thromboxane-a2 and Ureteral-Obstruction

Because of their vasodilator and vasoconstrictor properties, vasoactive prostaglandins and thromboxane A2 have been proposed as modulators of the hemodynamic changes that occur in experimental models of renal disease. Increased synthesis of vasodilatory prostaglandins (PGE2) and perhaps prostaglandin I2 (PGI2) play a role in the maintenance of renal blood flow and GFR during states of impaired perfusion. In contrast, thromboxane A2 has been implicated as the vasoconstrictor responsible for the reduction of renal blood flow and GFR in certain animal models of experimental renal disease. These products and other metabolites of arachidonic acid may also participate in the immunological events underlying the onset and/or progression of experimental renal disease. It is evident that the pathophysiologic role of eicosanoids in experimental renal disease is not fully understood. Additional studies and further understanding of the many other potential roles of eicosanoids on immunological events, hemodynamic states, mesangial cell physiology, etc. are needed to comprehend more fully the extent of the participation of eicosanoids in the pathogenesis and pathophysiology of renal disease.

Topics: Animals; Dietary Fats; Eicosanoids; Glomerulonephritis; Hypertension; Kidney Diseases; Nephritis; Prostaglandins; Rabbits; Rats; Thromboxane A2; Ureteral Obstruction

To evaluate the efficacy and potency of clinically available celecoxib for inhibition of ureteral contractility and prostanoid release. We have previously reported that the selective cyclooxygenase (COX)-2 inhibitor NS-398 inhibits ureteral contractility.. We evaluated the release of prostaglandin (PG) E2, F2alpha, D2, thromboxane B2 (a thromboxane2 metabolite), and 6-keto-PGF1alpha (a prostacyclin metabolite) by gas chromatography-mass spectrometry from porcine ureters in the presence and absence of tumor necrosis factor-alpha (TNF-alpha), a putative cyclooxygenase (COX)-2 inducer. PGE2 and PGF2alpha were the prostanoids released in greatest quantity in response to TNF-alpha. We subsequently measured spontaneous contractility and prostanoid release in porcine ureters treated with 0.1, 1.0, or 10 microM concentrations of indomethacin (nonselective COX inhibitor), NS-398, celecoxib, or 0.1% dimethyl sulfoxide (vehicle) for 2 hours. Ureteral contractility and prostanoid release were measured every 15 minutes after the addition of the various compounds. We also treated ureters with 10 ng/mL TNF-alpha and all three COX inhibitors or dimethyl sulfoxide for 2 and 4 hours and measured the PGE2 and PGF2alpha release.. Celecoxib, indomethacin, and NS-398 inhibited ureteral contractility and prostanoid release with similar efficacy and potency. All three compounds also reduced TNF-alpha-induced prostanoid release to control levels at concentrations as low as 0.1 microM.. Our data have indicated that celecoxib and indomethacin inhibit PG release by the ureter to a similar degree, even in the presence of COX-2 induction. Animal experiments and clinical trials evaluating the safety and efficacy of celecoxib for the treatment of symptomatic ureteral obstruction are warranted.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Celecoxib; Cyclooxygenase Inhibitors; Depression, Chemical; Dimethyl Sulfoxide; Dinoprost; Dinoprostone; Gas Chromatography-Mass Spectrometry; Humans; Indomethacin; Muscle Contraction; Nitrobenzenes; Prostaglandin Antagonists; Prostaglandin D2; Prostaglandins; Pyrazoles; Secretory Rate; Sulfonamides; Sus scrofa; Thromboxane A2; Tumor Necrosis Factor-alpha; Ureter; Ureteral Obstruction

