thromboxane-b2 and Ureteral-Obstruction

Inhibitors of cyclooxygenase (COX)-2 prevent suppression of aquaporin-2 and reduce polyuria in the acute phase after release of bilateral ureteral obstruction (BUO). We hypothesized that BUO leads to COX-2-mediated local accumulation of prostanoids in inner medulla (IM) tissue. To test this, rats were subjected to BUO and treated with selective COX-1 or COX-2 inhibitors. Tissue was examined at 2, 6, 12, and 24 h after BUO. COX-2 protein abundance increased in IM 12 and 24 h after onset of BUO but did not change in cortex. COX-1 did not change at any time points in any region. A full profile of all five primary prostanoids was obtained by mass spectrometric determination of PGE(2), PGF(2alpha), 6-keto-PGF(1alpha), PGD(2), and thromboxane (Tx) B(2) concentrations in kidney cortex/outer medulla and IM fractions. IM concentration of PGE(2), 6-keto-PGF(1alpha), and PGF(2alpha) was increased at 6 h BUO, and PGE(2) and PGF(2alpha) increased further at 12 h BUO. TxB(2) increased after 12 h BUO. 6-keto-PGF(1alpha) remained significantly increased after 24 h BUO. The COX-2 inhibitor parecoxib lowered IM PGE(2,) TxB(2), 6-keto-PGF(1alpha), and PGF(2alpha) below vehicle-treated BUO and sham rats at 6, 12 and, 24 h BUO. The COX-1 inhibitor SC-560 lowered PGE(2), PGF(2alpha), and PGD(2) in IM compared with untreated 12 h BUO, but levels remained significantly above sham. In cortex tissue, PGE(2) and 6-keto-PGF(1alpha) concentrations were elevated at 6 h only. In conclusion, COX-2 activity contributes to the transient increase in prostacyclin metabolite 6-keto-PGF(1alpha) and TxB(2) concentration in the kidney IM, and COX-2 is the predominant isoform that is responsible for accumulation of PGE(2) and PGF(2alpha) with minor, but significant, contributions from COX-1. PGD(2) synthesis is mediated exclusively by COX-1. In BUO, therapeutic interventions aimed at the COX-prostanoid pathway should target primarily COX-2.

Topics: Animals; Aquaporin 2; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprost; Dinoprostone; Immunohistochemistry; Kidney; Kidney Cortex; Kidney Medulla; Male; Prostaglandin D2; Prostaglandins; Rats; Rats, Wistar; Thromboxane B2; Ureteral Obstruction

We investigated glomerular filtration rate and renal function reserve after the surgical relief of partial obstruction.. We evaluated 4 boys and 1 girl 9 to 14 years old who underwent pyeloplasty because of unilateral ureteropelvic junction obstruction. Contralateral normal kidneys served as controls. The glomerular filtration rate (inulin clearance), and urinary excretion of prostaglandin E2, thromboxane B2 and endothelin were determined at baseline and after a meal of 4 gm./kg. cooked unsalted red meat on day 4 postoperatively. Tests were repeated the following day 1 hour after the oral administration of 20 mg./kg. aspirin, an inhibitor of prostaglandin E2 synthesis. Urine was collected separately through a bladder catheter and another catheter placed in the upper renal pelvis at surgery.. Glomerular filtration rate at baseline was significantly greater in normal than in surgically treated kidneys (77.2 ml. per minute, range 60 to 98 versus 63.6, range 43 to 78, p = 0.04). Aspirin did not change baseline inulin clearance in normal kidneys but it significantly decreased the glomerular filtration rate in operated renal units (-4% versus -26.4%, p = 0.04). The concentration of all vasoactive compounds was not significantly different in the urine specimens of normal and operated kidneys. The administration of aspirin resulted in a significant decrease in mean urinary prostaglandin E2 excretion plus or minus standard error in operated but not in normal renal units (0.64+/-0.12 ng. per minute versus 0.27+/-0.06, p = 0.04). When expressed as mean versus baseline values, protein induced glomerular hyperfiltration seemed lower in operated than in contralateral intact kidneys (6.9% and 12.4%, respectively).. In the immediate postoperative period previously obstructed kidneys maintain renal function via mechanisms that depend on the activation of prostaglandin, mimicking normal renal function. This effect is decreased by drugs that inhibit prostaglandin E2 production. Therefore, renal damage may be present when the glomerular filtration rate appears normal.

