6-ketoprostaglandin-f1-alpha and Uremia

We previously reported that thromboxane (TX)A2 synthesis and receptor blockade prevented recombinant human erythropoietin (rhEPO)-induced hypertension in chronic renal failure rats. The present study was designed to investigate the effect of a cyclooxygenase inhibitor, acetylsalicylic acid (ASA), on blood pressure, renal function, and the concentration of eicosanoïds and endothelin-1 (ET-1) in vascular and renal tissues of rhEPO-treated or rhEPO-untreated uremic rats. Renal failure was induced by a 2-stage 5/6 renal mass ablation. Rats were divided into 4 groups: vehicle, rhEPO (100 U/kg, s.c., 3 times per week), ASA (100 mg x kg(-1) x day(-1), and rhEPO + ASA; all animals were administered drugs for 3 weeks. The TXA2- and prostacyclin (PGI2)-stable metabolites (TXB2 and 6-keto-PGF1alpha, respectively), as well as ET-1, were measured in renal cortex and either the thoracic aorta or mesenteric arterial bed. The uremic rats developed anemia, uremia, and hypertension. They also exhibited a significant increase in vascular and renal TXB2 (p < 0.01) and 6-keto-PGF1alpha (p < 0.01) concentrations. rhEPO therapy corrected the anemia but aggravated hypertension (p < 0.05). TXB2 and ET-1 tissue levels further increased (p < 0.05) whereas 6-keto-PGF1alpha was unchanged in rhEPO-treated rats compared with uremic rats receiving the vehicle. ASA therapy did not prevent the increase in systolic blood pressure nor the progression of renal disease in rhEPO-treated or rhEPO-untreated uremic rats, but suppressed both TXB2 and 6-keto-PGF1alpha tissue concentrations (p < 0.05). ASA had no effect on vascular and renal ET-1 levels. Cyclooxygenase inhibition had no effect on rhEPO-induced hypertension owing, in part, to simultaneous inhibition of both TXA2 and its vasodilatory counterpart PGI2 synthesis, whereas the vascular ET-1 overproduction was maintained. These results stress the importance of preserving PGI2 production when treating rhEPO-induced hypertension under uremic conditions.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Aspirin; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Endothelin-1; Epoprostenol; Erythropoietin; Humans; Hypertension; Kidney Cortex; Kidney Function Tests; Male; Mesenteric Arteries; Rats; Rats, Wistar; Recombinant Proteins; Thromboxane B2; Uremia

A recently described method to evaluate the primary haemostatic mechanism under in vivo conditions was utilised to investigate thromboxane A2 (TXA2) and prostacyclin (PGI2) production by platelets and vascular endothelial cells, respectively, in patients with severe chronic renal failure. Unlike some previous studies, a decrease in TXA2 production by uraemic platelets could not be demonstrated. PGI2--produced by microvascular endothelial cells after a standardised injury--was, however, 59% higher in patients than controls (P less than 0.05). An increased local level of this potent platelet inhibitory eicosanoid could play an important role in the bleeding tendency exhibited in chronic renal failure.

Topics: 6-Ketoprostaglandin F1 alpha; Bleeding Time; Blood Platelets; Epoprostenol; Female; Humans; Kidney Failure, Chronic; Male; Microcirculation; Thromboxane A2; Uremia

Overall 14 patients with chronic renal failure treated by hemodialysis were examined. The content of the key metabolites of the arachidonic cascade thromboxane B2, 6-keto-prostaglandin F1 alpha and 12-hydroxyeicosatetraene acid (12-HETE) in blood plasma was reduced in the patients as compared to donors. By the end of hemodialysis, part of the patients showed a tendency towards its normalization, however, no complete recovery was practically recorded. Derangement of the formation of thromboxane A2, prostacyclin and 12-HETE in uremia is likely to be related to reverse inhibition of the function of platelet cyclooxygenase and lipoxygenase by plasma inhibitor. The recovery of the function can be attained after adequate hemodialysis.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Humans; Hydroxyeicosatetraenoic Acids; Kidney Failure, Chronic; Middle Aged; Renal Dialysis; Thromboxane A2; Thromboxane B2; Uremia

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

The present study examines extracorporeal prostaglandin production during routine and simulated haemodialysis in healthy volunteers. The roles of dialyser membranes and alcohol washing procedures were investigated. The source of extracorporeal prostaglandin E2 was estimated by a specific platelet cyclo-oxygenase antagonist. Extracorporeal thromboxane production, with and without antagonist, was compared in an attempt to substantiate the role of the cyclo-oxygenase pathway by sources other than platelets. Clinical investigations show that prostaglandin liberation in the extracorporeal bloodstream is detectable. Additionally, laboratory results suggest an association between the type of dialyser membrane and extracorporeal prostaglandin release. The amount of prostaglandin E2 was reduced when dialysers were pre-washed with alcohol. Furthermore, it was experimentally possible to determine that a large part of extracorporeal prostaglandin E2 is released by sources other than platelets, suggesting a possible role of monocytes in extracorporeal prostaglandin production.