We evaluated the intrarenal distribution of prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) on the rats that underwent unilateral ureteral obstruction (UUO), unilateral nephrectomy (UNX) or sham operation.. Male Sprague-Dawley rats were divided into three groups; left ureteral obstruction (UUO), left nephrectomy (UNX) and sham-operation (Control). They were sacrificed at 1, 3, 6, 12, 24 hours and Day 2, Day 3, Day 5, Day 7 and Day 9 after surgery. Intrarenal distribution of eicosanoids were immunohistochemically detected on both kidneys of UUO rats, and on right kidneys of UNX and Control rats.. PGE2: In the obstructed kidneys, immunostained PGE2 increased in medullary interstitium at one hour to 6 hours, and in glomeruli and cortical interstitium at 6 hours. An increase of immunostained PGE2 was observed again in cortical interstitium at Day 3 to 5, and in medullary interstitium at Day 2 to 5. In the intact opposite kidneys, expression of immunostained PGE2 increased in glomeruli at Day 5 to 7, and in medullary interstitium at Day 3 to 5. In UNX, immunostained PGE2 increased in the medullary interstitium of the remnant kidneys at 3 hours and Day 3 to 7. On the other hand, an increase of immunostained PGE2 observed in glomeruli and cortical interstitium of these kidneys at Day 5 to 7. TxB2: In the obstructed kidneys, immunostained TxB2 increased in glomeruli and cortical interstitium at 6 hours, and in medullary interstitium at 3 to 12 hours. Predominant expression of TxB2 was observed in medullary interstitium at 3 hours compared to PGE2. We also observed an increase of immunostained TxB2 in cortical interstitium at Day 3 to 5, and in medullary interstitium at Day 2 to 5. In the intact opposite kidneys, immunostained TxB2 increased in medullary interstitium at 3 hours and Day 3. In the remnant kidneys of UNX, an increase of immunostained TxB2 was demonstrated in glomeruli at 6 hours and Day 7, and in medullary interstitium at 3 to 6 hours and Day 3 to 7.. In the obstructed kidneys, imbalance between PGE2 and TxA2 may contribute to the progression of renal injuries. The fact that expression patterns of these eicosanoids in the opposite kidneys of UUO different from that of the remnant kidneys of UNK, even though both were similarly associated with functional loss of contralateral kidneys, suggested that the opposite kidneys of UUO were affected by any additional factors different from that responsible for the remnant kidneys of UNK.

Topics: Animals; Dinoprostone; Kidney; Male; Nephrectomy; Rats; Rats, Sprague-Dawley; Thromboxane A2; Ureteral Obstruction

Haemodynamic changes in partial unilateral ureteric obstruction (PUUO) may be related to altered prostaglandin synthesis. In 12 dogs the left ureter was partially obstructed for 5 weeks. In six dogs the ureter was reimplanted into the bladder and to investigate the effect of this procedure on the contralateral side the other six animals underwent ipsilateral nephroureterectomy. Renal blood flow (RBF) was measured by the distribution of radiolabelled microspheres. Changes in urinary prostaglandin (PG) concentrations were validated by renin activity using angiotensin I. Reduced left RBF during obstruction was associated with increased thromboxane A2 synthesis (P < 0.01). Increased RBF to the non-obstructed side was associated with elevated PGE2 formation (P < 0.05). Elevated angiotensin I levels (P < 0.01) corresponded to maximal increases in PG synthesis. Reimplantation of the obstructed kidney did not exert a direct effect on contralateral RBF or PG concentration. Haemodynamic changes in PUUO in vivo are associated with alterations in renal PGs.

Topics: Angiotensin I; Animals; Dinoprostone; Dogs; Hemodynamics; Prostaglandins; Renal Insufficiency; Thromboxane A2; Ureteral Obstruction