Topics: Adolescent; Aspirin; Child; Dinoprostone; Endothelins; Female; Glomerular Filtration Rate; Humans; Kidney Pelvis; Male; Postoperative Care; Thromboxane B2; Ureteral Obstruction

Renal vascular resistance in deoxycorticosterone acetate (DOCA) salt-treated uninephrectomized rats is increased by high dietary chloride. Because DOCA salt-hypertensive rats exhibit an increased urinary excretion of thromboxane B2 (TXB2), a metabolite of thromboxane A2 (TXA2), the increased TXB2 excretion by DOCA salt-treated rats could relate to elevated dietary chloride, increased blood pressure, and/or the presence of intact renal tubules. We hypothesized that high NaCl intake, resulting in an elevated tubular chloride excretion, stimulates TXA2 production. A result of that production could be renal vasoconstriction. Baseline blood pressures were measured for 10 days, and then the rats were treated with DOCA (30 mg/kg) and fed (1) normal NaCl, (2) normal sodium with high chloride, or (3) high sodium chloride (NaCl) for 4.5 weeks. Next, the rats were uninephrectomized (1K) or unihydronephrectomized (1KHK) to yield one kidney without an intact tubular system and therefore no macula densa. Two and a half weeks later, urinary excretion of TXB2 was determined. DOCA-high NaCl-fed 1KHK or 1K rats had significant increases in systemic blood pressure to 172 +/- 12 and 190 +/- 5 mm Hg, respectively, compared with no significant increase in blood pressure among the other groups. Urinary TXB2 excretion was increased to 29 +/- 4 pg per 24 hours per gram of body weight in all DOCA-treated 1KHK and 1K animals regardless of diet compared with DOCA-treated animals with two intact kidneys (13 +/- 2 pg per 24 hours per gram of body weight). DOCA treatment in rats with one functional kidney results in the excretion of high levels of urinary TXB2 unrelated to dietary chloride load, blood pressure, or intact renal tubules.

Topics: Animals; Blood Pressure; Chlorides; Desoxycorticosterone; Disease Models, Animal; Hydronephrosis; Hypertension; Ligation; Male; Nephrectomy; Rats; Rats, Sprague-Dawley; Renal Circulation; Sodium; Sodium Chloride, Dietary; Thromboxane B2; Ureteral Obstruction

We investigated an effect of ureteral obstruction on a progressive immune complex glomerulonephritis in murine lupus erythematosus. Unilateral ureteral obstruction for 8 days significantly decreased the expanded glomerular mesangial area, as measured by computer-assisted morphometry (4.44 +/- 0.33 x 10(-4) mm2 to 3.60 +/- 0.34 x 10(-4) mm2, P < .05), and reduced the staining for IgG, C3, and extracellular matrix components, whereas the nephritis was exacerbated in the contralateral non-obstructed kidney. The renal concentration of prostaglandin E2 (PGE2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) in the obstructed kidneys 8 days after obstruction significantly exceeded that of kidneys in sham-operated controls (344.2 +/- 83.9 pg/mg tissue protein vs 50.0 +/- 27.5 pg/mg tissue protein, P < .01; 71.9 +/- 11.4 pg/mg tissue protein vs 9.5 +/- 2.3 pg/mg tissue protein, P < .01), whereas thromboxane B2 (TxB2) levels were similar in the two groups (33.9 +/- 4.5 pg/mg tissue protein vs 31.3 +/- 2.6 pg/mg tissue protein). Next, an experiment was performed to evaluate the role of renal eicosanoids in the amelioration in the immune complex glomerulonephritis after ureteral obstruction. Treatment with the cyclooxygenase inhibitor indomethacin abolished the decrease in mesangial area induced by ureteral obstruction (7.7% +/- 6.9%). CV-4151, a thromboxane synthetase inhibitor, had no effect on the decrease in mesangial area (-25.8% +/- 6.8%, P < .05). We conclude that unilateral ureteral obstruction quickly decreased the mesangial expansion in immune complex glomerulonephritis, and vasodilatory eicosanoids such as PGE2 and PGI2 at least partly contribute to the amelioration of glomerular histology.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Complement C3; Cyclooxygenase Inhibitors; Dinoprostone; Epoprostenol; Extracellular Matrix Proteins; Female; Fluorescent Antibody Technique; Glomerular Mesangium; Immunoglobulin G; Indomethacin; Kidney Glomerulus; Ligation; Lupus Nephritis; Mice; Thromboxane B2; Ureter; Ureteral Obstruction

