6-ketoprostaglandin-f1-alpha and Liver-Cirrhosis--Alcoholic

Prostacyclin has been shown to increase portal hypertension, but the mechanism is unclear. This study aimed to investigate whether the overproduction of prostacyclin (PGI2) in cirrhosis participates in the splanchnic vascular hyporesponsiveness to vasoconstrictors in cirrhotic rats.. Cirrhotic model was created by subcutaneous injection of 60% carbon tetrachloride (CCl4) corn oil solution combined with intermittent drinking of 5% alcohol, and age-matched rats served as controls. The isolated third-generation mesenteric arterioles were used to examine the contractile response to norepinephrine. The changes in vascular diameter were observed under a microscope imaging device. The plasma concentration of 6-ketone-prostaglandin F1alpha (6-keto-PGF1alpha, a stable metabolite of PGI2) was tested via enzyme immunoassays and the expression of cyclooxygenase (COX) in mesenteric arteries was detected by Western blotting.. In parallel with the increase of plasma 6-keto-PGF1alpha, the contractile response of arterioles from cirrhotic rats to norepinephrine was significantly impaired compared with that from controls. Inhibition of PGI2 or protein kinase A with indomethacin or Rp-adenosine 3', 5'-cyclic monophosphothioate (Rp-cAMPS) partially reversed the vascular hypo-contractile response to norepinephrine in arterioles from cirrhotic rats. Indomethacin significantly decreased the plasma 6-keto-PGF1alpha. Furthermore, indomethacin significantly attenuated the effect of Rp-cAMPS on arterioles from cirrhotic rats. COX-1 expression was up-regulated in mesenteric arteries from cirrhotic rats, whereas COX-2 was not detectable in the mesenteric arteries from both cirrhotic and control rats.. Enhanced COX-1 expression in cirrhotic rats resulted in elevated PGI2 production which partially contributed to the splanchnic vascular hyporesponsiveness to a vasoconstrictor via the protein kinase A pathway.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterioles; Carbon Tetrachloride; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Epoprostenol; Ethanol; Liver Cirrhosis, Alcoholic; Liver Cirrhosis, Experimental; Male; Membrane Proteins; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Signal Transduction; Splanchnic Circulation; Up-Regulation; Vasoconstriction; Vasoconstrictor Agents

Plasma iPGE2 and i6-keto PGF1 alpha were measured with an EIA assay in twenty patients with alcohol-related liver cirrhosis (ALC group) and 13 patients with hepatitis B virus as an etiologic factor of liver cirrhosis (HLC group). Significant increase of both prostanoids was observed irrespectively of the etiology of liver cirrhosis. Their levels increased depending on the degree of liver insufficiency with the highest values in patients classified as Child-Pugh C class. A significant, positive correlation with Child-Pugh score was found regarding PGE2 (r = 0.657; p < 0.001) as well as 6-keto PGF1 alpha (r = 0.736; p < 0.001). Correlation (r = 0.789; p < 0.001) was also observed between levels of both prostaglandins. In conclusion we have shown that plasma iPGE2 and i6-keto PGF1 alpha arise simultaneously with the degree of liver insufficiency, that can be a result of activation of non-parenchymal liver cells accompanying hepatic fibrosis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Dinoprostone; Enzyme-Linked Immunosorbent Assay; Female; Hepatitis B; Humans; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male

To assess the effects of intrarenal thromboxane A2 generation on furosemide-induced sodium and water excretion we administered furosemide (40 mg i.v.) to 8 nonazotemic cirrhotic patients with ascites and 8 healthy subjects before and after the administration of OKY 046 (200 mg twice orally), a powerful thromboxane-synthase inhibitor. Selective thromboxane-synthase inhibition significantly reduced basal and postfurosemide (1 h) urinary thromboxane B2 excretion in healthy subjects (65% before and 62% after furosemide) as well as in cirrhotic patients (52% before and 67% after furosemide) without affecting urinary prostaglandin E2 and 6-keto prostaglandin F1 alpha excretion. During the first hour after furosemide administration, OKY 046 administration significantly enhanced postfurosemide water excretion (milliliters per minute) in both healthy subjects (from 8.5 +/- 2.0 to 11.6 +/- 2.1, p less than 0.001) and cirrhotic patients (from 1.1 +/- 0.8 to 4.2 +/- 0.5, p less than 0.005), whereas furesemide-induced natriuresis (microequivalents per minute) was significantly increased only in the latter group (from 973 +/- 125 to 1405 +/- 121, p less than 0.05). Our data indicate that intrarenal thromboxane A2 generation, elicited by furosemide administration, may reduce the effects of the drug on water and sodium diuresis. Such a reduction seems to be more marked in the presence of an activated intrarenal prostaglandin system, suggesting that renal thromboxane A2 may represent an additional factor in conditioning the impaired responsiveness to furosemide, which is frequently observed in cirrhotic patients with ascites.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Dinoprostone; Diuresis; Female; Furosemide; Humans; Kidney; Liver Cirrhosis, Alcoholic; Male; Methacrylates; Middle Aged; Prostaglandins E; Thromboxane A2; Thromboxane B2

Nonsteroidal antiinflammatory drugs impair renal function in susceptible patients with cirrhosis and ascites. A new antiinflammatory drug, sulindac, is reported not to affect renal function. To evaluate its renal-sparing mechanism, sulindac was administered for 5 days and ibuprofen for 1 day to 10 patients and paraaminohippurate and inulin clearances, serum and urine eicosanoids, and serum and urine sulindac metabolites were monitored. Ibuprofen reduced renal clearances in the 5 subjects with greatest sodium retention, whereas sulindac had no effect. Plasma concentration of the active sulfide metabolite was markedly increased in liver patients, and this concentration correlated with the inhibition of serum thromboxane (r = 0.75, p = 0.01). The percent inhibition of serum thromboxane with sulindac administration correlated with the inhibition of urinary eicosanoids (r = 0.68-0.81, all p less than 0.02). Ibuprofen was generally a more potent inhibitor of serum and urine eicosanoids. Thus, a major factor in the renal-sparing effect of sulindac appears to be its less potent inhibition of renal and extrarenal cyclooxygenase systems.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cyclooxygenase Inhibitors; Dinoprostone; Humans; Ibuprofen; Indenes; Kidney; Kidney Function Tests; Liver Cirrhosis, Alcoholic; Middle Aged; Prostaglandins E; Renal Circulation; Sulindac; Thromboxane B2; Time Factors