thromboxane-a2 and Acute-Kidney-Injury

Topics: Acute Kidney Injury; Animals; Bacterial Infections; Endothelins; Humans; Leukotrienes; Shock, Septic; Thromboxane A2

Thromboxane (Tx) A2 has been suggested to be involved in the development of sepsis-induced acute kidney injury (AKI). Therefore, we investigated the impact of cyclooxygenase (COX)-1 and COX-2 activity on lipopolysaccharide (LPS)-induced renal TxA2 formation, and on endotoxemia-induced AKI in mice. Injection of LPS (3 mg/kg ip) decreased glomerular filtration rate (GFR) and the amount of thrombocytes to ∼50% of basal values after 4 h. Plasma and renocortical tissue levels of TxB2 were increased ∼10- and 1.7-fold in response to LPS, respectively. The COX-1 inhibitor SC-560 attenuated the LPS-induced fall in GFR and in platelet count to ∼75% of basal levels. Furthermore, SC-560 abolished the increase in plasma and renocortical tissue levels of TxB2 in response to LPS. The COX-2 inhibitor SC-236 further enhanced the LPS-induced decrease in GFR to ∼40% of basal values. SC-236 did not alter thrombocyte levels nor the LPS-induced increase in plasma and renocortical tissue levels of TxB2. Pretreatment with clopidogrel inhibited the LPS-induced drop in thrombocyte count, but did not attenuate the LPS-induced decrease in GFR and the increase in plasma TxB2 levels. This study demonstrates that endotoxemia-induced TxA2 formation depends on the activity of COX-1. Our study further indicates that the COX-1 inhibitor SC-560 has a protective effect on the decrease in renal function in response to endotoxin. Therefore, our data support a role for TxA2 in the development of AKI in response to LPS.

Topics: Acute Kidney Injury; Animals; Blood Platelets; Cyclooxygenase 1; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Down-Regulation; Endotoxemia; Endotoxins; Glomerular Filtration Rate; Kidney; Male; Membrane Proteins; Mice, Inbred C57BL; Platelet Aggregation Inhibitors; Pyrazoles; Signal Transduction; Thromboxane A2; Time Factors

F(2)-isoprostanes are formed by oxidative modification of arachidonic acid and are the gold standard for detection of oxidative stress in vivo. F(2)-isoprostanes are biologically active compounds that signal through the thromboxane A(2) (TP) receptor; infusion of F(2)-isoprostanes reduces glomerular filtration in the kidney by constricting afferent arterioles. This study investigated whether endogenous F(2)-isoprostanes contribute to the pathogenesis of ischemic acute kidney injury, which is associated with oxidative stress and reduced glomerular filtration. TP receptor knockout mice-that lack F(2)-isoprostanes and thromboxane A(2) signalling-and wild-type control mice underwent 30 min of renal ischemia and 24 h of reperfusion. Kidney dysfunction, histological injury and the number of infiltrated neutrophils were similar between the two mouse strains, whereas TP receptor knockout mice had significantly more apoptotic cells and tissue lipid peroxidation than their wild-type counterparts. F(2)-isoprostanes and thromboxane B(2) were readily detectable in urine collections after surgery. The findings indicate that F(2)-isoprostanes and thromboxane A(2) signalling do not contribute critically to the pathogenesis of ischemic acute kidney injury and more generally provide evidence against a prominent role for F(2)-isoprostanes signalling in exacerbating acute disease states associated with oxidative stress.

Topics: Acute Kidney Injury; Animals; Antioxidants; Blood Urea Nitrogen; Creatine; F2-Isoprostanes; Gene Deletion; Glomerular Filtration Rate; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Thromboxane; Reperfusion Injury; Signal Transduction; Thromboxane A2

