thromboxane-a2 and Ascites

This study was undertaken to investigate the role of increased renal thromboxane (TX) A2 production in modulating renal hemodynamics and sodium and water retention in cirrhotic patients with ascites. In a randomized, double-blind, placebo-controlled, crossover trial, 15 nonazotemic cirrhotic patients with ascites and elevated urinary TXB2 excretion received the thromboxane-receptor antagonist ONO-3708 (3 micrograms.kg-1.min-1) in a 4-hour continuous infusion. Administration of ONO-3708 significantly blocked TXA2 receptors; bleeding time showed a twofold increase (432 +/- 65 vs. 131 +/- 17 seconds; P less than 0.005), and platelet aggregation to U-46619 (an agonist of TXA2 receptors) was abolished in all patients studied. The drug induced a significant increase in free water clearance (3.06 +/- 0.70 vs. 1.72 +/- 0.57 mL/min; P less than 0.001) and diuresis (4.74 +/- 0.79 vs. 3.94 +/- 0.66 mL/min; P less than 0.05) compared with placebo, as well as a significant (14%) increase in renal plasma flow. The increases in both free water clearance and diuresis induced by ONO-3708 were directly related to basal urinary TXB2 excretion. These results suggest a role for renal TXA2 as a modulator of water handling in cirrhotic patients with ascites.

Topics: Aged; Ascites; Body Water; Diuresis; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Liver Cirrhosis; Male; Middle Aged; Receptors, Prostaglandin; Receptors, Thromboxane; Sodium; Thromboxane A2; Thromboxane B2; Urodynamics

To assess the role of altered renal and systemic production of thromboxane A2 and prostacyclin in the hepatorenal syndrome, urinary excretion of their major renal and extrarenal metabolites was measured in patients with compensated and decompensated liver disease, chronic renal failure, and hepatorenal syndrome. Urinary excretion rates of all prostanoids (renal and extrarenal) were increased in subjects with liver disease compared with normal controls. Moreover, they were considerably higher in subjects with severe hepatic decompensation but good renal function compared with those with hepatorenal syndrome. In contrast, the excretion rate of all metabolites was reduced in patients with chronic renal failure. The excretion rate of all metabolites was markedly elevated during the early stages of hepatorenal syndrome and decreased in parallel with creatinine clearance. When corrected for creatinine clearance, there was a strong correlation between prostanoid excretion and serum bilirubin in subjects with liver disease; there was no difference, however, in the excretion of renal and extrarenal prostanoids between hepatorenal syndrome and severe hepatic decompensation. It is concluded that hepatic decompensation is associated with a progressive increase in prostanoid excretion but that changes in production of prostacyclin or thromboxane A2 are unlikely to be major factors in the pathogenesis of the hepatorenal syndrome.

Topics: Adult; Aged; Ascites; Bilirubin; Creatinine; Dinoprost; Epoprostenol; Female; Hepatorenal Syndrome; Humans; Kidney; Kidney Failure, Chronic; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Thromboxane A2; Thromboxane B2

To assess the possible role of increased renal thromboxane A2 (TXA2) synthesis in nonazotemic patients with cirrhosis and ascites and to establish the potential beneficial effect of inhibitors of renal TXA2 production in this clinical setting, we administered OKY 046, a selective TXA2 synthase inhibitor, 200 mg t.i.d. for 5 days, to 9 nonazotemic cirrhotic patients with ascites and avid sodium retention. OKY 046 inhibited platelet TXA2 production, as expressed by serum thromboxane B2 (TXB2) concentration, by approximately 85% (p less than 0.001 vs. baseline values) and reduced urinary TXB2 excretion by 72% (p less than 0.01). A significant increase of approximately 19% in inulin clearance was observed during the treatment (from 61.0 +/- 8.42 to 72.7 +/- 7.45 ml/min, p less than 0.05), whereas renal blood flow was unchanged (from 408.50 +/- 19.97 to 424.50 +/- 30.84 ml/min). Drug administration did not affect positive sodium balance [sodium excretion was 4.67 +/- 1.22 mEq/day before drug administration and 6.26 +/- 1.05 mEq/day during drug administration (on day 7)], plasma renin activity, plasma aldosterone concentration, or the urinary excretion of prostaglandin E2, 6-keto prostaglandin F1 alpha, or prostaglandin F2 alpha. These results suggest that renal TXA2 synthesis contributes to the regulation of renal hemodynamics in nonazotemic cirrhotic patients with ascites and avid sodium retention, but it does not seem to affect sodium balance.

Topics: Acrylates; Adult; Aged; Ascites; Female; Humans; Kidney; Kidney Function Tests; Liver Cirrhosis; Male; Methacrylates; Middle Aged; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

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

The hepatorenal syndrome is considered to be a functional renal failure due to active renal vasoconstriction. The purpose of this work was to study the urinary elimination of prostaglandins and the plasmatic polyunsaturated fatty acid precursors of prostaglandins. The urinary elimination of PGE2 was not significantly different in the groups of patients studied: controls, group I (193 +/- 42 ng/24 h), cirrhotic patients without ascites, group II (274 +/- 43 ng/24 h), cirrhotic patients with ascites, group III (269 +/- 41 ng/24 h). The urinary elimination of PGE1 and PGF2 alpha varied in the same way as PGE2. In cirrhotics with hepatorenal syndrome (group IV) the urinary elimination of vasodilating prostaglandins was greatly decreased (p less than 0.001); PGE2 (53 +/- 16 ng/24 h), PGE1 (65 +/- 11 ng/24 h). The urinary elimination of PGF2 alpha was also decreased (293 +/- 75 ng/24 h). On the other hand, the urinary elimination of thromboxane, a vasoconstrictor, increased progressively from group I (287 +/- 75 ng/24 h) to group IV (980 +/- 266 ng/24 h) (p less than 0.05). Plasmatic arachidonic acid was significantly decreased in group IV (5.0 +/- 0.6 p. 100) compared to group I (10.0 +/- 0.6 p. 100) (p less than 0.001), to group II (10.3 +/- 0.5 p. 100) (p less than 0.001), and to group III (8.5 +/- 0.7 p. 100) (p less than 0.05). In conclusion, in hepatorenal patients, urinary excretion of a vasoconstricting prostaglandin (thromboxane) is increased while urinary excretion of vasodilating prostaglandins is decreased. This decrease could be secondary to a lack of plasmatic arachidonic acid, precursor of prostaglandins.

Topics: Acute Kidney Injury; Ascites; Fatty Acids, Unsaturated; Humans; Kidney Diseases; Liver Cirrhosis; Prostaglandins; Syndrome; Thromboxane A2; Thromboxanes