We examined prostaglandin (PG) E2, 6-keto PGF1alpha, and thromboxane B2 (TxB2) production in cortical and medullary tubules from sham-operated control (SOC) rats and rats with bilateral ureteral obstruction (BUO) of 24 h duration. In SOC rats medullary tubules produced significantly greater amounts of the three eicosanoids than cortical tubules. Again, the production of PGE2, 6-keto PGF1alpha, and TxB2 by cortical and medullary tubules was significantly greater in BUO rats than in SOC rats. To elucidate the mechanisms involved, we examined the activity of phospholipase A2 (PLA2) reactive against phosphatidylcholine or phosphatidylethanolamine (PE), the activity of phospholipase C (PLC), and the levels of cyclooxygenase (COX) in cortical and medullary tubules from SOC and BUO rats. In SOC rats the activity of phosphatidylcholine-PLA2 and PE-PLA2, the activity of PLC, and the mass of COX were significantly greater in medullary tubules than in cortical tubules. On the other hand, the activity of PLC in membranes of cortical tubules and the activity of PE-PLA2 and PLC in membranes of medullary tubules, which were in active location, were significantly greater in BUO rats than in SOC rats. COX levels were also significantly greater in cortical and medullary tubules of BUO rats than in those of SOC rats. Thus, we indicate that medullary tubules from SOC rats have greater production of eicosanoids through increased activity of the PLA2 and PLC-COX pathway than cortical tubules from the same group of rats. Again, in rats with BUO, the tubular eicosanoid production may be enhanced via activation of the PLC-COX pathway in cortical tubules or through activation of the PE-PLA2 and PLC-COX pathway in medullary tubules. The enhanced production of tubular eicosanoids observed in rats with BUO may affect tubular function, particularly sodium and water reabsorption.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cell Membrane; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Eicosanoids; Female; Isoenzymes; Kidney Cortex; Kidney Medulla; Kidney Tubules; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipases A; Phospholipases A2; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thromboxane B2; Type C Phospholipases; Ureteral Obstruction

Eicosanoid excretion from the contralateral kidney in pigs with unilateral ureteral occlusion (UUO) was examined, and the effects of blockade of angiotensin II synthesis and cyclooxygenase inhibition were investigated.. Urine obtained from contralateral kidneys in pigs with UUO and from the right kidney in sham-operated pigs was examined for prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) by radioimmunoassay.. Excretion rate of PGE2 increased from 307 +/- 69 pg. per minute to 542 +/- 149 pg. per minute (p < 0.05) during UUO. Indomethacin blocked the synthesis of both PGE2 and TxB2. Administration of an inhibitor of the angiotensin I converting enzyme resulted in a significant (p = 0.02) reduction of PGE2 excretion as well as a decrease in TxB2 excretion which was significantly lower 15 hours after UUO. Blockade of angiotensin II synthesis in the sham-operated pigs did not affect prostanoid excretion from their kidneys.. This study demonstrates that the presence of angiotensin is important for a full expression of these prostanoids in the contralateral kidney during UUO.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Dinoprostone; Eicosanoids; Indomethacin; Kidney; Swine; Thromboxane B2; Ureteral Obstruction