Platelet-activating factor (PAF) is a powerful vasodilator with important effects on kidney function. It has been suggested that the renal effects of PAF are mediated by thromboxane A2 (TxA2). We examined the effect of PAF on renal function in sham-operated rats and rats that had undergone unilateral release of bilateral ureteral obstruction (BUO) of 24-hr duration, a condition in which the synthesis of TxA2 is increased. To eliminate systemic hemodynamic changes, PAF was infused directly into the left renal artery using the lowest dose that affected renal function (2.3 x 10(-13) moles/min). Infusion of PAF significantly decreased the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in normal rats and rats with BUO. Normal (sham-operated) rats pretreated with an inhibitor of TxA2 synthesis also had a significant decrease in GFR after administration of PAF (ERPF also decreased, but not significantly). Rats with BUO pretreated with an inhibitor of TxA2 synthesis had significantly greater basal GFR and ERPF (increases of 72 and 171%, respectively) than untreated BUO rats. Administration of PAF to the former group further increased GFR and ERPF (by 37 and 39%, respectively; P less than 0.001). The role of endogenous PAF was evaluated by administering a specific PAF receptor antagonist. Sham-operated rats pretreated with high doses of the PAF receptor antagonist had significantly higher mean arterial pressure values than normal untreated rats, and had no decrease in GFR and ERPF during PAF infusion. Rats with BUO pretreated with the PAF antagonist had a significant, dose-dependent decrease in basal GFR and ERPF. These data suggest that endogenous PAF has a vasodilatory role in obstructive nephropathy. No significant differences in eicosanoid excretion in the urine corrected per GFR were observed during infusion of PAF in any of the groups examined. In BUO rats with intact TxA2 synthesis, exogenous administration of PAF decreased renal function, presumably through further increases in the production of TxA2. However, when TxA2 production was inhibited, PAF administration increased GFR and ERPF, presumably due to its unopposed vasodilatory properties. The data suggest an important role of PAF in the hemodynamic changes seen in obstructive nephropathy.

Topics: Animals; Female; Furans; Glomerular Filtration Rate; Kidney; Methacrylates; Platelet Activating Factor; Radioimmunoassay; Rats; Rats, Inbred Strains; Renal Circulation; Thromboxane A2; Thromboxane-A Synthase; Ureteral Obstruction

Platelet activating factor (PAF) and thromboxane A2 (TxA2) are two vasoactive mediators which can decrease renal blood flow. Both are synthesized by various intrarenal cell types or by macrophages which may infiltrate the kidney during unilateral ureteral obstruction (UUO). In several experimental systems, PAF receptor activation is accompanied by TxA2 release; pharmacological modification of TxA2 synthesis or receptor activation modulates the response to PAF. The involvement of PAF in UUO has not been studied previously, and the role of TxA2 has not been clearly defined by previous investigations. The hemodynamic response to acute UUO is characterized by decreases in renal blood flow (RBF) and glomerular filtration rate and an acute increase in ureteral pressure. In the present experiments, the involvement of either PAF or TxA2 in the acute response to UUO was studied by determining if blockade of either the TxA2 or PAF receptor would affect the renal hemodynamic response to UUO. In addition, the effect of blockade of the TxA2 receptor on the renal response to PAF was determined. Our results indicate that only a small portion of the renal response to PAF is mediated by TxA2, and that neither PAF nor TxA2 can be implicated in the acute hemodynamic response to UUO. TxA2 or PAF involvement in the chronic response to UUO still remains to be determined.

Topics: Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Fatty Acids, Unsaturated; Female; Hydrazines; Platelet Activating Factor; Pressure; Prostaglandin Endoperoxides, Synthetic; Quinolinium Compounds; Receptors, Prostaglandin; Receptors, Thromboxane; Renal Circulation; Thromboxane A2; Ureter; Ureteral Obstruction; Vascular Resistance; Vasoconstriction

We have previously demonstrated that, after the release of 24-h unilateral ureteral obstruction (UUO), glomerular filtration rate (GFR), and renal blood flow (RBF) are reduced because of increased production of the potent vasoconstrictors thromboxane A2 (TxA2) and angiotensin II (ANG II). Captopril, which blocks ANG II production, increases GFR and RBF. Sequential administration of aprotinin, a kallikrein inhibitor, has an additive effect to further decrease renal vasoconstriction, even though kinins are generally thought to be vasodilators. Therefore, we assessed mechanisms by which aprotinin might improve renal function of previously obstructed anesthetized rats. When given alone to UUO rats, aprotinin improved renal hemodynamics. Since kinins stimulate TxA2 production by UUO kidneys perfused in vitro, our data suggest that aprotinin improved postobstructive function by decreasing kinin-stimulated TxA2 production, although this may not be its only effect. Aprotinin also improved postobstructive function, even if TxA2 formation was blocked with indomethacin. But when both ANG II and TxA2 formation were blocked by the simultaneous administration of captopril and indomethacin, aprotinin had no effect. This suggests that aprotinin may also affect ANG II formation. These pharmacological effects of aprotinin suggest that the kallikrein-kinin system may also contribute to postobstructive renal vasoconstriction by stimulating the production of both vasoconstrictor eicosanoids and ANG II.

