cyclic-gmp and Cholestasis

Acute-on-chronic liver disease is a clinical syndrome characterized by decompensated liver fibrosis, portal hypertension and splanchnic hyperdynamic circulation. We aimed to determine whether the alpha-1 agonist phenylephrine (Phe) facilitates endothelial nitric oxide (NO) release by mesenteric resistance arteries (MRA) in rats subjected to an experimental microsurgical obstructive liver cholestasis model (LC). Sham-operated (SO) and LC rats were maintained for eight postoperative weeks. Phe-induced vasoconstriction (in the presence/absence of the NO synthase -NOS- inhibitor L-NAME) and vasodilator response to NO donor DEA-NO were analysed. Phe-induced NO release was determined in the presence/absence of either H89 (protein kinase -PK- A inhibitor) or LY 294002 (PI3K inhibitor). PKA and PKG activities, alpha-1 adrenoceptor, endothelial NOS (eNOS), PI3K, AKT and soluble guanylate cyclase (sGC) subunit expressions, as well as eNOS and AKT phosphorylation, were determined. The results show that LC blunted Phe-induced vasoconstriction, and enhanced DEA-NO-induced vasodilation. L-NAME increased the Phe-induced contraction largely in LC animals. The Phe-induced NO release was greater in MRA from LC animals. Both H89 and LY 294002 reduced NO release in LC. Alpha-1 adrenoceptor, eNOS, PI3K and AKT expressions were unchanged, but sGC subunit expression, eNOS and AKT phosphorylation and the activities of PKA and PKG were higher in MRA from LC animals. In summary, these mechanisms may help maintaining splanchnic vasodilation and hypotension observed in decompensated LC.

Topics: Acute-On-Chronic Liver Failure; Adrenergic alpha-1 Receptor Antagonists; Animals; Cholestasis; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Hypertension, Portal; Isoquinolines; Liver; Liver Cirrhosis; Male; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; Phenylephrine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1; Sulfonamides; Vasoconstriction

To find out if N-acetylcysteine (NAC) would improve hepatic circulation in dogs with obstructive jaundice.. Open laboratory study.. University hospitals, Japan and France.. 14 male beagle dogs and 10 male Wistar rats.. Obstructive jaundice was produced by ligation of the common bile duct (CBD) for 7 days in both dogs and rats. Either 5% dextrose (control group, n = 7) or NAC (NAC group, n = 7) was given to dogs. Sinusoidal endothelial cells were obtained from rats after ligation by elutriation, and varying amounts of NAC were given.. The volumes of portal blood flow and hepatic microcirculatory tissue flow were reduced after ligation of the CBD, but those increased after NAC had been given to dogs with obstructive jaundice. NAC increased the concentrations of plasma cyclic 3',5'-guanosine monophosphate (cGMP). It also increased concentrations of serum and hepatic-reduced glutathione, and hepatic adenosine triphosphate (ATP) in cholestatic dogs, and secretion of cGMP from sinusoidal endothelial cells from rats with obstructive jaundice.. These results suggest that NAC given intravenously effectively improves hepatic circulation and hepatic function in dogs with obstructive jaundice.

Topics: Acetylcysteine; Adenosine Triphosphate; Animals; Cholestasis; Common Bile Duct; Cyclic GMP; Dogs; Glutathione; Ligation; Liver; Liver Circulation; Male; Microcirculation; Portal Vein; Rats; Rats, Wistar; Regional Blood Flow; Stimulation, Chemical

The purpose of this study was to assess the participation of the atrial natriuretic peptide (ANP)-cGMP system in electrolyte and volume handling of cholestatic rats submitted to an acute oral sodium load. Cholestasis was induced by ligation and section of the common bile duct (n = 51). Control rats were sham operated (n = 56). Three weeks after surgery, 24-hr urinary volume, sodium, potassium, cGMP and creatinine excretion were measured. Three days later, animals received 10 mmol/kg NaCl (1 M) by gavage, and urinary excretion was measured for 6 hr. In parallel groups of rats, plasma volume, electrolytes and ANP concentration, extracellular fluid volume (ECFV), and renal medullary ANP-induced cGMP production were determined in basal conditions or 1 hr after oral sodium overload. As compared with controls, cholestatic rats had a larger ECFV and higher plasma ANP (67.2 +/- 5.2 vs 39.7 +/- 3.5 pg/ml), but lower hematocrit and blood volume, and were hyponatremic. Cholestatic rats showed higher basal excretion of sodium, potassium, and volume than controls, but equal urinary cGMP. After the NaCl overload, cholestatic rats showed a reduced sodium excretion but equal urinary cGMP. One hr after sodium overload, both groups showed hypernatremia, but whereas in control rats ECFV and ANP increased (50.7 +/- 4.1 pg/ml), in cholestatic rats ECFV was unchanged, and plasma volume and ANP were reduced (37.5 +/- 5.8 pg/ml). ANP-induced cGMP production in renal medulla was similar in cholestatic and control nonloaded rats (14.2 +/- 5.2 vs 13.4 +/- 2.6 fmol/min/mg). One hr after the load, medullary cGMP production rose significantly in both groups, without difference between them (20.6 +/- 3.1 vs 22.7 +/- 1. 7 fmol/min/mg). We conclude that the blunted excretion of an acute oral sodium load in cholestatic rats is associated with lower plasma ANP due to differences in body fluid distribution and cannot be explained by renal refractoriness to ANP.

Topics: Animals; Atrial Natriuretic Factor; Bile Ducts; Blood Volume; Cholestasis; Creatinine; Cyclic GMP; Diuresis; Female; Hematocrit; Kidney Medulla; Ligation; Natriuresis; Potassium; Rats; Rats, Sprague-Dawley; Sodium; Urine