Dietary protein restriction ameliorates the decrease in GFR and renal plasma flow that occurs 24 hours after the onset of bilateral ureteral obstruction (BUO). The vasoactive hormones, prostaglandins (PGs) and thromboxane (Tx), have a role in the changes in renal function described above. Thus, we evaluated the effect of dietary protein restriction on the production of PGE2. 6-keto PGF1 alpha and TxB2 and on the activities of cyclooxygenase and phospholipases A2 and C in glomeruli isolated from sham-operated control (SOC) and BUO rats fed a low (6% casein) or a normal protein (23% casein) diet for approximately four weeks. A normal protein diet compared to a low protein diet significantly increased the glomerular production of PGE2, 6-keto PGF1 alpha and TxB2 in SOC rats. Glomeruli of rats with BUO fed a normal protein diet had further increased production of eicosanoids when compared to glomeruli of SOC rats ingesting the same diet. The production rates of eicosanoids correlated well with the activity of cyclooxygenase in the two groups of rats. On the other hand, a low protein diet completely abolished the increase in glomerular eicosanoid production seen in rats with BUO. The synthetic levels of eicosanoids were comparable in low protein-fed SOC and BUO rats, indicating normalization of glomerular eicosanoid production in BUO rats fed a low protein diet. Moreover, there were no significant differences in the activities of cyclooxygenase and phospholipases A2 and C between the SOC and BUO rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Weight; Dietary Proteins; Dinoprostone; Eicosanoids; Female; Kidney Glomerulus; Organ Size; Phospholipases; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Thromboxane B2; Ureteral Obstruction

The regional production of prostaglandin E2 and thromboxane B2 was investigated in the kidney with unilateral or bilateral ureteral obstruction for 24 hours in rats. The production of these eicosanoids was highest in the inner medulla both with or without ureteral obstruction, although the production rate by the tubules was relatively low in the obstructed kidney compared to the sham-operated control. A greater production of these vasoactive compounds was noted by glomeruli from the kidneys with unilateral or bilateral obstruction and the contralateral kidney with unilateral obstruction. Glomeruli obtained from the kidney with unilateral obstruction produced more thromboxane B2 than the kidney with bilateral obstruction, and the resultant TxB2/PGE2 ratio was higher in the unilaterally obstructed kidney. This difference in the glomerular thromboxane B2 production may be responsible for the haemodynamic changes between unilateral and bilateral ureteral obstructions. An increased prostaglandin E2 production by glomeruli from the contralateral kidney with unilateral obstruction may contribute to a compensatory response.

Topics: Animals; Constriction, Pathologic; Dinoprostone; Female; Kidney; Kidney Diseases; Rats; Rats, Sprague-Dawley; Thromboxane B2; Ureteral Obstruction

Glomeruli isolated from rats with bilateral ureteral obstruction (BUO) of 24 hr duration produced significantly greater amounts of prostaglandin (PG) E2, 6-keto-PGF1 alpha, thromboxane B2, and leukotriene B4 than glomeruli isolated from sham-operated control (SOC) rats. To examine the mechanisms underlying the greater production of eicosanoids by glomeruli isolated from rats with BUO, we measured the activities of enzymes related to eicosanoid formation such as cyclooxygenase, 5-lipoxygenase, PGE2 isomerase, and PGI2 and thromboxane synthase in glomeruli isolated from SOC rats and rats with BUO. Glomeruli isolated from rats with BUO had a significantly increased activity of cyclooxygenase with de novo synthesis of this enzyme and a markedly augmented activities of PGE2 isomerase and both PGI2 and thromboxane synthases relative to glomeruli isolated from SOC rats. Similarly, the activity of membrane-bound 5-lipoxygenase, the active location of this enzyme, was significantly greater in glomeruli isolated from rats with BUO than in glomeruli isolated from SOC rats. Thus, BUO of 24 hr duration enhances the glomerular production of eicosanoids via the activation of enzymes in both the cyclooxygenase and 5-lipoxygenase pathways.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonate 5-Lipoxygenase; Cytochrome P-450 Enzyme System; Dinoprostone; Eicosanoids; Female; Intramolecular Oxidoreductases; Isomerases; Kidney Glomerulus; Leukotriene B4; Prostaglandin-E Synthases; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Thromboxane B2; Thromboxane-A Synthase; Ureteral Obstruction

