6-ketoprostaglandin-f1-alpha and Liver-Cirrhosis

A double-blind crossover study versus placebo of the renal effects of the nonsteroidal anti-inflammatory drug imidazole 2-hydroxybenzoate was conducted in 10 patients with compensated liver cirrhosis. The administration of the drug (750 mg, t.i.d., for three days) did not affect renal plasma flow, glomerular filtration rate, free water clearance nor the urinary excretion of sodium or potassium. Values of plasma renin activity also did not change after drug administration. Direct tubular damage from imidazole 2-hydroxybenzoate was also excluded by normal excretion of beta-2-microglobulin and N-acetyl-beta-D-glucosaminidase. Urinary 6-keto-PGF1 alpha output were comparable during imidazole 2-hydroxybenzoate and placebo administration. These data indicate that this nonsteroidal antiinflammatory drug does not affect the renal function in patients with compensated liver cirrhosis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Double-Blind Method; Female; Humans; Imidazoles; Kidney; Kidney Function Tests; Liver Cirrhosis; Male; Metabolic Clearance Rate; Middle Aged; p-Aminohippuric Acid; Pilot Projects; Renal Circulation; Salicylates

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome secondary to acute or chronic liver failure. However, its pathophysiology remains obscure. Recently, we found that the inhibition of cyclooxygenase by indomethacin aggravated HE in rats with thioacetamide-induced acute hepatic failure, suggesting a pivotal role of cyclooxygenase in HE. This study was aimed at surveying the roles of cyclooxygenase isoforms responsible for prostaglandins synthesis, cyclooxygenase-1 (COX1) and COX2, in cirrhotic rats with HE.. Liver cirrhosis was induced (using formalin) in male Sprague-Dawley rats with bile duct ligation (FBDL). Sham-operated rats served as the surgical controls. The severity of HE was assessed by motor activity counts. Plasma 6-keto-prostaglandin-F. The FBDL group showed lower motor activity counts than the sham group in total (1472 ± 156 vs. 2174 ± 262 counts/30 min, p = 0.034), ambulatory (824 ± 99 vs. 1443 ± 206 counts/30 min, p = 0.014), and vertical movement (431 ± 69 vs. 849 ± 145 counts/30 min, p = 0.018). The mRNA expression of hepatic COX2 was significantly higher in the FBDL group. Plasma ALK-P and bilirubin levels were negatively correlated with total movements, respectively (both p < 0.05). In addition, hepatic COX2 mRNA expression was positively correlated with AST, ALK-P, total bilirubin, and 6-keto-PGF. Hepatic COX2 expression and PGI

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Epoprostenol; Hepatic Encephalopathy; Liver; Liver Cirrhosis; Male; Motor Activity; Rats; Rats, Sprague-Dawley

Cannabinoids have been reported to participate in the pathogenesis of peripheral vasodilatation in cirrhosis. However, their roles in increased intrahepatic resistance (IHR) in cirrhotic livers are unknown. We aimed to investigate the effects of cannabinoids in the hepatic microcirculation of cirrhotic rats produced by bile duct ligation. In isolated liver perfusion, portal perfusion pressure (PPP) and the production of eicosanoids in the perfusate were measured. In addition, various hepatic protein levels [cyclooxygenase (COX) isoform and 5-lipoxygenase (5-LOX)] were also determined. Finally, concentration-response curves for PPP and the corresponding production of eicosanoids in response to anandamide (1.44 x 10(-10)-1.44 x 10(-3) M) after indomethacin (COX inhibitor), piriprost (5-LOX inhibitor), or furegrelate (thromboxane A(2) synthase inhibitor) preincubation were obtained. The study showed that cirrhotic livers had significantly higher levels of PPP, COX-2 and 5-LOX protein expression, and production of thromboxane B(2) (TXB(2)) and cysteinyl leukotrienes (Cys-LTs) than normal livers. Anandamide induced a dose-dependent increase in PPP in both normal and cirrhotic livers. The anandamide-induced increase in PPP was found concomitantly with a significant increase in TXB(2) and Cys-LT production in the perfusate. In response to anandamide administration, cirrhotic livers exhibited a significantly greater increase in IHR and production of TXB(2) and Cys-LTs than normal livers. Indomethacin and furegrelate, but not piriprost, significantly ameliorated the anandamide-induced increase in IHR in cirrhotic livers. In conclusion, anandamide plays, in part, an important role in increased IHR of cirrhotic livers. The anandamide-induced increase in IHR in cirrhotic livers may be mediated by increased COX-derived eicosanoid (mainly thromboxane A(2)) production.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Blood Pressure; Blotting, Western; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Cysteine; Eicosanoids; Endocannabinoids; In Vitro Techniques; Leukotrienes; Lipoxygenase Inhibitors; Liver; Liver Circulation; Liver Cirrhosis; Male; Microcirculation; Perfusion; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Thromboxane B2

