cyclic-gmp and Liver-Diseases

Topics: Asthma; Biomarkers; Cyclic GMP; Diagnostic Techniques, Endocrine; Heart Failure; Humans; Hyperparathyroidism; Liver Diseases; Myocardial Infarction; Neoplasms; Nitric Oxide; Radioimmunoassay; Reference Values; Specimen Handling

The glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of chronic moderate hyperammonemia either with or without liver failure. The impairment occurs at the level of activation of soluble guanylate cyclase by nitric oxide (NO). It has been suggested that the impairment of this pathway may be responsible for some of the neurological alterations found in hyperammonemia and hepatic encephalopathy. Soluble guanylate cyclase is also present in lymphocytes. Activation of guanylate cyclase by NO is also altered in lymphocytes from hyperammonemic rats or from rats with portacaval anastomosis. We assessed whether soluble guanylate cyclase activation was also altered in human patients with liver disease. We studied activation of soluble guanylate cyclase in lymphocytes from 77 patients with liver disease and 17 controls. The basal content of cGMP in lymphocytes was decreased both in patients with liver cirrhosis and in patients with chronic hepatitis. In contrast, cGMP concentration was increased in plasma from patients with liver disease. Activation of guanylate cyclase by NO was also altered in liver disease and was higher in lymphocytes from patients with cirrhosis or hepatitis than that in lymphocytes from controls. Successful treatment with interferon of patients with hepatitis C reversed all the above alterations. Altered modulation of soluble guanylate cyclase by NO in liver disease may play a role in the neurological and hemodynamic alterations in these patients.

Topics: Animals; Cyclic GMP; Glutamic Acid; Guanylate Cyclase; Humans; Hyperammonemia; Liver Diseases; Nitric Oxide; Solubility

Pg E, F2 alpha and F1 alpha, protein-bound plasmic oxyproline (PBPO) as well as 24-h oxyprolinuria (OPU) were measured in 119 patients suffering from various forms of chronic hepatic diseases. Composition of cellular infiltrates in histological specimens was assessed quantitatively for chronic hepatitis patients. Hepatic levels of Pg E, OPU and PBPO were elevated in all the patients, whereas PgF2 alpha and 6-keto-PgF1 alpha values were similar to controls. There were relationships between PBPO and OPU, PgE and 6-keto-PgF1 alpha. Unlike patients with active hepatitis and hepatic cirrhosis, those with chronic persistent hepatitis demonstrated a direct correlation between cellular infiltrate fibroblasts and PgE, PgF2 alpha; between PgF2 alpha and Kupffer's cells content. Inverse relationship occurred between PgE and free hepatic macrophages. In response to prostenon (PGE2) moderate PBPO decline went in line with elevation of cAMP/cGMP. A significant increase of PBPO during introduction of ensaprost-F (PgF2 alpha) did not result in changes in cyclic nucleotides. Prostenon treatment decreased PBPO under no shifts in OPU. A regulatory role of PgE is suggested in collagen metabolism stabilization. Prostenon is proposed for therapeutic use to inhibit sclerotic processes in liver impairment.

Topics: Adolescent; Adult; Aged; Chronic Disease; Collagen; Cyclic AMP; Cyclic GMP; Female; Hepatitis, Chronic; Humans; Liver Diseases; Male; Middle Aged; Prostaglandins

Polycystic kidney disease (PKD) involves progressive hepatorenal cyst expansion and fibrosis, frequently leading to end-stage renal disease. Increased vasopressin and cAMP signaling, dysregulated calcium homeostasis, and hypertension play major roles in PKD progression. The guanylyl cyclase A agonist, B-type natriuretic peptide (BNP), stimulates cGMP and shows anti-fibrotic, anti-hypertensive, and vasopressin-suppressive effects, potentially counteracting PKD pathogenesis. Here, we assessed the impacts of guanylyl cyclase A activation on PKD progression in a rat model of PKD. Sustained BNP production significantly reduced kidney weight, renal cystic indexes and fibrosis, in concert with suppressed hepatic cystogenesis in vivo. In vitro, BNP decreased cystic epithelial cell proliferation, suppressed fibrotic gene expression, and increased intracellular calcium. Together, our data demonstrate multifaceted effects of sustained activation of guanylyl cyclase A on polycystic kidney and liver disease. Thus, targeting the guanylyl cyclase A-cGMP axis may provide a novel therapeutic strategy for hepatorenal fibrocystic diseases.