Neutral endopeptidase (NEP: EC 3.4.24.11) is involved in the degradation of peptides such as atrial natriuretic peptide, angiotensin II (AngII), and endothelin-1 (ET-1). In this study we propose that NEP inhibition provides protection in glycerol-induced acute renal failure (ARF). Renal vascular responses were evaluated in ARF rats where ARF was induced by injecting 50% glycerol in candoxatril, a NEP inhibitor (30 mg/kg, orally; for 3 weeks) pretreated rats. AngII and U46619 (a TxA2 mimetic) vasoconstriction was increased (2- to 4-fold) in ARF while ET-1 vasoconstriction was surprisingly reduced (23+/-3%; p<0.05). In ARF, candoxatril paradoxically enhanced ET-1 response (60+/-20%; p<0.05) but reduced AngII vasoconstriction (51+/-11%; p<0.05) without affecting U46619 response. However, candoxatril treatment was without effect on plasma ET-1 and TxB2 levels in ARF. Candoxatril reduced plasma AngII by 34+/-4% (p<0.05) in ARF which was approximately 3.5-fold higher compared to control. Candoxatril doubled the nitrite excretion in control but was without effect on proteinuria or nitrite excretion in ARF. Candoxatril enhanced Na+ and creatinine excretion in ARF by 73+/-9% and 33+/-2%, respectively. These results suggest that NEP inhibition may confer protection in glycerol-induced ARF by stimulating renal function but without a consistent effect on renal production and renal vascular responses to endogenous vasoconstrictors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acute Kidney Injury; Administration, Oral; Angiotensin II; Animals; Antihypertensive Agents; Creatinine; Endothelin-1; Indans; Kidney; Male; Natriuresis; Neprilysin; Nitrates; Propionates; Proteinuria; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear transcription factor, modulates vascular responses to angiotensin II (AII) or thromboxane A(2) (TxA(2)) via regulation of their gene/receptor. Increased vasoconstriction and deteriorating renal function in glycerol-induced acute renal failure (ARF) may be attributed to down-regulation of PPARgamma. In this study, we investigated the effect of ciglitazone (CG), a PPARgamma inducer, on AII and TxA(2) production and activity in glycerol-induced ARF. Vascular responses to AII or 9,11-dideoxy-11alpha,9alpha-epoxymethano prostaglandin F(2alpha) (U46619), a TxA(2) mimetic, were determined in preglomerular vessels following induction of ARF with glycerol. Renal damage and function were assessed in CG-treated (9 nmol/kg for 21 days) rats. PPARgamma protein expression and activity, which were significantly lower in ARF rats, were enhanced by CG (26 and 30%). CG also increased PPARgamma mRNA by 67 +/- 6%, which was reduced in ARF. In ARF, there was significant tubular necrosis and apoptosis, a 5-fold increase in proteinuria and a 2-fold enhancement in vasoconstriction to AII and U46619. CG reduced proteinuria (49 +/- 3%), enhanced Na(+) (124 +/- 35%) and creatinine excretion (92 +/- 25%), markedly diminished tubular necrosis, and reduced ARF-induced increase in AII (40 +/- 3%) and TxA(2) (39 +/- 2%) production, the attending increase in vasoconstriction to AII (36 +/- 2%) and U46619 (50 +/- 11%), and the increase in angiotensin receptor-1 (AT(1)) (23 +/- 3%) or thromboxane prostaglandin (TP) receptor (13 +/- 1%). CG reduced free radical generation by 55 +/- 14% while elevating nitrite excretion (65 +/- 13%). Our results suggest that enhanced activity of AII and TxA(2), increased AT(1) or TP receptor expression, and renal injury in glycerol-induced ARF are consequent to down-regulation of PPARgamma gene. CG ameliorated glycerol-induced effects through maintaining PPARgamma gene.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acute Kidney Injury; Angiotensin II; Animals; Creatinine; Dinoprost; Gene Expression; Glycerol; Hypoglycemic Agents; Kidney Glomerulus; Male; Nitric Oxide; Nitrites; PPAR gamma; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, Thromboxane A2, Prostaglandin H2; Renal Artery; Sodium; Thiazolidinediones; Thromboxane A2; Thromboxane B2; Vasoconstriction

