipitated by shock, infection, surgery, large volume paracentesis or nephrotoxic drugs. Type I hepatorenal syndrome which usually develops over acute liver failure is rapidly progressive and has poor outcome. Type II hepatorenal syndrome is usually associated with refractory ascites and is slowly progressive with relatively good prognosis. Peripheral vasodilation with intrarenal vasoconstriction is the main pathophysiologic change. Diagnostic criteria, ascertained by international ascites club, is helpful to reach at a proper diagnosis. Management includes pharmacologic therapy to induce splanchnic vasoconstriction which improve renal circulation. Dopamine, vasopressin analogs (ornipressin and terlipressin), midodrine, noradrenaline have been used mainly as a bridge to the liver transplant or in anticipation of improvement in hepatic function. The molecular adsorbent recycling system (MARS) have been recently used in patients with hepatorenal syndrome. Transjugular intrahepatic portosystemic shunt is also another modality which has been used as a bridge to liver transplant in such patients.
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PMID:Hepatorenal syndrome. 1269 50

In cirrhosis, cardiac symptoms and physical signs occur as the liver functions worsen. Cirrhosis is associated with hyperdynamic circulation and beta-adrenergic system activation responsible for the cardiovascular changes. The purpose of the present study was to explore the cardiovascular response to exercise in cirrhotic patients. A total of 20 patients (16 men, four women) with cirrhosis of hepatitis B or C without any cardiac dysfunction were included in the study. Ten people (eight men, two women) were enrolled in the control group. Plasma noradrenaline and adrenaline concentrations, blood pressures in supine and standing positions, exercise echocardiography and exercise radionuclide ventriculography were carried out. In cirrhotics, the exercise capacity was lower and also there was an impaired cardiovascular response to exercise with lower than expected peak heart rate without any cardiac dysfunction, which may have important clinical implications for the ability of these patients to withstand cardiovascular stress.
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PMID:Cardiac dysfunction in cirrhosis. 1285 Jun 89

1. Portal hypertension (PH), a major syndrome in cirrhosis, producing hyperdynamic splanchnic circulation and hyperaemia. In order to elucidate the contribution of heme oxygenase to the vascular hyporeactivity, we assessed the activity of heme oxygenase-1 (HO-1), measured the in vivo pressure response to noradrenaline (NA) and investigated the effects of blocking the carbon monoxide (CO) and nitric oxide (NO) pathways in a prehepatic model of PH in rats. 2. Portal hypertension was induced by partial portal vein ligation (PPVL). Noradrenaline was injected intravenously. Liver, spleen and mesentery homogenates were prepared for measurement of HO-1 activity and expression. Four groups of rats were used: (i) a sham group; (ii) a PPVL group; (iii) a sham group pretreated with Zn-protoporphyrin IX (ZnPPIX); and (iv) a PPVL group pretreated with ZnPPIX. Each group was studied before and after treatment with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). 3. For basal pressures and the pressure response to NA, inhibition of CO and NO pathways by ZnPPIX and L-NAME, respectively, produced an increase in mean arterial pressure (MAP) in sham-operated and in PH rats. Similarly, when both inhibitors were used together in either sham or PPVL rats, a greater increase in MAP was observed. 4. These results, together with the increased HO-1 activity and expression only in the PH group, have led us to suggest that the heme oxygenase/CO pathway is involved in the vascular response to NA in PH rats.
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PMID:Role of heme oxygenase/carbon monoxide pathway on the vascular response to noradrenaline in portal hypertensive rats. 1574 3

In patients with cirrhosis and type 1 hepatorenal syndrome (HRS), systemic vasodilation, which is mainly attributable to splanchnic vasodilation, plays a critical role in the activation of endogenous vasoconstrictor systems, resulting in renal vasoconstriction and functional renal failure. It has been suggested that the use of splanchnic (and systemic) vasoconstrictors such as terlipressin (a vasopressin analog) or alpha-1-adrenoceptor agonists (midodrine or noradrenaline) may improve renal function in patients with type 1 HRS. Six studies (with only one randomized study in a small series of patients) have shown that terlipressin improves renal function in these patients. However, there is evidence that terlipressin alone may be less effective than terlipressin combined with intravenous albumin in improving renal function. Future randomized studies should confirm this difference and evaluate the impact of terlipressin therapy (with or without intravenous albumin) on survival. Interestingly, in nonrandomized studies, the use of alpha-1 agonists combined with other therapies (octreotide and albumin for midodrine; furosemide and albumin for noradrenaline) has been shown to improve renal function in patients with type 1 HRS. The efficacy and safety of combined therapies including alpha-1 agonists should be confirmed in randomized studies. Finally, preliminary evidence suggests that vasoconstrictor administration may be a novel therapeutic approach targeting vasodilation involved in the mechanism of: (1) renal failure in type 2 HRS; (2) paracentesis-induced circulatory dysfunction; and (3) arterial hypotension induced by byproducts of gram-negative bacteria. Further studies are needed in all these fields.
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PMID:The use of vasoconstrictors in patients with cirrhosis: type 1 HRS and beyond. 1649 52