In cirrhotic livers, increased resistance to portal flow, in part due to an exaggerated response to vasoconstrictors, is the primary factor in the pathophysiology of portal hypertension. Our aim was to evaluate the response of the intrahepatic circulation of cirrhotic rat livers to the alpha(1)-adrenergic vasoconstrictor methoxamine and the mechanisms involved in its regulation. A portal perfusion pressure dose-response curve to methoxamine was performed in control and cirrhotic rat livers preincubated with vehicle, the nitric oxide synthase blocker N(G)-nitro-L-arginine (L-NNA), indomethacin cyclooxygenase (COX) inhibitor, L-NNA + indomethacin, or the thromboxane (TX) A(2) receptor blocker SQ 29,548. TXA(2) production, COX-1 and COX-2 mRNA expression, and immunostaining for TXA(2) synthase were evaluated. Cirrhotic livers exhibited a hyperresponse to methoxamine associated with overexpression of COX-2 and TXA(2) synthase as well as with increased production of TXA(2). The hyperresponse to methoxamine of cirrhotic livers disappeared by COX inhibition with indomethacin but not after NO inhibition. SQ 29,548 also corrected the hyperresponse of cirrhotic livers to methoxamine. In conclusion, COX-derived prostanoids, mainly TXA(2), play a major role in regulating the response of cirrhotic livers to methoxamine.

Topics: 6-Ketoprostaglandin F1 alpha; Adrenergic alpha-Agonists; Animals; Arachidonic Acid; Blood Pressure; Carbon Tetrachloride; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Isoenzymes; Liver Circulation; Liver Cirrhosis; Male; Membrane Proteins; Methoxamine; Nitric Oxide; Portal System; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Receptors, Thromboxane; RNA, Messenger; Thromboxane A2; Vascular Resistance

Despite the suppression of glucagon release, an adaptive response aimed at maintaining vasodilatation after octreotide treatment may exist in portal hypertension. The present study was undertaken to evaluate the possible interaction between endothelium and non-endothelium-derived vasodilators after 1-wk octreotide administration in cirrhotic rats. Rats were allocated to receive either vehicle or octreotide (30 or 100 microg/kg every 12 h subcutaneously). Hemodynamic values, plasma glucagon levels, endothelium-related vasodilatory activities, and aortic endothelial nitric oxide synthase (eNOS) expression were determined after treatment. Octreotide administration decreased plasma glucagon and increased serum 6-keto-PGF(1 alpha) and NOx levels without affecting the hemodynamic values. In cirrhotic rats receiving octreotide, there was a blunt response to either L-NAME or indomethacin administration alone, but this blunt pressor response disappeared after simultaneous administration of the two drugs. Additionally, an increased aortic eNOS expression was observed in cirrhotic rats receiving 1-wk octreotide. It is concluded that 1-wk octreotide treatment did not correct the hemodynamic derangement in cirrhotic rats. The enhanced endothelium-related vasodilatory activity was noted after octreotide treatment that overcame the octreotide-induced hemodynamic effects in portal hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Blotting, Western; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glucagon; Hypertension, Portal; Indomethacin; Liver Cirrhosis; Male; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitrites; Octreotide; Rats; Rats, Sprague-Dawley; Somatostatin; Splanchnic Circulation; Vasoconstrictor Agents; Vasodilation