Animal experiments have shown that after ureter obstruction hydronephrotic kidneys release increased amounts of prostaglandin E2 (PGE2) and thromboxane A2 (TxA2), suggesting that these prostanoids modify renal blood flow and excretory function in this model. To test the hypothesis that these mechanisms are also operative in congenital obstructive uropathy, we measured prostanoid excretion rates in 12 neonates and infants with congenital unilateral or bilateral hydronephrosis. Prostanoid determinations were performed by gas chromatography mass spectrometry. PGE2 and thromboxane B2 (TxB2) (non-enzymatic metabolite of TxA2) excretion exceeded the normal range in eight and 11 of 12 patients, respectively. Median PGE2 excretion was 22, range 4-572 ng/h/1.73 m2 (normal 3-16). Median TxB2 excretion was 22, range 3-188 ng/h/1.73 m2 (normal 3-7). No other renal prostanoids (prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha) or systemic prostanoid metabolites (PGE-M, 2,3-dinorthromboxane B2, 11-dehydro-thromboxane B2, 2,3-dinor-6-keto-prostaglandin F1 alpha) were consistently elevated. A second group of 12 neonates with congenital obstructive uropathy was followed sequentially. PGE2 and thromboxane B2 excretion rates increased even further after surgical decompression and gradually normalized during follow-up. There was a significant relationship between elevated FeNa and enhanced PGE2 and TxB2 excretion. These data suggest that endogenous renal formation of PGE2 and TxA2 is selectively stimulated in hydronephrotic kidneys in neonates and infants. PGE2 and TxA2 may be involved in modulating renal function in these infants.

Topics: Child, Preschool; Dinoprostone; Female; Humans; Hydronephrosis; Infant; Infant, Newborn; Kidney; Male; Thromboxane B2; Ureteral Obstruction

The renal excretion of prostaglandins E2 and 6-keto-F1 alpha, thromboxane B2 and cyclic adenosine 3', 5'-monophosphate was measured in a solitary kidney model of chronic ureteral obstruction in rabbits. The presence of obstruction was confirmed by intravenous pyelography. Growth rate of the animals and furosemide-stimulated diethylenetriaminepentaacetic acid renography were used to grade the obstruction. As correlated to urinary creatinine concentration the excretion of 6-keto-PGF1 alpha dominated in nephrectomized, unobstructed control animals. With the degree of ureteral obstruction becoming more severe, the output of PGE2 increased, while that of 6-keto-PGF1 alpha and TxB2 decreased. As a result the ratios PGE2/6-keto-PGF1 alpha and PGE2/TxB2 were three times as high in severely obstructed rabbits as in control animals. The renal output of cyclic AMP was unaffected by chronic obstruction. We conclude that the renal metabolism of prostanoids is affected in a unique way in chronic partial obstruction of the ureter.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclic AMP; Dinoprostone; Kidney; Kidney Concentrating Ability; Male; Rabbits; Thromboxane B2; Ureteral Obstruction

Unilateral ureteral obstruction (UUO) results in increased renal resistance as well as in exaggerated prostaglandin (PG) release from the obstructed hydronephrotic kidney (HNK). We have reported previously that platelet-activating factor (PAF) dose-dependently stimulates the release of PGs from both the HNK and unobstructed contralateral kidney (CLK), with CLK release being 10% that of the HNK. In the present report, we studied the interaction of PAF with its receptor by examining the effects of PAF-receptor antagonists on the release of PGs from the isolated perfused rabbit HNK and CLK stimulated by PAF; angiotensin II (AII), and bradykinin (BK) were also used as agonists. In the HNK, kadsurenone (3 microM) inhibited PAF-stimulated PGE2 and thromboxane B2 (TxB2) release by 28.2 and 62.5% respectively. CV-3988 (20 microM) and triazolam (5 microM) also preferentially diminished PAF-stimulated TxB2 release. In addition, all three drugs significantly diminished BK- and AII-stimulated TxB2 release, while CV-3988 was the only antagonist to affect peptide-stimulated PGE2 release. While effective against agonist-stimulated PG synthesis, these drugs had no direct effect on arachidonic acid metabolism to PGs. Furthermore, in the CLK, CV-3988 had no effect on BK- or AII-stimulated PGE2 release, whereas it totally inhibited PAF-stimulated release of PGE2. These results show that PAF-receptor antagonists in the HNK preferentially inhibit TxB2 release whether stimulated by PAF, AII or BK; in the CLK only PAF-stimulated PG release is affected. This biochemical difference may be of physiological significance and explain some of the functional differences between the HNK and CLK. Therefore, PAF may be an important mediator of some of the biochemical and functional changes associated with UUO.