Topics: Angiotensin II; Animals; Aprotinin; Captopril; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Kidney; Male; Rats; Rats, Inbred Strains; Regional Blood Flow; Thromboxane A2; Ureteral Obstruction

The PGE2, PGI2, PGF2 alpha and TxA2 synthesizing activities were studied in an isolated microsomal fraction of rat kidney after temporary, unilateral ureter obstruction and E. coli infection. In the early phase of regeneration the synthesis of vasodilatory PGI2 was increased, whereas that of vasoconstrictory PGF2 alpha was decreased. An increased PGE2 synthesizing activity was observed when renal obstruction was associated with infection. The role of these changes in regenerating the haemodynamics and function of postobstructive kidney is discussed.

Topics: Animals; Dinoprost; Dinoprostone; Epoprostenol; Escherichia coli Infections; Female; Kidney; Prostaglandin Endoperoxides; Prostaglandins E; Prostaglandins F; Prostaglandins G; Rats; Thromboxane A2; Ureteral Obstruction

Topics: Acute Kidney Injury; Angiotensin II; Animals; Dietary Proteins; Humans; Thromboxane A2; Ureteral Obstruction; Urologic Diseases

The development of hydronephrotic atrophy as measured by dry and wet weight in relation to wholebody weight, in rats after complete unilateral ureteral obstruction could be influenced by oral administration of OKY 1581, an inhibitor of thromboxane A2 synthesis. The data are consistent with the thesis that preglomerular thromboxane A2-mediated active vasoconstriction is involved, most likely by ischemia, in the development of hydronephrotic atrophy, at least in the renal cortex.

Topics: Animals; Atrophy; Female; Hydronephrosis; Kidney Cortex; Kidney Medulla; Methacrylates; Rats; Thromboxane A2; Ureteral Obstruction

Whole kidney inulin (CIn) and PAH (CPAH) clearances were measured after unilateral release of bilateral ureteral obstruction (BUO) of 24-h duration in rats fed for 4 wk isocaloric diets containing either 40% casein (high protein diet) or 6% casein (low protein diet). Values for CIn and CPAH were markedly depressed in both groups but to a greater extent in high protein-fed rats, averaging less than 60% of values measured in low protein-fed animals. Captopril, an inhibitor of the angiotensin I converting enzyme, increased CIn and CPAH markedly but comparably in high or low protein fed rats. Micropuncture studies performed after unilateral release of BUO in another group of rats fed a high or a low protein diet revealed lower levels of glomerular plasma flow rate (QA) and single nephron glomerular filtration rate (SNGFR) in rats fed a high protein diet. Values for renal arteriolar resistances were nearly twofold in high as compared with low protein-fed animals. Infusion of OKY-1581, an inhibitor of thromboxane A2 synthetase, increased both QA and SNGFR, decreased arteriolar resistances, and increased glomerular capillary ultrafiltration coefficient in high but not in low protein-fed rats. Urinary thromboxane B2 excretion per milliliter of GFR was greater in rats fed a high protein diet than in those fed a low protein diet after release of BUO but not in normal rats. In normal rats infusion of OKY-1581 did not increase CIn or CPAH.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Animals; Dietary Proteins; Glomerular Filtration Rate; Kidney; Rats; Rats, Inbred Strains; Renal Circulation; Thromboxane A2; Time Factors; Ureteral Obstruction; Vascular Resistance; Vasoconstriction