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

Plasma levels and gastric mucosal contents of prostaglandin (PG) E2 and prostacyclin were determined in cirrhotic patients with portal hypertensive gastropathy (PHG), in cirrhotic patients without PHG and in healthy controls. PGE2 and 6-keto-PGF1 alpha (a stable metabolite of prostacyclin) levels were measured in 30 cirrhotic patients and 10 controls, using radioimmunoassay. Of 30 cirrhotics, 13 had PHG of the fundus and the corpus. Plasma concentrations of 6-keto-PGF1 alpha in the cirrhotic patients were significantly higher than in the controls (p < 0.01), but there was no significant difference between cirrhotics and controls with regard to plasma levels of PGE2. The gastric mucosal contents of 6-keto-PGF1 alpha in the fundus was significantly higher in cirrhotics with PHG than those without PHG (p < 0.05) and controls (p < 0.01). However, the gastric mucosal contents of PGE2 in the fundus were not significantly different in cirrhotics with and without PHG. The gastric mucosal contents of 6-keto-PGF1 alpha significantly correlated to the plasma levels (r = 0.37, p < 0.05), but there was no significant correlation between plasma levels and gastric mucosal contents of PGE2. Since prostacyclin has vasodilator and gastric acid inhibitory effects, we speculate that high contents of prostacyclin in the gastric mucosa may have some role in the pathogenesis of PHG.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Dinoprostone; Female; Gastric Fundus; Gastric Mucosa; Humans; Hypertension, Portal; Japan; Liver Cirrhosis; Male; Middle Aged; Stomach Diseases

Topics: 6-Ketoprostaglandin F1 alpha; Epoprostenol; Humans; Liver Cirrhosis; Liver Transplantation; Thromboxane A2

Patients with cirrhosis and ascites are especially sensitive to the adverse renal effects of indomethacin-induced inhibition of prostaglandin synthesis. The aim of this study was to determine whether indomethacin affects renal function in patients with well-compensated cirrhosis.. Clearance techniques were used to assess renal hemodynamics and sodium and water homeostasis.. The oral administration of 50 mg of indomethacin to well-compensated patients with alcoholic cirrhosis was followed by a significant decrease in glomerular filtration rate (GFR) and effective renal plasma flow because of a preferential increase in afferent arteriolar tone. Indomethacin was both antidiuretic and antinatriuretic due principally to decreased free water clearance and increased proximal tubular reabsorption of sodium. The acute changes in renal function were not sustained. Patients with a high basal GFR were particularly sensitive to the adverse renal effects of indomethacin.. This study indicates that in patients with well-compensated cirrhosis renal prostaglandins are functionally active and may contribute to the pathogenesis of glomerular hyperfiltration. Nonsteroidal anti-inflammatory drugs should be used with caution in all patients with cirrhosis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Dinoprostone; Female; Glomerular Filtration Rate; Humans; Indomethacin; Kidney; Liver Cirrhosis; Male; Middle Aged; Renin; Sodium

We measured blood platelet count and plasma beta-thromboglobulin concentration in 67 patients with acute or chronic liver diseases. Plasma TXB2 and 6-keto-PGF1a concentration were also measured in these patients. The results showed that blood platelet count of less than 100 x 10(9)/L was found in 14% of the patients with acute hepatitis, 23% with chronic hepatitis, 67% with hepatic cirrhosis but without splenectomy and 40% with primary liver carcinoma. Platelet count is lowest in patients with hepatic cirrhosis without splenectomy but normal in patients with hepatic cirrhosis after splenectomy. Plasma beta-TG concentration increased in patients with acute or chronic liver diseases. A negative correlation was found between beta-TG concentration and platelet count in chronic liver diseases. It is suggested that platelet is in activated state in vivo and this may be one of the important reasons for both decrease of platelet count and impairment of platelet function. Plasma TXB2 concentration increased in chronic liver diseases, while plasma 6-keto-PGF1a concentration decreased. The balance between TXA2 and PGI2 is upset; this may be an important mechanism for activation of platelets in vivo.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; beta-Thromboglobulin; Female; Hepatitis, Viral, Human; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Platelet Count; Thromboxane B2