Topics: Animals; Cell Proliferation; Cyclic AMP; Cyclic GMP; Cysts; Disease Models, Animal; Disease Progression; Epithelial Cells; Female; Fibrosis; Genetic Vectors; Humans; Hypertension; Kidney; Liver; Liver Diseases; Male; Natriuretic Peptide, Brain; Parvovirinae; Polycystic Kidney, Autosomal Recessive; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; Signal Transduction; Vasopressins

Remote ischemic preconditioning (RIPC) protects against liver ischemia reperfusion (IR) injury. An essential circulating mediator of this protection is nitric oxide (NO) induced by lower limb RIPC. One of the mechanisms through which NO generally acts is the soluble guanylyl cyclase-cyclic GMP (sGC-cGMP) pathway. The present study aimed to assess the role of hepatic sGC-cGMP in lower limb RIPC-induced protection against liver IR injury.. Mice were allocated to 4 groups: 1.Sham; 2.IR: 40 min of lobar hepatic ischemia and 2 hr reperfusion; 3.RIPC+IR: 6 cycles of 4x4 min IR of the lower limb followed by IR group procedure; (4) 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ)+RIPC+IR: ODQ (sGC inhibitor) was administered followed by RIPC+IR group procedure. Hepatic microcirculatory blood flow (MBF) was measured throughout the experiment. Plasma transaminases, hepatic histopathological and transmission electron microscopy studies were performed at the end of the experiment. Hepatic cGMP levels were measured in groups 1-3 in addition to an RIPC alone group.. Compared to liver IR alone, RIPC+IR increased hepatic MBF during liver reperfusion (P<0.05), and reduced plasma transaminases (P<0.05) and ultrastructural markers of injury. In contrast compared to RIPC+IR, ODQ+RIPC+IR decreased hepatic MBF (P<0.05) and ultrastructural markers of injury. However, plasma transaminases were not significantly different in the ODQ+RIPC+IR compared to the RIPC+IR group. Hepatic cGMP levels were significantly elevated in the RIPC compared to sham group.. The hepatic sGC-cGMP pathway is required for mediating the protective effects of lower limb RIPC on hepatic MBF in liver IR injury.

Topics: Animals; Cyclic GMP; Disease Models, Animal; Follow-Up Studies; Guanylate Cyclase; Ischemic Preconditioning; Liver; Liver Circulation; Liver Diseases; Mice; Microcirculation; Microscopy, Electron, Transmission; Receptors, Cytoplasmic and Nuclear; Reperfusion Injury; Soluble Guanylyl Cyclase