The pathogenesis of NASH is being unraveled by studies of animal models and humans with this disorder. The necro-inflammatory component of NASH appears to be modulated by interactions among various factors (for example cytokines, hormones, neurotransmitters) that regulate the biological activity of TNF- and other proinflammatory (Th-1) cytokines. Hepatic necroinflammation is necessary, but not sufficient, for progression to cirrhosis. Factors such as leptin inducible factors (for example, noradrenaline), that regulate the activity of profibrogenic cytokines, such as IL-10 and TGF-beta, dictate the extent of fibrosis that occurs during liver injury. A better understanding of how these and other soluble and cell associated factors regulate the phenotypes of different types of liver cells should help us to develop rationale treatments for NASH and other disorders in the metabolic syndrome.
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PMID:The role of cytokines in non-alcoholic steatohepatitis. A review. 1720 49

In patients with cirrhosis, acute renal failure is due to prerenal failure (a result of decreased renal perfusion) and tubular necrosis. There are 3 main causes of prerenal failure: 'true hypovolemia' (which complicates hemorrhage, gastrointestinal or renal fluid losses), sepsis, and type 1 hepatorenal syndrome (HRS). Prerenal failure may also be due to the administration of non-steroidal antiinflammatory drugs, or intravascular radiocontrast agents. Prerenal failure is reversible after restoration of renal blood flow. Treatments target the cause of hypoperfusion, and fluid replacement is used to treat 'non-HRS' prerenal failure. In patients with type 1 HRS with very low short-term survival rate, liver transplantation is the ideal treatment. Systemic vasoconstrictor therapy with terlipressin (combined with intravenous human albumin), noradrenaline (combined with albumin and furosemide) or midodrine (combined with octreotide and albumin) may improve renal function in patients with type 1 HRS waiting for liver transplantation. MARS (for Molecular Adsorbent Recirculating System) and the transjugular intrahepatic portosystemic shunt may also improve renal function in these patients. In patients with cirrhosis, acute tubular necrosis is mainly due to an ischemic insult to the renal tubules. Studies are needed on the natural course and treatment (e.g., renal-replacement therapy) of acute tubular necrosis in patients with cirrhosis.
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PMID:Diagnosis and treatment of acute renal failure in patients with cirrhosis. 1722

In cirrhosis, despite augmented blood volume, effective circulating volume is decreased. This implies abnormal regulation of blood volume, i.e., venous pooling. Because gut veins are the main blood reservoir, we studied mesenteric venous capacitance and compliance in a rat model of cirrhosis. Cirrhosis was induced by bile duct ligation (4 wk). Controls were sham operated. Changes in first-order mesenteric vein diameters induced by drugs, hemorrhage, and stepwise increases in portal pressure (inflatable cuff) were directly observed by intravital microscopy. Effects of nitric oxide on responses to acute graded hemorrhage were studied by use of selective NO synthase (NOS) isoform inhibitors. Pressures were related to diameters to assess capacitance and compliance. Compared with controls, cirrhotic rats demonstrated increased mesenteric venous capacitance and decreased compliance. Norepinephrine induced venoconstriction but did not affect compliance. Prazosin markedly diminished compliance in controls but not cirrhotics. Conversely, the nonspecific NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME) decreased compliance in cirrhotics, but not controls. Tetrodotoxin venodilated controls, venoconstricted cirrhotics, and markedly decreased compliance in both groups. When hemorrhaged, controls rapidly venoconstricted to compensate for initial hypotension, whereas cirrhotic rats remained hypotensive because venoconstriction was severely blunted. Pretreatment with l-NAME or the selective neuronal NOS inhibitors S-methyl-l-thiocitrulline and 7-nitroindazole normalized the homeostatic responses of cirrhotic rats, whereas the selective endothelial-constitutive NOS inhibitor N-iminoethyl-l-ornithine did not affect the response. In conclusion, mesenteric veins of cirrhotic rats showed enhanced capacitance, attenuated compensatory constrictive response to hemorrhage, and decreased compliance. The first two abnormalities were caused by neuronal NOS-derived nitric oxide.
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PMID:Altered mesenteric venous capacitance and volume pooling in cirrhotic rats are mediated by nitric oxide. 1855 20

Type 1 hepatorenal syndrome (HRS) is prerenal failure specific to decompensated cirrhosis. In patients with HRS, there is marked splanchnic/systemic vasodilation resulting in arterial hypotension, arterial baroreceptor unloading, overstimulation of the sympathetic nervous and renin-angiotensin systems. This reflex neurohumoral hyperactivity via endogenous vasoconstrictors/vasopressors such as angiotensin II and noradrenaline induces arterial vasoconstriction in different extrasplanchnic vascular beds (including preglomerular arteries in the kidneys). Decreased arterial pressure (i.e. low renal perfusion pressure) and preglomerular vasoconstriction are thought to play a major role in the decline of the glomerular filtration rate (GFR). Nonrandomized studies in patients with HRS have shown that the administration of a splanchnic vasoconstrictor (vasopressin analogue or alpha(1)-adrenoceptor agonist), usually combined with intravenous albumin, causes increases in arterial pressure, arterial baroreceptor uploading, decreased neurohumoral activity, decreased renal vascular resistance, and increased GFR. Randomized clinical trials have shown that treatment with a combination of the vasopressin analogue terlipressin and intravenous albumin improves renal function in patients with type 1 HRS. Vasopressor therapy with terlipressin plus intravenous albumin is the medical treatment of choice for type 1 HRS.
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PMID:Acute kidney injury: new concepts. Hepatorenal syndrome: the role of vasopressors. 1880 78


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