The total body production of prostacyclin was shown to be increased in cirrhotic patients, suggesting that its synthesis by blood vessels of the systemic circulation is enhanced. However, the mechanism by which the synthesis of systemic prostacyclin is stimulated is not known. The present study investigated the urinary excretion of 2,3-dinor-6-keto-PGF1 alpha, an index of total body prostacyclin synthesis, first, in cirrhotics with portal hypertension (n = 19) as compared with cirrhotics with reduced portal pressure after portacaval shunt surgery (n = 18) and with control noncirrhotic subjects (n = 11), and; second, in cirrhotics before and after intestinal decontamination by oral nonabsorbable antibiotics (n = 9 antibiotic treated patients, n = 10 control nontreated cirrhotics). Control noncirrhotic subjects showed lower urinary excretion of 2,3-dinor-6-keto-PGF1 alpha than both groups of cirrhotics (P less than 0.001). Interestingly, urinary excretion of 2,3-dinor-6-keto-PGF1 alpha was significantly higher in cirrhotics with portacaval shunt than in those with portal hypertension (P less than 0.01). The urinary excretion of 2,3-dinor-6-keto-PGF1 alpha decreased significantly after intestinal decontamination in the antibiotic-treated group (580.1 +/- 232.4 vs. 431.2 +/- 219.2 pg/mg creatinine; P less than 0.05) but not in nontreated patients (543.9 +/- 214.4 vs. 581.2 +/- 281.4 pg/mg creatinine; P = NS). These data suggest that the increased urinary excretion of 2,3-dinor-6-keto-PGF1 alpha observed in cirrhotics is not directly related to portal hypertension itself but to portal blood factors that bypass the liver. Some such factors may be of intestinal bacterial origin.

Topics: 6-Ketoprostaglandin F1 alpha; Anti-Bacterial Agents; Bacteria; Epoprostenol; Humans; Hypertension, Portal; Intestines; Liver Cirrhosis; Portacaval Shunt, Surgical

The influence of prostaglandins on renal function changes induced by furosemide was analyzed in 21 non-azotemic cirrhotic patients with ascites. Patients were studied in two periods of 120 min immediately before and after furosemide infusion (20 mg, ev). Furosemide caused an increase in creatinine clearance in 15 patients (group A: 99 +/- 7 vs. 129 +/- 5 ml/min; mean +/- S.E.) and a reduction in the remaining six (group B: 102 +/- 13 vs. 71 +/- 9 ml/min). Parallel changes were observed in the urinary excretion of 6-Keto-prostaglandin-F1 alpha (metabolite of renal prostacyclin) which augmented after furosemide in 14 of the 15 patients from group A (478 +/- 107 vs. 1034 +/- 159 pg/min, p less than 0.001) and decreased in all patients from group B (1032 +/- 240 vs. 548 +/- 136 pg/min, p less than 0.05). In contrast, the urinary excretion of prostaglandin E2 was stimulated by furosemide in all patients (group A, 92 +/- 19 vs. 448 +/- 60 pg/min, p less than 0.001; and group B, 209 +/- 63 vs. 361 +/- 25 pg/min, p less than 0.05). In all of the patients furosemide-induced changes (post- minus pre-furosemide values) in creatinine clearance were closely correlated in a direct and linear fashion with those in 6-Keto-prostaglandin-F1 alpha (r = 0.74; p less than 0.001). These changes were associated with a higher furosemide-induced natriuresis in group A than in group B (641 +/- 68 vs. 302 +/- 46 mumol/min, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Dinoprostone; Epoprostenol; Female; Furosemide; Humans; Kidney; Liver Cirrhosis; Male; Uremia