Nitroalkene derivatives of nitro-oleic acid (OA-NO2) are endogenous lipid products with potent anti-inflammatory properties in vitro. The present study was undertaken to evaluate the in vivo anti-inflammatory effect of OA-NO2 in mice given LPS. Two days before LPS administration, C57BL/6J mice were chronically infused with vehicle (LPS vehicle) or OA-NO2 (LPS OA-NO2) at 200 microg x kg(-1) x day(-1) via osmotic minipumps; LPS was administered via a single intraperitoneal (ip) injection (10 mg/kg in saline). A third group received an ip injection of saline without LPS or OA-NO2 and served as controls. At 18 h of LPS administration, LPS vehicle mice displayed multiorgan dysfunction as evidenced by elevated plasma urea and creatinine (kidney), aspartate aminotransferase (AST) and alanine aminotransferase (ALT; liver), and lactate dehydrogenase (LDH) and reduced ejection fraction (heart). In contrast, the severity of multiorgan dysfunction was less in LPS OA-NO2 animals. The levels of circulating TNF-alpha and renal TNF-alpha mRNA expression, together with renal mRNA expression of monocyte chemoattractant protein-1, ICAM-1, and VCAM-1, and with renal mRNA and protein expression of inducible nitric oxide synthase and cyclooxygenase 2, and renal cGMP and PGE2 contents, were greater in LPS vehicle vs. control mice, but were attenuated in LPS OA-NO2 animals. Similar patterns of changes in the expression of inflammatory mediators were observed in the liver. Together, pretreatment with OA-NO2 ameliorated the inflammatory response and multiorgan injury in endotoxin-induced endotoxemia in mice.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Aspartate Aminotransferases; Blood Urea Nitrogen; Body Temperature; Cell Adhesion Molecules; Chemokines; Creatinine; Cyclic GMP; Cyclooxygenase 2; Cytokines; Dinoprostone; Disease Models, Animal; Drug Administration Schedule; Endotoxemia; Heart Diseases; Hematocrit; Inflammation Mediators; Infusion Pumps, Implantable; Kidney; Kidney Diseases; Lipopolysaccharides; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Myocardium; Nitric Oxide Synthase Type II; Oleic Acids; Stroke Volume; Time Factors

Topics: Cyclic AMP; Cyclic GMP; Diabetes Insipidus, Nephrogenic; Humans; Liver Diseases; Myocardial Infarction; Parathyroid Diseases

Sinusoidal endothelial dysfunction with decreased nitric oxide (NO) production contributes to increased hepatic resistance in cirrhosis. Statins improve endothelial dysfunction in peripheral vasculature. This study was designed to characterize the hemodynamic and molecular effects of statins in cirrhotic rats.. Systemic and splanchnic hemodynamics were evaluated in CCl(4) ascitic cirrhotic rats treated with placebo or simvastatin (25 mg/kg/day, for 3 days), at baseline and after volume expansion. Vascular responses of liver vasculature were evaluated after isolation and perfusion of the liver.. There were no differences in baseline hemodynamics in rats treated with simvastatin or placebo. However, in rats treated with simvastatin the increase in portal pressure induced by volume expansion was significantly attenuated. In isolated and perfused cirrhotic livers simvastatin pre-treatment significantly attenuated the pressure response to methoxamine, and significantly improved paradoxical vasoconstriction induced by acetylcholine. These effects were not observed in the presence of a nitric oxide synthase inhibitor. Simvastatin increased eNOS expression, Akt-dependent eNOS phosphorylation and cGMP liver content.. The administration of simvastatin might constitute a new way to selectively increase NO availability in the cirrhotic liver circulation and, therefore improve the vascular disturbances that contribute to portal hypertension.

Topics: Animals; Anticholesteremic Agents; Carbon Tetrachloride; Cyclic GMP; Liver; Liver Cirrhosis; Liver Diseases; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Perfusion; Phosphorylation; Rats; Rats, Wistar; Simvastatin

The generation of reactive oxygen species (ROS) by activated Kupffer cells contributes to liver injury following liver preservation, shock, or endotoxemia. Pharmacological interventions to protect liver cells against this inflammatory response of Kupffer cells have not yet been established. Atrial natriuretic peptide (ANP) protects the liver against ischemia-reperfusion injury, suggesting a possible modulation of Kupffer cell-mediated cytotoxicity. Therefore, we investigated the mechanism of cytoprotection by ANP during Kupffer cell activation in perfused rat livers of male Sprague-Dawley rats. Activation of Kupffer cells by zymosan (150 microgram/ml) resulted in considerable cell damage, as assessed by the sinusoidal release of lactate dehydrogenase and purine nucleoside phosphorylase. Cell damage was almost completely prevented by superoxide dismutase (50 U/ml) and catalase (150 U/ml), indicating ROS-related liver injury. ANP (200 nM) reduced Kupffer cell-induced injury via the guanylyl cyclase-coupled A receptor (GCA receptor) and cGMP: mRNA expression of the GCA receptor was found in hepatocytes, endothelial cells, and Kupffer cells, and the cGMP analog 8-bromo-cGMP (8-BrcGMP; 50 microM) was as potent as ANP in protecting from zymosan-induced cell damage. ANP and 8-BrcGMP significantly attenuated the prolonged increase of hepatic vascular resistance when Kupffer cell activation occurred. Furthermore, both compounds reduced oxidative cell damage following infusion of H2O2 (500 microM). In contrast, superoxide anion formation of isolated Kupffer cells was not affected by ANP and only moderately reduced by 8-BrcGMP. In conclusion, ANP protects the liver against Kupffer cell-related oxidant stress. This hormonal protection is mediated via the GCA receptor and cGMP, suggesting that the cGMP receptor plays a critical role in controlling oxidative cell damage. Thus ANP signaling should be considered as a new pharmacological target for protecting liver cells against the inflammatory response of activated Kupffer cells without eliminating the vital host defense function of these cells.