Topics: Angiotensin II; Animals; Benzofurans; Dinoprostone; Kidney; Lignans; Male; Peptides; Platelet Activating Factor; Platelet Membrane Glycoproteins; Prostaglandins; Prostaglandins E; Rabbits; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Thromboxane B2; Triazolam; Ureteral Obstruction

In patients with chronic urinary obstruction the excretion of prostaglandin E(2) (PGE2) and thromboxane B(2) (TXB2) was measured. During obstruction signs of an increased vasoconstrictor (TXB2)- and a decreased vasodilator (PGE2) activity were found. After percutaneous nephropyelostomy a reverse pattern with decrease of the initially high (TXB2) excretion and increase of the PGE(2)excretion was observed. It is suggested that these changes of the arachidonic acid metabolism previously found in animals also take part in the pathophysiological changes in humans after relief of urinary obstruction having significant effect of renal blood flow, glomerular filtration rate and tubular function in obstructive nephropathy in humans.

Topics: Adult; Dinoprostone; Female; Humans; Hydronephrosis; Kidney Calculi; Male; Middle Aged; Nephrostomy, Percutaneous; Prostatic Neoplasms; Thromboxane B2; Tissue Adhesions; Ureteral Obstruction

Kidneys from rats subjected to bilateral ureteral obstruction (BUO), unilateral ureteral obstruction (UUO) and UUO with subsequent release were analyzed for leukocyte infiltration. A time-dependent influx of leukocytes, predominantly macrophages and suppressor T lymphocytes, occurred in both the cortex and medulla following obstruction, and disappeared with release of the obstruction. Glomerular macrophages declined following obstruction but increased to levels above control following release. The influx of leukocytes following obstruction was paralleled by an increase in thromboxane B2 excretion by the kidney and coincided with a decrease in glomerular filtration rate (GFR). This would suggest that an influx of immune cells is a prominent feature of the acute renal response to ureteral obstruction. These cells may modulate some of the post-obstructive alterations in renal function via the production of vasoactive substances, such as thromboxane A2.

Topics: Acute Disease; Animals; Kidney; Leukocytes; Macrophages; Rats; Rats, Inbred Strains; T-Lymphocytes; Thromboxane B2; Ureteral Obstruction

In 8 female pigs complete unilateral ureteral obstruction was investigated over a 4 weeks period. The pigs were monitored with intrapelvic pressure measurements and by 131-I-hippuran scintigraphy twice a week; one group without and one with TxA2 blocking, UK-38,485 [3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indol-1-propanoic acid], which is a well-known selective thromboxane synthetase inhibitor. During the course of obstruction there was an ipsilateral linear reduction of split function to background level and a net reduction in total hippuran clearance in both groups. On the obstructed side there was a linear reduction of hippuran clearance from 116 +/- 26 ml/min to 11 +/- 3 ml/min during the first 2 weeks of obstruction. The TxA2 synthetase inhibitor, 5 mg/kg reduced se-TxB2 to almost zero for at least one hour after i.v. administration. One week after obstruction the pelvic pressure was 45 +/- 5 cm H2O) administration of the TxA2 synthetase inhibitor. The pelvic pressure remained elevated throughout the period of observation. The study confirmed earlier work which showed that total ureteral obstruction caused complete cessation of kidney function within a few weeks, but contradicts previous studies because there was no increase in renal blood flow after thromboxane blockade. These differences may be explained by several mechanisms. The continuing increase in pelvic pressure suggested that it was not only a preglomerular vasoconstriction which was responsible for the renal flow reduction, but that there was also a postglomerular vasoconstriction.

Topics: Animals; Imidazoles; Iodohippuric Acid; Kidney; Pelvis; Pressure; Regional Blood Flow; Swine; Thromboxane B2; Thromboxane-A Synthase; Ureteral Obstruction; Vasoconstriction

A marked decrease in renal blood flow (RBF) and glomerular filtration rate (GFR) was found after 24, 48 and 72 hours of total unilateral ureteral obstruction (UUO) in the rabbit. Contralateral GFR showed a modest increase consistent with compensatory hypertrophy. The urinary excretion of thromboxane B2 (TxB2), the stable metabolite of the vasoconstrictor prostaglandin, thromboxane A2 (TxA2) was significantly elevated in the urine obtained following release of the obstructed ureter when compared to the TxB2 level in the urine from the contralateral kidney. Continuous infusion of OKY-046 at 100 micrograms./kg./min. over 24 hours during UUO decreased TxB2 excretion by greater than 80 per cent. However there was no significant preservation of RBF or GFR of the obstructed kidney following ureteral release despite the selective inhibition of TxA2. Moreover the increase in contralateral GFR was also abolished. Taken together with other studies these results strongly suggest that the potent vasoconstrictor TxA2 is not responsible for the rise in renal resistance that follows acute UUO.