Unilateral ureter obstruction induces an exaggerated prostaglandin release from isolated perfused rabbit kidneys in response to vasoactive peptides. Perfused hydronephrotic kidneys also exhibit the release of thromboxane A2 which is not detected with normal or contralateral kidneys. Reversal of the ureteral obstruction causes a decreased production of PGs and TxA2 in response to bradykinin. Morphological examination of the HNK demonstrates an enlarged interstitial space containing a fibroblast-like cell and the presence of mononuclear cells. Administration of endotoxin to the perfused HNK elicits the release of PGE2 and TxB2 consistent with the ability of endotoxin to stimulate arachidonic acid metabolism in cultured macrophage. Rabbit CLK and the cat HNK, which are deficient in macrophages, exhibit minimal PGE2 and no detectable TxA2 release after endotoxin stimulation. Cells cultured from the rabbit HNK cortex contain fibroblast-like cells and phagocytic cells which respond to BK with a profound PG production. Conditioned media from mononuclear cells have been shown by others to stimulate PGE2 production from fibroblasts. Other models of renal disease (renal venous constriction and glycerol-induced tubular necrosis) exhibit exaggerated PG and TxA2 release and facilitated cortical microsomal AA metabolism. These data suggest that proliferation of fibroblast-like cells and the presence of mononuclear cells may be involved in this exaggerated PG and TxA2 production underlying renal injury.

Topics: Animals; Biological Assay; Bradykinin; Cells, Cultured; Dinoprostone; Endotoxins; Functional Laterality; Hydronephrosis; Inflammation; Kidney; Kidney Cortex; Kidney Medulla; Male; Prostaglandins E; Rabbits; Thromboxane A2; Thromboxanes; 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

Unilateral ureter obstruction in rabbits produced profound changes in endogenous and exogenous renal arachidonic acid metabolism. Isolated perfused hydronephrotic kidneys (removed after 3 or 10 d of ureter obstruction) responded to bradykinin stimulation with a markedly enhanced release of prostaglandin E2 and thromboxane A2. Reversal (3 or 10 d) of the ureter obstruction resulted in a reduction in the vasoactive peptide-induced release of prostaglandin E2 and thromboxane A2 from the perfused hydronephrotic kidney. However, postobstruction reversal of prostaglandin production by the agonist-stimulated perfused kidney was not reflected in the cortical microsomal cyclooxygenase activity, which is greatly enhanced during ureter obstruction and does not decrease after removal of the obstruction. Histological analysis of the renal cortex in rabbits with ureteral obstruction revealed a proliferation of fibroblast-like cells and the presence of mononuclear cells; removal of the obstruction did not result in a disappearance of cortical fibroblasts but did result in a decrease of monocytes. The critical involvement of mononuclear cells in the exaggerated arachidonate metabolism that occurs during hydronephrosis was exhibited by the demonstration that: (a) only the perfused hydronephrotic rabbit kidney responded to administration of endotoxin with a sustained release of prostaglandin E2 and thromboxane A2; (b) the contralateral rabbit kidney, which is devoid of mononuclear cells, did not respond to endotoxin; and (c) the hydronephrotic cat kidney, which exhibits a fibroblast proliferation with a low number of mononuclear cells, did not respond to endotoxin. Thus, proliferation of fibroblast-like cells and the presence of mononuclear cells appear to be involved in the exaggerated prostaglandin and thromboxane production underlying hydronephrosis. The increase in microsomal cyclooxygenase activity is apparently most closely correlated with the increased fibroblastic activation and cellularity, whereas mononuclear cells (possibly via monokines) seem to be critical for the markedly enhanced prostaglandin and thromboxane release induced by endotoxin and bradykinin.

Topics: Animals; Arachidonic Acids; Bradykinin; Cats; Disease Models, Animal; Endotoxins; Fibroblasts; Inflammation; Microsomes; Monocytes; Prostaglandins E; Rabbits; Thromboxane A2; Thromboxanes; 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