Topics: 6-Ketoprostaglandin F1 alpha; Dinoprostone; Humans; Kidneys, Artificial; Membranes, Artificial; Middle Aged; Prostaglandins E; Renal Dialysis; Thromboxane B2; Uremia

Fourteen subjects with persistent azotemia and normal glomerular filtration rate were studied by renal clearances and hormonal determinations to establish the nephron site of altered urea transport and the mechanism(s) responsible for their azotemia. During constant alimentary protein, urea nitrogen appearance was normal and urea clearance was much lower than in 10 age-matched control subjects (23.3 +/- 2.1 ml/min and 49.6 +/- 2.6 ml/min per 1.73 m2, P less than 0.001). Inulin and para-aminohippurate clearances, blood volume and plasma concentration of antidiuretic hormone were within normal limits. During maximal antidiuresis, in spite of greater urea filtered load, the urinary excretion of urea was less, and both the maximum urinary osmolality and the free-water reabsorption relative to osmolar clearance per unit of GFR were greater than in control subjects. After sustained water diuresis, the plasma urea concentration markedly decreased to near normal levels in azotemic subjects. The basal urinary excretion of prostaglandins E2 was significantly reduced in azotemic subjects and was directly correlated with fractional urea clearance (r = 0.857, P less than 0.001). An additional group of control subjects (N = 8) showed a marked reduction of fractional clearance of urea after inhibition of prostaglandin synthesis (P less than 0.01). These data suggest that azotemia is due to increased tubular reabsorption of urea in the distal part of nephron, presumably because of increased back diffusion in the papillary collecting duct, accounting for the enhanced maximum urinary osmolality and free-water reabsorption. Renal prostaglandin E2 may participate in the pathogenesis of azotemia by altering recycling of urea in the medulla.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Urea Nitrogen; Dinoprostone; Female; Glomerular Filtration Rate; Humans; Kidney Concentrating Ability; Kidney Tubules; Male; Middle Aged; Prostaglandins E; Renin; Uremia; Vasopressins; Water-Electrolyte Balance

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

Rat aortic rings stop producing prostacyclin upon prolonged washing in buffer. This 'exhaustion' is caused by inhibition of cyclo-oxygenase, since these rings still convert cyclic endoperoxides but not arachidonic acid into prostacyclin, and most probably is due to high concentrations of peroxides: it can be accelerated by H2O2 or by interrupting the glutathione cycle, while it is delayed by reduced glutathione. Incubation of exhausted rings in human plasma or in a plasma filtrate restores to some extent prostacyclin formation. This filtrate, in particular from uraemic subjects, also inhibits the H2O2 initiated oxidation of guaiacol by ram seminal vesicle microsomes or horseradish peroxidase. The prostacyclin regulating plasma factor has been partially purified and identified as a stable and very polar molecule of mol. wt. 300-400, able to reactivate prostacyclin generation by exhausted rings. We suggest that one or more low mol. wt. plasma components prolong vascular prostacyclin formation by acting as reducing cofactor for cyclo-oxygenase peroxidase. The main physiological role of this plasma activity is probably to protect the vascular prostacyclin forming system from exhaustion during persistent irritation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Cattle; Cells, Cultured; Cyclooxygenase Inhibitors; Epoprostenol; Guaiacol; Humans; Hydrogen Peroxide; In Vitro Techniques; Male; Molecular Weight; Rats; Rats, Inbred Strains; Ultrafiltration; Uremia

To study the effects of uremia and hemodialysis on the production rates of antiaggregatory prostacyclin (PGI2) and proaggregatory thromboxane A2 (TxA2), we collected serial plasma samples from eight patients with chronic uremia before, during and after hemodialysis and assayed them for 6-keto-PGF1 alpha and TxB2, the stable metabolites of PGI2 and TxA2, respectively. In addition, the capacity of the platelets to produce TxB2 during spontaneous clotting was studied by measuring the TxB2 levels in serum incubated at +37 degrees C for 60 minutes. The PGI2 production of the uremia patients before hemodialysis was less (P less than 0.001) than that of healthy volunteers. It rose significantly following heparinization and remained elevated during hemodialysis. TxB2 generation by platelets during clotting was diminished in uremia. Plasma TxB2 levels were normal before, but increased during hemodialysis. Thus, profound changes in the PGI2/TxA2-system seem to be associated with uremia and hemodialysis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Platelets; Epoprostenol; Female; Glomerulonephritis; Heparin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prostaglandins; Pyelonephritis; Renal Dialysis; Thromboxane A2; Thromboxane B2; Thromboxanes; Uremia

The activation of platelets due to foreign surface interaction is a well known fact. Earlier, we found an increase of circulating platelet microaggregates (method of Wu and Hoak) during hemodialysis. Since this phenomenon might cause a PGI2-release by lung and/or vascular tissue, we studied the plasma 6-oxo-PGF 1 alpha-levels in 6 patients during hemodialysis. We found an initial increase of plasma 6-oxo-PGF 1 alpha. Coincidently, hypoxemia, fall in platelet and lekocyte count and a decrease in platelet count ratio were observed. An effect of heparin was excluded in a control group. The findings support the hypothesis that PGI2 acts as a defense mechanism against platelet deposition on vascular wall by a temporary increased synthesis which could be monitored by a temporarily enhanced plasma 6-oxo-PGF 1 alpha-level during the initial phase of hemodialysis.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Chronic Disease; Female; Humans; Leukocyte Count; Male; Middle Aged; Oxygen; Platelet Aggregation; Platelet Count; Prostaglandins F; Renal Dialysis; Uremia