Peroxisome proliferator activated receptor-gamma (PPAR-gamma), a nuclear transcription factor, modulates angiotensin II (AII) or thromboxane A(2) (TxA(2)) response in the vasculature via transcriptional regulation of their gene or receptor expression. Increased AII or TxA(2) vasoconstriction and deteriorating renal function observed in glycerol-induced acute renal failure (ARF) may be attributed to a down-regulated PPAR-gamma expression/activity probably via an increased free radical generation. In this study, we investigated the effect of PPAR-gamma induction in glycerol-induced ARF by examining renal vascular reactivity to AII and TxA(2) and by renal expression/activity of PPAR-gamma. Vascular responses to AII or U46619, a TxA(2) mimetic were determined in rat isolated perfused kidney following induction of ARF with glycerol (50%, v/v, i.m.). Extent of renal damage and function were assessed with or without pre-treatment with ciglitazone (9 nmol kg(-1) x 21 days), a PPAR-gamma inducer. In ARF, vasoconstriction was enhanced to AII (three-fold; p<0.05) and U46619 (82%; p<0.05). Ciglitazone reduced AII and U46619 vasoconstriction by 59+/-1% (p<0.05) and 56+/-1% (p<0.05), respectively. Ciglitazone reduced proteinuria (38+/-3%) which was two-fold higher in ARF. Similarly, ciglitazone enhanced Na(+) excretion by 1.5 times while reducing BUN by 49+/-6%. On the contrary, ciglitazone did not change plasma creatinine which was significantly higher in ARF rats. Ciglitazone reduced free radical generation by 30+/-3% while elevating nitrite excretion approximately 2-fold. PPAR-gamma expression and activity were significantly lower in ARF rats and ciglitazone enhanced PPAR-gamma protein expression and activity by 45+/-3% and 52+/-4%, respectively. Data from this study suggest that reduced PPAR-gamma expression and activity may be involved in the pathology of glycerol-induced ARF and induction of PPAR-gamma by ciglitazone confers protection through reduced AII and TxA(2) vasoconstriction and/or enhanced renal function via reducing free radical generation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acute Kidney Injury; Angiotensin II; Animals; Ascorbic Acid; Clofibrate; Down-Regulation; Free Radicals; Glycerol; Kidney; Male; Nitric Oxide; Nitriles; PPAR gamma; Rats; Rats, Sprague-Dawley; Renal Circulation; Thiazolidinediones; Thromboxane A2; Vasoconstriction

To study endothelial function in different variants of acute renal failure (ARF) at various stages of the disease.. The study of 36 patients with severe ARF at the stages of oliguria and recovery of diuresis included a clinico-laboratory analysis of characteristics of ARF of various etiology and follow-up of plasmic concentrations of endothelin-1, thromboxan A2 and prostacyclin in different ARF variants at different ARF stages.. The oliguric phase of severe ARF ran with significant elevation of the level of vasoconstrictive endothelial hormones (endothelin-1 and thromboxan A2 and a fall of a vasodilator prostacyclin. Recovery of diuresis normalized the above parameters.. Mechanisms of ARF development involve endothelial dysfunction manifesting with alteration of vasoactive hormones synthesis with a dominant rise of a vasoconstrictive hormones concentration.

Topics: Acute Kidney Injury; Adult; Down-Regulation; Endothelin-1; Endothelium, Vascular; Epoprostenol; Female; Humans; Male; Middle Aged; Thromboxane A2; Up-Regulation

The experiments were carried out on 36 male rats with an acute renal insufficiency--sublimate-induced nephropathy. An increased amount of both tromboxan A2, and prostaglandine F2a has been shown to play a pathogenic role in the disorders of the main energy-dependent process in kidney--reabsorbtion of sodium ions. The negative correlative relation between the concentration of sodium ions in plasma and an increased amount of prostaglandine E2 in a kidney papilla can be explained by the hyperfunction of the interstitial cells of a kidney papilla and with a natriuretic effect of prostaglandine E2 at the level of collective tubules.

Topics: Absorption; Acute Kidney Injury; Animals; Dinoprost; Dinoprostone; Kidney; Kidney Medulla; Kidney Tubules, Collecting; Male; Prostaglandins; Rats; Sodium; Thromboxane A2

The interaction of endothelium-derived vasoconstrictor prostaglandins, the angiotensins (Ang), and the sympathetic nervous system in acute renal failure still remains to be determined. In this study, acute renal failure (ARF) was induced in male Wistar Kyoto rats (N = 7) in a 2K/2C model of 30-minute clamping. Contractions to Ang I and II and norepinephrine (NE) were studied in isolated aortic and renal artery rings 24 hours after clamp release. Sham-operated animals served as controls (N = 7). In ARF, contractions to NE were increased in the aorta and even further enhanced in the renal artery (P < 0.05 to 0.001), whereas contractions to Ang I and II were blunted (P < 0.05). Contractions were inhibited by SQ 30741, a thromboxane A2 (TXA2)/prostaglandin H2 (PGH2) receptor antagonist. We conclude that ARF is characterized by abnormal vascular reactivity both in the renal as well as the systemic vasculature that is in part mediated by endothelium-derived vasoconstrictor prostaglandins.