Following hepatectomy, arterial concentrations of thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), which are stable metabolites of thromboxane A2(TXA2) and prostaglandin I2(PGI2), were measured by radioimmunoassay in 17 cirrhotic and 9 non-cirrhotic patients to assess the role of TXB2 and PGI2 in patients with liver dysfunction during hepatectomy. In both cirrhotic and non-cirrhotic patients, arterial TXB2 and 6-keto-PGF1 alpha levels significantly increased during hepatectomy and decreased to preoperative levels at the 1st postoperative day (1-POD). The TXB2/6-keto-PGF1 alpha ratio significantly decreased during hepatectomy and at 1-POD. There were no significant differences in changes of TXB2 and PGI2 levels between cirrhotic and non-cirrhotic patients. In cirrhotic patients with poor hepatic reserve, whose ICG K values were less than 0.08, arterial 6-keto-PGF1 alpha levels were significantly higher and the ratio were significantly lower than in cirrhotic patients with good hepatic reserve and non-cirrhotic patients before and after operation. Based on these results, it is concluded that the TXA2/PGI2 ratio becomes low after hepatectomy and the ratio is lower in cirrhotic patients with poor hepatic reserve.

Topics: 6-Ketoprostaglandin F1 alpha; Female; Hepatectomy; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Postoperative Period; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Female; Glomerulonephritis; Humans; Hypertension; Kidney Diseases; Liver Cirrhosis; Male; Nephrotic Syndrome; Radioimmunoassay; Thromboxane B2; Uremia

Urinary excretion rates of prostaglandin (PG) E2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane (TX) B2 were evaluated in three groups of cirrhotic patients [without ascites (group 1, 13 cases), with ascites and normal renal function (group 2, 15 cases), and with ascites and renal failure (group 3, 5 cases)] and in 14 healthy controls. All urinary arachidonate metabolites were significantly increased in group 2 patients. Patients with renal failure showed lower PGE2, PGF2 alpha, and TXB2 values than those from group 2; PGF2 alpha values were also lower than controls. Platelet TXA2 production during whole blood clotting was significantly reduced in all groups of patients. Administration of low-dose aspirin and sulindac, two cyclooxygenase inhibitors selectively sparing renal cyclooxygenase activity, effectively inhibited platelet TXA2 production without affecting urinary TXB2 excretion, thus ruling out platelets as a possible source of urinary TXB2. We conclude that patients with ascites and normal renal function show an overall activation of the renal PG system. Renal production of vasodilating PGE2 and PGI2 may be involved in supporting renal function in these patients. A reduced platelet synthesis of proaggregatory TXA2 also occurs in cirrhotic patients. This may play a role in the bleeding tendency of cirrhosis.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adult; Aged; Arachidonic Acid; Arachidonic Acids; Aspirin; Blood Platelets; Creatinine; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Epoprostenol; Female; Humans; Kidney; Liver Cirrhosis; Male; Middle Aged; Natriuresis; Prostaglandins E; Prostaglandins F; Renin-Angiotensin System; Sulindac; Thromboxane A2; Thromboxane B2

The aim of the study was to investigate the urinary excretion of 6-keto-PGF1 alpha (a stable metabolite of PGI2), thromboxane B2 (TxB2; a stable metabolite of TxA2), and PGE2 in 18 normal subjects, 49 cirrhotics with ascites without renal failure (GFR = 90 +/- 4 ml/min, means +/- S.E.M.) and 20 cirrhotics with functional renal failure (FRF) (GFR = 36 +/- 3). The study was made after 5 days on a 50 mEq sodium diet and without diuretics. Plasma renin activity (PRA), plasma norepinephrine concentration (NE) and plasma antidiuretic hormone concentration (ADH) were also measured. Cirrhotics without FRF showed a significantly higher urinary excretion of 6-keto-PGF1 alpha, TxB2 and PGE, (15.9 +/- 1.7 ng/h, 3.0 +/- 0.3 ng/h, and 6.2 +/- 1.0 ng/h) than did normal subjects (9.2 +/- 0.9, 1.3 +/- 0.1 and 2.3 +/- 0.4). On the contrary, the urinary excretion of these prostaglandins was normal or reduced in patients with FRF (5.3 +/- 0.8, 1.3 +/- 0.2 and 1.9 +/- 0.4). PRA, NE and ADH were significantly increased in cirrhotics with FRF (15.2 +/- 3.9 ng/ml/h, 1026 +/- 149 pg/ml and 4.1 +/- 0.3 pg/ml) and in patients without FRF (8.0 +/- 1.4, 667 +/- 67 and 3.9 +/- 0.3) as compared to normal controls (1.3 +/- 0.2, 275 +/- 46 and 2.4 +/- 0.2). These results suggest that renal hemodynamics in cirrhosis depends upon a critical equilibrium between the activity of endogenous vasoconstrictor systems and the renal production of the vasodilator prostaglandins PGI2 and PGE2. In addition, they do not support FRF in cirrhosis being related to an increased renal production of the vasoconstrictor prostaglandin TxA2.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Dinoprostone; Female; Glomerular Filtration Rate; Humans; Kidney; Liver Cirrhosis; Male; Prostaglandins E; Renal Circulation; Syndrome; Thromboxane B2