Topics: Animals; Atrial Natriuretic Factor; Catalase; Cyclic GMP; Endothelium, Vascular; Gene Expression; Guanylate Cyclase; Kupffer Cells; L-Lactate Dehydrogenase; Liver; Liver Diseases; Male; Oxidative Stress; Purine-Nucleoside Phosphorylase; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; Reperfusion Injury; Superoxide Dismutase

Blunted volume expansion (VE) natriuresis and renal resistance to atrial natriuretic peptide (ANP) characterize states of pathological sodium retention. This study examined rats 1 to 3 wk after common bile-duct ligation (CBDL), at which time they had hyperbilirubinemia and hypoalbuminemia. Sham-operated normal rats (Sham) showed an increased sodium excretion rate (UNaV) from 1.0 +/- 0.1 to 16.3 +/- 3.9 muEq/min in response to acute VE (iv saline, 2 mL/100 g body wt over 5 min), whereas CBDL rats had a blunted response that was apparent after 1 wk and became maximal at 2 and 3 wk (0.3 +/- 0.1 to 3.2 +/- 0.4 muEq/min at 3 wk, P < 0.01 versus Sham response). The peak urinary cGMP excretion rate (UcGMPV) was also blunted (37.9 +/- 3.6 versus 87.5 +/- 8.3 pmol/min, P < 0.01) despite an even greater increase in plasma ANP concentration (Sham, 9.6 +/- 0.4 pg/mL in hydropenia to 22.8 +/- 2.6 pg/mL after VE; CBDL, 15.3 +/- 2.3 to 41.8 +/- 6.8 pg/mL). ANP-dependent cGMP accumulation by isolated inner medullary collecting duct (IMCD) cells from both Sham and CBDL rat kidneys was dose-dependent; however, at higher concentrations of ANP (> 10(-8) M), accumulation by cells from CBDL rats was significantly blunted, indicating resistance to ANP. Binding of 125I-ANP to IMCD cells was not different in CBDL rats compared with Sham control rats. Renal denervation improved but did not completely reverse the blunted natriuresis, and ANP resistance persisted in IMCD cells from denervated kidneys of CBDL rats. Incubation of IMCD cells with the phosphodiesterase inhibitors isomethylbutylxanthine or Zaprinast (each at 10(-3) M) restored ANP responsiveness in both innervated and denervated kidneys from CBDL rats, and intrarenal infusion of Zaprinast (10 micrograms/min) corrected the blunted increase in UNaV and UcGMPV after VE in rats with CBDL. These results suggest that ANP resistance in a model of abnormal sodium metabolism devoid of intrinsic renal disease may be related to increased activity of phosphodiesterase in renal target cells for ANP as well as to heightened renal nerve activity.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Atrial Natriuretic Factor; Blood Volume; Common Bile Duct; Cyclic GMP; Drug Resistance; Kidney; Ligation; Liver Diseases; Male; Natriuresis; Nervous System; Phosphodiesterase Inhibitors; Purinones; Rats; Rats, Sprague-Dawley

