thromboxane-a2 and Hydronephrosis

Topics: Animals; Coronary Disease; Diabetes Mellitus; Epoprostenol; Humans; Hydronephrosis; Male; Platelet Aggregation; Shock; Thromboxane A2; Thromboxanes; Vasoconstriction

Angiotensin II (Ang II), arginine vasopressin (AVP) and tromboxane A(2) (TxA(2)) are dissimilar vasoconstrictors involved in regulating renal circulation. Whereas Ang II is primarily a physiological modulator, AVP and TxA(2) play important roles under pathological conditions. Previously, we have shown variable importance of intracellular Ca(2+) and protein kinase C for their mode of action (Ang II > AVP >U-46619), but the cell signalling via rho-associated kinase (ROK) is a common pathway. The aim of this study was to determine their sites of action in the renal vascular bed and the corresponding role of ROK at the microvascular level.. Glomerular blood flow (GBF) and luminal diameter of different vessels (10-70 micro m) were measured in the split hydronephrotic kidney of anaesthetized rats. The tissue bath concentration of Ang II, AVP or the TxA(2) agonist U-46619 was adjusted to reduce GBF by approximately 50%. The measurements were repeated after adding a sub-maximal dose of the ROK inhibitor Y-27632 into the bath.. Ang II constricted all vessels significantly, the constriction being least in the proximal segment of the arcuate artery ( approximately 70 micro m). Significant constrictions due to AVP were found only in interlobular and arcuate arteries (20-70 micro m), but not in the afferent and efferent arterioles. U-46619 constricted only the arcuate artery (> or = 50 micro m). Y-27632 (10(-4) M) dilated all vessels significantly and increased GBF by 65%. Thereafter, effects of all agonists were severely attenuated. Control reductions in GBF could be obtained at higher concentrations of AVP (10-fold) and U-46619 (5-fold) and a lesser GBF reduction with Ang II (100-fold) without changes in the respective patterns of vascular constriction.. Our data indicate that the agonists, in the order Ang II, AVP and TxA(2), constrict larger vessels within the renal vascular tree via activation of ROK. Therefore, ROK inhibitors may provide a therapeutic tool to antagonize pathological vasospasm of conduit vessels, which are resistant to other vasodilators.

Topics: Angiotensin II; Animals; Arginine Vasopressin; Female; Hydronephrosis; Intracellular Signaling Peptides and Proteins; Kidney; Models, Animal; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; Renal Circulation; rho-Associated Kinases; Signal Transduction; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

We have previously shown that rats with congenital, unilateral hydronephrosis exhibit a reduction in GFR that returns to normal when either the renin angiotensin system or thromboxane A2 (TxA2) is blocked. The current study defines the single nephron defect in congenital, unilateral hydronephrosis and evaluates the roles of angiotensin II (Ang II) and TxA2 in this renal derangement. Renal micropuncture experiments were performed on the right kidney of rats from an inbred colony with unilateral right-sided hydronephrosis (HYDRO), or non-affected litter mates (CONTROL). In addition, four separate groups of hydronephrotic animals were treated with either the TxA2 receptor antagonist SQ-29548 (SQ), one of two Ang II receptor antagonists [saralasin (SAR) or DuP-753 (DUP)]; or combined treatment with DuP-753 and SQ-29,548 (S&D). SNGFR was significantly reduced (P < 0.05) in HYDRO compared to CONTROL (17.6 +/- 2.0 vs. 35.9 +/- 3.7 nl/min, respectively). Treatment with SQ-29,548 normalized SNGFR (29.0 +/- 3.0 nl/min), while saralasin and DuP-753 resulted in only a partial recovery of function (25.6 +/- 1.6 and 27.8 +/- 1.4 nl/min, respectively). Combined SQ-29,548 and DuP-753 treatment resulted in full recovery of SNGFR to 32.9 +/- 4.4 nl/min. The glomerular ultrafiltration coefficient (Kf) was reduced (P < 0.05) approximately 45% in HYDRO compared to CONTROL (1.64 +/- .08 vs. 2.84 +/- .22 nl/min/mm Hg, respectively). Kf returned to control levels in SAR, DUP and SQ, and increased above control in S&D (5.58 +/- 1.6 nl/min/mm Hg). There were no differences (P > 0.05) in hydrostatic or oncotic pressures across the glomerular capillary between any of the groups studied. The observation that Kf increases above CONTROL with combined blockade of TxA2 and Ang II suggests that these regulatory hormones decrease Kf via independent mechanisms. These data indicate that the reduction in SNGFR in congenital, unilateral hydronephrosis is a result of a marked fall in Kf that is mediated by both Ang II and TxA2.