The effect of spironolactone on the urinary excretion of prostaglandins was studied in patients with liver cirrhosis and ascites. Patients were kept in bed and given a sodium-restricted diet for at least 4 days before spironolactone treatment was considered. Starting from the 5th day of protocol, patients were treated with this diuretic if their spontaneous weight loss had been less than 600 g during the 2 previous days. Patients were distributed in groups according to weight loss during the first 4 days on diuretic therapy: Group I (high responders), II (medium responders) and III (low responders). Group I patients showed higher basal values (4th day of protocol) of urinary sodium (P less than 0.02) and urinary 6-keto-PGF1 alpha (P less than 0.02) than the other patients, but there were no significant differences in the basal excretion rates of PGE2 nor TXB2 among the groups. The therapeutic requirement for spironolactone treatment in patients from Group I was delayed as compared with the other two groups (P less than 0.001) due to the fact that their spontaneous weight loss took place over a long period. For all patients, spironolactone administration produced a significant increase in 6-keto-PGF1 alpha excretion (P less than 0.01) without affecting significantly urinary elimination of PGE2 nor TXB2. A close relationship was found between the spironolactone-induced increments in urinary sodium and urinary 6-keto-PGF1 alpha excretion (r = 0.74, P less than 0.001). It is suggested that the ability of the kidney to synthetize prostacyclin can influence the natriuretic response to spironolactone therapy in patients with liver cirrhosis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Aged, 80 and over; Ascites; Body Weight; Dinoprostone; Female; Humans; Kidney; Liver Cirrhosis; Male; Middle Aged; Prostaglandins; Prostaglandins E; Sodium; Spironolactone; Thromboxane A2

Urinary excretion of two prostacyclin metabolites was investigated in 48 subjects: 8 controls and 40 cirrhotics (9 without ascites, 22 with ascites and preserved renal function, and 9 with functional renal failure). Urinary 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), believed to reflect renal prostacyclin production, was significantly increased in patients without ascites and in ascitic patients with preserved renal function, but cirrhotics with renal failure showed rates similar to controls. Excretion of 2,3-dinor-6-keto-PGF1 alpha (PGI-M), the major urinary metabolite of systemic prostacyclin, was increased in all groups of patients, including those with renal failure. A single dose of sulindac, a renal-sparing prostaglandin synthesis inhibitor, reduced PGI-M but not 6-keto-PGF1 alpha in 5 cirrhotic patients. This would be consistent with the predicted renal origin of the latter and the systemic origin of the former. Ascitic patients with high urinary excretion of PGI-M (above the median value) showed significantly lower mean arterial pressure and higher plasma renin activity and aldosterone than patients with excretion below the median. Urinary 6-keto-PGF1 alpha was higher in patients with low PGI-M. Finally, creatinine clearance corrected excretion of PGI-M, as an estimation of relative plasma levels correlates both with plasma renin activity and plasma aldosterone in the 31 subjects who presented with ascites. It is suggested that enhanced synthesis of systemic prostacyclin may influence hemodynamic changes in patients with liver cirrhosis. Overproduction of systemic prostacyclin in the absence of increased renal prostacyclin synthesis appears to be characteristic of patients with functional renal failure.