Topics: Asthma; Cyclic GMP; Humans; Liver Diseases; Myocardial Infarction; Neoplasms; Radioimmunoassay

Topics: Adult; Animals; Cyclic GMP; Hepatitis; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Liver Regeneration; Male; Rats; Rats, Inbred Strains; Receptors, Muscarinic

Rats having a non-necrotic damaged liver or a necrotic damaged liver produced by D-galactosamine administration were restrained in water for 0.5, 1, 2, 4, 6, 8 and 12 hours. Serial changes in intrahepatic energy metabolism were compared with those in normal liver. Energy charge, which represents the degree of equilibrium between the energy producing and consuming systems, and cyclic AMP, an intracellular messenger mediating the action of hormones, showed biphasic increases before and after 2 hr in the damaged livers. The lactate/pyruvate ratio, which reflects the cytosolic redox state, markedly increased at 0.5 hr in the damaged livers but returned to the pre-stress level after 1 hr in the non-necrotic damaged liver and after 4 hr in the necrotic damaged liver, showing a transient reduced state. The beta-hydroxybutyrate/acetoacetate ratio, which represents the mitochondrial redox state, decreased at 0.5 hr and returned to the pre-stress level at 1 hr in the non-necrotic damaged liver, exhibiting a transient oxidized state. However, in the necrotic damaged liver, the value decreased at 0.5 hr remained low thereafter, demonstrating a persistent oxidized state. These findings show that, in severely damaged liver, stress has more marked effects on hepatic energy metabolism.

Topics: Acetyl Coenzyme A; Animals; Chemical and Drug Induced Liver Injury; Cyclic AMP; Cyclic GMP; Energy Metabolism; Galactosamine; Ketone Bodies; Lactates; Lactic Acid; Liver Diseases; Male; Pyruvates; Pyruvic Acid; Rats; Rats, Inbred Strains; Stress, Physiological

To clarify the factor(s) responsible for changes in the plasma cyclic GMP concentration in liver diseases, we measured the plasma levels of cyclic GMP, along with cyclic AMP, in various clinical stages of chronic liver diseases and acute hepatitis. The level of cyclic GMP was found to increase significantly in the early stage of acute hepatitis, in the decompensated stage of liver cirrhosis, and in malignant diseases. In the former two states, it is postulated that decreased hepatic mass is responsible for the changes in the plasma cyclic GMP concentration. The retention rate of indocyanin green (ICGR15) was highly correlated with the plasma cyclic GMP level. The result suggests that the determination of plasma cyclic GMP is useful as an index of the reserve function of the liver in disease states.

Topics: Carcinoma, Hepatocellular; Cyclic AMP; Cyclic GMP; Hepatitis; Humans; Indocyanine Green; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Nucleotides, Cyclic

To investigate the prediction that urinary cGMP (UcGMP) and cAMP (UcAMP) excretion is altered in a manner consistent with unregulated cell growth in hepatocellular carcinoma (HCC), we studied 31 patients with this disease, 25 without apparent disease, 16 with various hepatic diseases, and 16 with nonhepatic neoplasms. Results were expressed as UcGMP excretion per 100 ml glomerular filtration because reduced creatinine excretion in patients with muscle wasting or renal dysfunction may spuriously elevate UcGMP. UcGMP excretion was elevated in 80% of patients with HCC, 75% of patients with hepatic disease and 68% of patients with other neoplasms. Mean values for UcAMP excretion did not differ significantly from normal values. Plasma and ascitic fluid cGMP concentrations in HCC and hepatic diseases were raised. These results support the hypothesis of a shift in cyclic nucleotide metabolism toward cGMP in malignant diseases. However, UcGMP measurement does not detect progression of cirrhosis to HCC.

Topics: Adolescent; Adult; Aged; Body Fluids; Carcinoma, Hepatocellular; Child; Cyclic AMP; Cyclic GMP; Female; Humans; Liver; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Male; Metabolic Clearance Rate; Middle Aged