Topics: Acrylates; Animals; Glomerular Filtration Rate; Kidney; Male; Methacrylates; Rabbits; Renal Circulation; Thromboxane B2; Thromboxane-A Synthase; Time Factors; Ureteral Obstruction; Vascular Resistance

Twenty-four hours of complete unilateral ureteral obstruction (UUO) produces intense renal vasconstriction in the rat even after release of obstruction. In the ex vivo perfused hydronephrotic rabbit kidney, bradykinin stimulates increased production of the vasoconstrictor autocoid thromboxane. In the present study, we measured basal and bradykinin-stimulated thromboxane and prostaglandin E2 production by UUO and contralateral rat kidneys perfused ex vivo. Furthermore, we evaluated thromboxane synthetase inhibition by imidazole and by two of its substituted derivatives, UK 37248 and UK 38485, in vitro. We compared these in vitro findings with in vivo measurements of renal hemodynamics and excretory function before and after the intrarenal artery administration of thromboxane synthetase inhibitors. Both basal and bradykinin-stimulated thromboxane and prostaglandin E2 production were significantly increased in hydronephrotic kidneys. Imidazole and its substituted congeners were effective inhibitors of bradykinin-stimulated thromboxane B2 production in vitro. However, the substituted imidazoles were more potent, more efficacious, and more selective for thromboxane synthetase inhibition than the parent compound. In vivo, administration of imidazole into the renal artery of the UUO kidney improved function slightly, whereas administration of UK 37248 or UK 38485 doubled renal blood flow and excretory function but did not restore them to normal. We conclude that the hydronephrotic rat kidney produces increased amounts of the vasoconstrictor eicosanoid thromboxane and that thromboxane is an important mediator of vasoconstriction in this model of disease.

Topics: Animals; Dinoprostone; Dose-Response Relationship, Drug; Hydronephrosis; Imidazoles; Methacrylates; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase; Ureteral Obstruction

The effect of the thromboxane synthetase inhibitor OKY-046 on renal blood flow and ureteral pressure in awake dogs during 18 hours of complete unilateral ureteral obstruction was studied. OKY-046 was infused continuously throughout the period of obstruction and post-release. Renal blood flow and ureteral pressure were constantly monitored during the study. Urinary thromboxane B2 and prostaglandin E2 excretion served as markers for inhibition of renal thromboxane A2 synthesis. The triphasic relationship between ipsilateral renal blood flow and ureteral pressure previously found following unilateral ureteral obstruction was observed despite OKY-046 infusion. Inhibition of ipsilateral urinary thromboxane B2 excretion was greater than 90% compared to control while ipsilateral urinary prostaglandin E2 excretion was not consistently decreased showing specific thromboxane inhibition. These results suggest that urinary thromboxane B2 may serve as a useful marker for determining the effects of inhibition on renal thromboxane A2 production. At the level of inhibition of thromboxane synthesis achieved we did not observe any change in the late decrease in renal blood flow which is typically seen with chronic unilateral ureteral obstruction.

Topics: Acrylates; Animals; Dinoprostone; Dogs; Female; Methacrylates; Pressure; Prostaglandins E; Renal Circulation; Thromboxane B2; Thromboxane-A Synthase; Ureter; Ureteral Obstruction; Urodynamics

Platelet-activating factor (PAF), a lipid with potent platelet-stimulating and hypotensive properties, has been shown to stimulate the release of prostaglandins (PGs) from a number of cell types. It is produced by a variety of inflammatory cells and the renal medulla. However, no studies to date have examined the effect of PAF on the intact kidney. We, therefore, studied the effect of bolus injections of PAF on the isolated perfused rabbit kidney subjected to aseptic ureteral ligation for 72 hr. Intrarenal resistance and release of PGs by both the hydronephrotic (HNK) and contralateral kidney (CLK) were quantified. Intrarenal administration of PAF causes a dose-dependent stimulation of the release of PGE2, thromboxane B2 (TxB2) and the PGI2 metabolite, 6-keto-PGF1 alpha from the HNK and CLK. The magnitude of the release from the HNK is much greater than that for the CLK. A 100-ng bolus injection of PAF into the HNK results in the release of 1561.0 +/- 312.0 and 117.7 +/- 38.2 ng of PGE2 and TxB2, respectively, whereas administration of this dose to the CLK causes 291.0 +/- 35.0 ng of PGE2 and 19.0 +/- 4.2 ng of TxB2 to be released. Renal vascular resistance (RVR) is increased by PAF in the HNK. Product identity was confirmed using selective inhibitors and bioassay. These data show that PAF is a potent stimulus for renal PG release and that this release may have vascular consequences.