Topics: Angiotensin II; Animals; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Fatty Acids, Unsaturated; Glomerular Filtration Rate; Hydrazines; Hydronephrosis; Imidazoles; Kidney Glomerulus; Losartan; Male; Rats; Rats, Inbred Strains; Rats, Wistar; Saralasin; Tetrazoles; Thromboxane A2

The effects of DP-1904, a thromboxane (TX) A2 synthase inhibitor, on renal function were investigated by analysis of prostanoid metabolism in hydronephrotic and ischemic rat kidney models, and in isolated perfused normal and hydronephrotic rat kidneys. The increase in production of TXB2 in hydronephrotic or ischemic kidneys was significantly suppressed by intraperitoneal DP-1904 (10 mg/kg), with the 6-keto-prostaglandin F1 alpha to TXB2 ratio being significant increased. Urine volume, glomerular filtration rate and renal plasma flow were all improved. DP-1904 (0.3 micrograms/min) blocked the effects of infused arachidonic acid on isolated perfused normal rat kidneys thus reducing TXB2 levels and perfusion pressure but the pressor response to norepinephrine or angiotensin II remained unchanged. In isolated perfused hydronephrotic rat kidneys, DP-1904 suppressed the increase in perfusion pressure and TXB2 production caused by platelet-activating factor. These findings suggested that DP-1904 improved renal failure by specifically inhibiting TXA2 production.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Hydronephrosis; Imidazoles; Ischemia; Kidney; Male; Perfusion; Rats; Rats, Inbred Strains; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The tubuloglomerular feedback (TGF) system is less sensitive after extracellular volume expansion (VE). In rats with partial ureteral obstruction, however, we have previously found increased TGF sensitivity during such expansion. Thromboxane A2 (TXA2) has been reported to be increased in the hydronephrotic kidney, and the present study was undertaken to investigate whether TXA2 might be responsible for these findings. The TGF characteristics were studied, by means of the stop-flow technique, in control and hydronephrotic rats before and after intravenous injection of either a thromboxane synthetase inhibitor or a thromboxane receptor antagonist during hydropenia. After VE, TGF was studied again. Proximal tubular stop-flow pressure (Psf) was measured during perfusion of the loop of Henle with a modified Ringer's solution, the maximal response (delta Psf) to an increased tubular flow rate was determined and the tubular perfusion rate which elicited a half-maximal decrease in Psf, designated the turning point, was recorded. In hydropenic control or hydronephrotic animals, TXA2 did not permanently change the TGF characteristics. During VE of the TXA2-blocked hydronephrotic animals, blocked both with synthetase inhibitor or receptor-antagonist, TGF was reset to a lower sensitivity like VE controls, as indicated by a high turning point and a low delta Psf. It was therefore concluded that thromboxane A2 inhibition does not influence the TGF system in hydropenia, but that the production of thromboxane A2 is responsible for the resetting of the TGF system during VE in hydronephrotic animals.

Topics: Animals; Carbazoles; Extracellular Space; Feedback; Hydronephrosis; Imidazoles; Indomethacin; Kidney Glomerulus; Kidney Tubules; Rats; Rats, Inbred Strains; Thromboxane A2