Topics: Acute Kidney Injury; Adrenergic Fibers; Angiotensin I; Angiotensin II; Animals; Aorta; Endothelium, Vascular; Kidney; Male; Norepinephrine; Rats; Rats, Inbred WKY; Renal Artery; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

1. Patients with obstructive jaundice are especially susceptible to acute renal failure. We have previously observed that in rats with bile duct ligation impaired renal function is associated with increased urinary thromboxane excretion. 2. In the present study we therefore investigated, in rats with bile duct ligation, renal function, urinary thromboxane excretion and thromboxane B2 synthesis by isolated glomeruli as well as the effects of the thromboxane A2/prostaglandin H2 receptor antagonist Daltroban on renal function in rats with bile duct ligation as compared with sham-operated rats. 3. On the fourth day after bile duct ligation (n = 7 rats) endogenous creatinine clearance as an estimate of glomerular filtration rate was significantly reduced to 0.74 +/- 0.05 (SEM) as compared with 1.06 +/- 0.09 ml min-1 g-1 kidney weight in sham-operated rats (n = 7, P < 0.01). In rats with bile duct ligation, urine volume was slightly increased, whereas urinary sodium (Na+) (P < 0.001) and potassium (K+) (P < 0.01) excretion as well as urine osmolarity (P < 0.05) were significantly reduced and lower than in sham-operated rats. 4. Urinary thromboxane excretion was significantly higher in rats with bile duct ligation than in sham-operated rats: 116.6 +/- 22.3 versus 56.8 +/- 10.2 pmol 24 h-1 100 g-1 body weight (P < 0.05). Thromboxane B2 synthesis in glomeruli isolated from rats with bile duct ligation was also significantly higher than in sham-operated rats: 12.6 +/- 2.0 versus 6.4 +/- 0.9 pmol h-1 mg-1 protein (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Animals; Blood Pressure; Body Weight; Cholestasis; Female; Kidney; Kidney Glomerulus; Ligation; Organ Size; Phenylacetates; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Thromboxane B2

Acute renal failure (ARF) induced with large doses of Gentamicin (GM) (an aminoglycoside) was associated with increased urinary TXB (TXA) excretion which provoked a decrease of the ratios of urinary PGE2/TXB2 and 6-keto-PGF1 alpha (PGI2)/TXB2 excretions. Furthermore, as indicated by light microscopy most of the epithelial cells lining the proximal tubules show obvious lesions varying from swelling of their cytoplasm to complete necrosis. Either the inhibitor, OKY-O46, of TXA-synthetase, or volume expansion (VE) with isotonic saline (IS) of the experimental animals diminished urinary TXB excretion which provoked 1) augmentation of the ratios of urinary PGE/TXB and 6-keto-PGF1 alpha/TXB excretions, 2) elevation of creatinine clearance (Ccr) and 3) diminution of proteinuria (PU). This protection against ARF-by OKY-O46 and VE can a can be seen in microscopic sections where necrosis of proximal tubules is almost absent. Only a few proximal tubules show swelling of their epithelial cells and some focal areas of tubule necrosis. We suggest that the metabolites of arachidonic acid (AA), TXA2 a (potent vasoconstrictor agent) and prostaglandins (PGE2 and PGI2), (potent vasodilator factors), play an important role in the development (TXA2) or in the prevention (PGs) of ARF induced by this antibiotic.

Topics: Acute Kidney Injury; Animals; Arginine Vasopressin; Catecholamines; Female; Gentamicins; Kidney; Methacrylates; Prostaglandins; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Thromboxane A2; Thromboxane-A Synthase

The relative role of thromboxane (TxA2) and sulfidopeptide leukotrienes C4 (LTC4) and D4 (LTD4) in the acute renal failure induced by cyclosporine was studied in the rats. Bolus i.v. administration of 20 mg/kg of CsA but not vehicle to adult male Sprague-Dawley rats resulted in a significant fall in glomerular filtration rate from 0.85 +/- 0.10 and renal plasma flow (RPF) 2.45 +/- 0.14 ml/min/100 g body wt to values at 20 min of 0.47 +/- 0.03 and 1.01 +/- 0.12 ml/min/100 g body wt (P less than 0.01), respectively, without a fall in mean arterial pressure. This hemodynamic effect was maintained for the following 40-min period. Pretreatment of rats with the TxA2 receptor antagonist GR32191 (3 mg/kg i.v.) allowed a partial but significant preservation of GFR (0.60 +/- 0.05 ml/min/100 g body wt) and RPF (1.55 +/- 0.12 ml/min/100 g body wt). In addition, the antagonism of endogenously produced LTC4 and LTD4 with the putative receptor antagonist L-649,923 (1 mg/kg i.v.) partially prevented the fall in GFR (0.65 +/- 0.07 ml/min/100 g body wt) and RPF (1.80 +/- 0.18 ml/min/100 g body wt) at 20 min after CsA injection. The combined administration of GR32191 and L-649,923 completely abolished the CsA-induced decline in GFR (0.80 +/- 0.09 ml/min/100 g body wt) and RPF (2.40 +/- 0.12 ml/min/100 g body wt). These findings suggest that TxA2 and LTC4/LTD4 participate in mediating renal function deterioration induced by acute CsA administration in the rat.