Topics: 6-Ketoprostaglandin F1 alpha; Ascites; Chromatography, High Pressure Liquid; Epoprostenol; Humans; Kidney; Kidney Failure, Chronic; Liver Cirrhosis; Radioimmunoassay; Sulindac

In 5 patients with cirrhosis and ascites the glomerular filtration rate (GFR), free water clearance (CH2O) and urinary excretion of prostaglandin E2(PGE2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were measured before and after a 3-day treatment with sulindac (400 mg/day). The administration of sulindac induced a marked fall of urinary excretion of PGE2 (from 24.2 +/- 5.5 to 3.8 +/- 1.1 ng/h; p less than 0.05), 6-keto-PGF1 alpha (from 19.9 +/- 2.9 to 5.6 +/- 1.1 ng/h; p less than 0.02) GFR (from 111 +/- 15 to 67 +/- 10 ml/min; p less than 0.01) and CH2O (from 7 +/- 1.5 to 3.7 +/- 1.3 ml/min; p less than 0.02) in all patients studied. The plasma concentration of the active metabolite sulindac sulfide in cirrhotics was 400% of that found in 6 healthy volunteers (9.6 +/- 1.7 vs. 2.4 +/- 0.6 ng/ml). Our results indicate that sulindac, at a dose of 400 mg/day, inhibits the renal synthesis of prostaglandins and impairs renal function in cirrhotics with ascites. These effects are probably related to the marked alteration of sulindac kinetics that occurs in these patients.

Topics: 6-Ketoprostaglandin F1 alpha; Ascites; Body Water; Dinoprostone; Glomerular Filtration Rate; Humans; Indenes; Kidney; Kinetics; Liver Cirrhosis; Norepinephrine; Prostaglandins E; Renin; Sulindac; Vasopressins

Urinary prostaglandin excretion was studied in 42 patients with liver cirrhosis and in nine control subjects on restricted sodium intake and on bed rest. Creatinine clearance (CCr), sodium excretion (UNaV), plasma renin activity (PRA) and plasma aldosterone were also evaluated. Patients without ascites and ascitic patients without renal failure showed increased urinary excretion of immunoreactive 6-ketoprostaglandin F1 alpha (i6-keto-PGF1 alpha), prostaglandin E2 (iPGE2) and thromboxane B2 (iTXB2) when compared with controls, while immunoreactive PGF2a (iPGF2 alpha) levels did not differ from those in the control group. Patients with functional renal failure (FRF) presented a significant reduction of vasodilator prostaglandins but urinary excretion of iTXB2 was higher than in controls. On the whole, cirrhotic patients with higher urinary excretion of prostaglandins had normal or nearly normal PRA and aldosterone levels. i6-keto-PGF1 alpha and iPGE2 inversely correlated with PRA and aldosterone. The relationship between i6-ketoPGF alpha alpha and CCr was found to be highly significant in cirrhotic patients but not in the control group. On the other hand, iPGE2 significantly correlated with UNaV and with the fractional excretion of sodium (FENa). We concluded that: (a) enhanced renal prostaglandin synthesis in cirrhosis, inversely related to PRA and aldosterone, may be dependent on volume status; and (b) preserved renal function in these patients is associated with the ability to synthesize prostacyclin and PGE2.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adult; Aged; Aldosterone; Creatinine; Dinoprost; Dinoprostone; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Prostaglandins; Prostaglandins E; Prostaglandins F; Renin; Sodium; Thromboxane B2

A method for 2,3-dinor-6-ketoprostaglandin F1 alpha quantification based on high-performance liquid chromatography-radioimmunoassay is described. Samples are acidified to pH 3 and processed through C18 disposable cartridges. The prostanoids are eluted with methyl formate and further separated on a reversed-phase column using acetonitrile-acetic acid-triethylamine buffer (32:68). Studies of the effect of eluent pH were performed in order to optimize resolution and separation of 2,3-dinor-6-keto-PGF1 alpha from other prostanoids. Eluates were collected and assayed by radioimmunoassay using a heterologous system, with 6-keto-PGF1 alpha as radioligand and an antiserum with high cross-reactivity for 2,3-dinor-6-keto-PGF1 alpha. Sensitivity, precision and accuracy of the assay procedure are reported together with the validation of its specificity. The proposed method has been applied to the determination of this prostacyclin metabolite in human urine.

Topics: 6-Ketoprostaglandin F1 alpha; Chromatography, Liquid; Female; Humans; Liver Cirrhosis; Male; Prostaglandins; Radioimmunoassay; Sulindac