Topics: Animals; Biological Assay; Dinoprostone; Dose-Response Relationship, Drug; Kidney; Male; Perfusion; Platelet Activating Factor; Prostaglandins; Prostaglandins E; Rabbits; Rats; Stomach; Thromboxane B2; Time Factors; Ureteral Obstruction

A bolus injection of a very low dose (100 ng) of endotoxin into an isolated perfused hydronephrotic (3 day unilateral ureter obstructed) kidney resulted in the appearance of substances in the venous effluent, which caused a biphasic chronic contraction of intestinal and vascular smooth muscle bioassay strips. Indomethacin pretreatment blocked the effect. The contralateral (unobstructed) rabbit kidney, postobstructed hydronephrotic rabbit kidney (i.e., release of ureter obstruction for 3-10 days) and the hydronephrotic cat kidney did not respond to endotoxin. Histological examination demonstrated that the hydronephrotic rabbit kidney contains mononuclear cells, whereas the unobstructed contralateral rabbit kidney as well as the postobstructed rabbit hydronephrotic kidney and the hydronephrotic cat kidney have considerably fewer mononuclear cells. The responsiveness of the hydronephrotic rabbit kidney to endotoxin is dependent on ex vivo perfusion time and is suppressed by inhibition of protein synthesis with cycloheximide. These data suggest that ureter obstruction in the rabbit stimulates the infiltration of macrophages which are sensitive to endotoxin and which participate in the exaggerated prostaglandin production.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cats; Dinoprostone; Endotoxins; Inflammation; Macrophages; Male; Prostaglandins; Prostaglandins E; Rabbits; Thromboxane A2; Thromboxane B2; Thromboxanes; Ureteral Obstruction

The production of prostaglandin E2- (PGE2) like and thromboxane A2-(TXA2) like substances is increased after release of unilateral ureteral obstruction (UUO) for 3 days in the isolated perfused rabbit kidney. It has been postulated that this increase in TXA2 biosynthesis might contribute to the development of vasoconstriction in the obstructed kidney. In the present studies, the production of TXA2 and PGE2 in the kidney was further investigated in rats after UUO for 2-18 h. Radioimmunoassay was used to determine thromboxane B2 (TXB2), a chemically stable metabolite of TXA2, and PGE2 production during the incubation of renal slices in vitro. Unlike previous studies, an increase in TXB2 and PGE2 production was demonstrable in the obstructed kidney even in the absence of pharmacological stimulation by bradykinin or angiotensin II. The effect of UUO on prostaglandin production differed in the different anatomical parts of the kidney. In the papilla, production of both TXB2 and PGE2 was increased in the obstructed kidney. In the cortex, however, UUO had a stimulatory effect only on TXB2 production but not on PGE2 production. The increase in TXB2 and PGE2 production was demonstrable as early a 2 h (tested) after ureteral obstruction. Prolongation of ureteral obstruction for 18 h diminished the stimulatory effect of UUO on PGE2 production but not on TXB2 production.

Topics: Animals; Dinoprostone; Imidazoles; Indomethacin; Kidney; Male; Prostaglandins E; Radioimmunoassay; Rats; Thromboxane B2; Thromboxanes; Time Factors; Ureteral Obstruction

Topics: Animals; Dinoprostone; Glutathione; Hydronephrosis; Intramolecular Oxidoreductases; Isomerases; Kidney; Male; Microsomes; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandin-E Synthases; Prostaglandins E; Prostaglandins H; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase; Ureteral Obstruction

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Glycerol; Hydronephrosis; Kidney; Prostaglandins; Prostaglandins F; Rabbits; Thromboxane A2; Thromboxane B2; Ureteral Obstruction; Vascular Resistance