Topics: Acute Kidney Injury; Analysis of Variance; Animals; Biphenyl Compounds; Blood Pressure; Cyclosporine; Drug Antagonism; Glomerular Filtration Rate; Heptanoic Acids; Injections, Intravenous; Kidney; Male; Metabolic Clearance Rate; Phenylbutyrates; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; SRS-A; 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 roles of intrarenal angiotensin (A) and thromboxane (TX) in the vascular hypersensitivity to renal nerve stimulation (RNS) and paradoxical vasoconstriction to renal perfusion pressure (RPP) reduction in the autoregulatory range in 1 wk norepinephrine (NE)-induced acute renal failure (ARF) in rats were investigated. Renal blood flow (RBF) responses were determined before and during intrarenal infusion of an AII and TXA2 antagonist. Saralasin or SQ29548 alone partially corrected the slopes of RBF to RNS and RPP reduction in NE-ARF rats (P less than 0.02). Saralasin + SQ29548 normalized the RBF response to RNS. While combined saralasin + SQ29548 eliminated the vasoconstriction to RPP reduction, similar to the effect of renal denervation, appropriate vasodilatation was not restored. Renal vein norepinephrine efflux during RNS was disproportionately increased in NE-ARF (P less than 0.001) and was suppressed by saralasin + SQ29548 infusion (P less than 0.005). It is concluded that the enhanced sensitivity to RNS and paradoxical vasoconstriction to RPP reduction in 1 wk NE-ARF kidneys are the result of intrarenal TX and AII acceleration of neurotransmitter release to adrenergic nerve activity.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Blood Flow Velocity; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Kidney; Norepinephrine; Rats; Rats, Inbred Strains; Renal Circulation; Saralasin; Sympathetic Nervous System; Thromboxane A2

Six hours after glycerol (G) injection in normal rats (NR), creatinine clearance (Ccr) decreased while urinary TXB2 (TXA2), 6-keto-PGF1 alpha (PGI2) and PGE2 significantly increased. The administration of OKY-046, a selective TXA-synthase inhibitor in glycerol-treated rats (GTR), significantly prevented the decrease in Ccr (indicating a partial protection against the development of acute renal failure) (ARF) and the increase in urinary TXA2 excretion, while it did not significantly alter urinary prostaglandin (PG) excretion. However, although TXB2 synthesis by the isolated glomeruli (IG) obtained from rats sacrificed 2 and 6 h after G injection was significantly enhanced, PGE2 and 6-keto-PGF1 alpha (6kPGF1 alpha) synthesis was augmented only by the IG obtained from rats killed 6 h after G administration. TXB2 and 6kPGF1 alpha synthesis by the IG obtained from rats killed 24 h after G injection returned to normal levels, while PGE2 synthesis continued to be elevated. Thus the enhanced release of PGE2 and 6kPGF1 alpha observed in intact animals in the early phase of ARF must be of medullary origin, while the augmented release of TXB2 (TXA2) by the IG must be responsible for the afferent arteriolar contraction during the early phase of this syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Creatinine; Dinoprostone; Female; Glycerol; In Vitro Techniques; Kidney Glomerulus; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane A2

Glycerol-treated rats exhibited significantly increased urinary thromboxane B2(TXB)2, prostaglandin E2 (PGE2) and 6-ketoprostaglandin F1 alpha (6kPGF1 alpha) excretion and urine volume (UV). These increases were associated with significant decreases in creatinine clearance (CCr), urinary sodium concentration (UNa), urinary sodium excretion (UNaV), and fractional excretion of sodium (FENa%), which is consistent with the development of the prerenal (reversible) phase of acute renal failure (ARF). When glycerol-treated rats were pretreated with a selective inhibitor of thromboxane A2 (TXA2) synthesis (imidazole), urinary PGE2 and 6kPGF1 alpha excretion and UV remained unchanged, whereas CCr, UNa, UNaV decreases were partially prevented. Additionally, FENa% was increased, indicating inhibition of sodium reabsorption. The findings indicate that inhibition of TXA2 synthesis increases UNaV and partially improves CCr in glycerol-treated rats. Further histologic observation and functional follow-up over longer periods of time are needed to clarify the role of TXA2 in the development of ARF.