Ureteral obstruction in rabbits is characterized by mononuclear cell invasion of the renal cortex and proliferative fibrosis that is associated with exaggerated prostaglandin synthesis in response to vasoactive and inflammatory cell agonists. In this investigation, we studied the effects of the chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) and bradykinin (BK) on eicosanoid synthesis and renal vascular resistance in the ex vivo perfused hydronephrotic kidney (HNK). Administration of fMLP resulted in the dose-dependent synthesis of leukotrienes, thromboxane A2 (TXA2), prostaglandin E2 (PGE2), and prostacyclin (PGI2). Peptidoleukotriene synthesis was monitored by specific radioimmunoassay and by guinea pig ileum bioassay and it was then validated by inhibition of the ileal contractile activity with the peptidoleukotriene receptor antagonist FPL-55712. The leukotrienes produced were identified as LTB4, LTC4, LTD4, and LTE4 by comigration with authentic standards on reverse phase high-performance liquid chromatography (RP-HPLC) and by ultraviolet spectroscopy. BK administration stimulated the synthesis of TXA2, PGE2, and PGI2 but not the synthesis of leukotrienes, in contrast to the results with fMLP, suggesting the involvement of different cell types. Administration of fMLP to the HNK also resulted in a renal vasoconstriction that was partially inhibited by FPL-55712 and that was completely inhibited by the thromboxane synthase inhibitor OKY-1581. Consistent with this result, exogenous administration of LTC4 resulted in the synthesis of TXA2 and in a renal vasoconstriction that was inhibited by either FPL-55712 or OKY-1581.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Bradykinin; Hydronephrosis; Kidney; Leukotriene B4; Male; N-Formylmethionine Leucyl-Phenylalanine; Rabbits; Renal Circulation; SRS-A; Thromboxane A2; Vascular Resistance

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

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

Thromboxane A2 is not produced in normal rabbit kidneys, but its synthesis is induced in numerous renal pathological states. The presence of this potent vasoconstrictor could readily compromise renal hemodynamics. We found that the thromboxane synthetase inhibitor, OKY-1581 (sodium-3-[4,3-pyridylmethyl)phenyl]-2-methylacrylate) is effective in the perfused hydronephrotic kidney in selectively inhibiting thromboxane production without altering prostaglandin E2 or prostacyclin release. The vasoactive peptides bradykinin and angiotensin cause the hydronephrotic kidney to produce thromboxane A2, which results in a profound renal vasoconstriction which is reversed by pretreatment with OKY-1581. Thus, OKY-1581 provides a powerful tool which can be used to assess the participation of thromboxane in pathophysiological states and to ascertain the therapeutic potential of thromboxane synthetase inhibitors in numerous disease states.

Topics: Animals; Bradykinin; Dinoprostone; Epoprostenol; Hydronephrosis; Methacrylates; Perfusion; Prostaglandins E; Rabbits; Renal Circulation; Thromboxane A2; Thromboxanes; Vascular Resistance

Human cortical hydronephrotic microsomes converted [14C] arachidonic acid to [14C] thromboxane B2 as the major metabolic product. Using [14C] PGH2 as substrate, similar enzymatic conversions were noted with HHT greater than TXB2 less than 6KPGF1 alpha greater than PGE2 greater than PGE2 alpha as the major products. Inhibition of thromboxane synthetase with imidazole 5 mM reduced thromboxane B2 production by 60% and the major product then was 6 keto PGF1 alpha. After addition of imidazole, the metabolic profile showed PKPGF1 alpha greater than PGE2 greater than HHT greater than PGF 2 alpha. Control experiments were carried out using normal cortical tissue obtained from kidneys removed surgically for carcinoma of kidney and rejected for transplantation secondary to fracture as a consequence of blunt trauma. These control kidneys, while they demonstrated an ability to generate thromboxane B2 in vitro, had much less activity than hydronephrotic kidneys and with PGH2 as substrate PGE2 greater than TxB2. In addition, inhibition with imidazole produced mainly PGE2. Thus, like the rabbit and rat, there is enhanced thromboxane and prostacyclin synthesis in human ureteral obstruction and are, therefore, potential vasoactive compounds which may in part be responsible for the hemodynamic alterations occurring in human obstructive uropathy.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acids; Fatty Acids, Unsaturated; Humans; Hydronephrosis; Hydroxy Acids; Imidazoles; Kidney Cortex; Microsomes; Prostaglandins E; Prostaglandins F; Prostaglandins H; Thromboxane A2; Thromboxane B2; Thromboxanes

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

Topics: Angiotensin II; Animals; Arachidonic Acids; Bradykinin; Cats; Epoprostenol; Hydronephrosis; In Vitro Techniques; Kidney; Male; Microsomes; Perfusion; Prostaglandins; Prostaglandins E; Rabbits; Thromboxane A2; Time Factors