Topics: Acute Kidney Injury; Animals; Creatinine; Female; Glycerol; Imidazoles; Natriuresis; Prostaglandins; Rats; Thromboxane A2

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

Urinary excretion rates of prostaglandin (PG) E2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane (TX) B2 were evaluated in three groups of cirrhotic patients [without ascites (group 1, 13 cases), with ascites and normal renal function (group 2, 15 cases), and with ascites and renal failure (group 3, 5 cases)] and in 14 healthy controls. All urinary arachidonate metabolites were significantly increased in group 2 patients. Patients with renal failure showed lower PGE2, PGF2 alpha, and TXB2 values than those from group 2; PGF2 alpha values were also lower than controls. Platelet TXA2 production during whole blood clotting was significantly reduced in all groups of patients. Administration of low-dose aspirin and sulindac, two cyclooxygenase inhibitors selectively sparing renal cyclooxygenase activity, effectively inhibited platelet TXA2 production without affecting urinary TXB2 excretion, thus ruling out platelets as a possible source of urinary TXB2. We conclude that patients with ascites and normal renal function show an overall activation of the renal PG system. Renal production of vasodilating PGE2 and PGI2 may be involved in supporting renal function in these patients. A reduced platelet synthesis of proaggregatory TXA2 also occurs in cirrhotic patients. This may play a role in the bleeding tendency of cirrhosis.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adult; Aged; Arachidonic Acid; Arachidonic Acids; Aspirin; Blood Platelets; Creatinine; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Epoprostenol; Female; Humans; Kidney; Liver Cirrhosis; Male; Middle Aged; Natriuresis; Prostaglandins E; Prostaglandins F; Renin-Angiotensin System; Sulindac; Thromboxane A2; Thromboxane B2

Acute renal failure (ARF) was induced in 35 week-old conscious female Wistar rats, by intramuscular (IM) injection of glycerol. Intraperitoneal (IP) injection of imidazole, an inhibitor of thromboxane (TXA2) synthesis, partially protected the animals against ARF. This protection was accompanied by a significant decrease in renal TXB2 (the stable chemical metabolite of TXA2) and a significant increase in renal 6-keto-PGF1 alpha (the stable chemical metabolite of PGI2) synthesis. Intraperitoneal injection of captopril (SQ 14225) an angiotensin-converting-enzyme inhibitor, did not protect the animals against ARF. This lack of protection was accompanied by a significant increase in renal TXB2 and a significant decrease in renal 6-keto-PGF1 alpha synthesis. The results suggest that: (a) the renin-angiotensin (R-A) system does not play a role, or has only a secondary one in the development of ARF; (b) thromboxane A2 (the most potent vasoconstrictor and platelet aggregator agent known) is the preponderant agent responsible for the development of this pathological syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Angiotensin II; Animals; Captopril; Dinoprostone; Female; Glycerol; Imidazoles; Prostaglandins; Prostaglandins E; Rats; Thromboxane A2; Thromboxane B2; Thromboxanes

Acute renal failure (ARF) was associated with increased urinary thromboxane (TXA2) excretion and lessened excretion of sodium (UNaV) and fractional excretion of sodium (FENa%). The inhibitor of thromboxane A2-synthetase OKY-046 enhanced sodium excretion and fractional excretion of sodium in normal and saline loaded animals whereas it partially prevented the reduction in sodium excretion and creatinine clearance and significantly increased fractional excretion of sodium in glycerol treated rats suggesting a partial protection against the development of acute renal failure.

Topics: Acrylates; Acute Kidney Injury; Animals; Dinoprostone; Epoprostenol; Female; Glomerular Filtration Rate; Glycerol; Kidney; Methacrylates; Natriuresis; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Vascular Resistance

Bolus i.v. administration of 100 micrograms/kg of E. Coli lipopolysaccharide endotoxin (LPS) to adult male Munich-Wistar rats (N = 18) resulted in a progressive fall in RBF and GFR from 6.9 +/- 0.2 SE and 1.1 +/- 0.05 ml/min to minimal values at 50 minutes of 3.8 +/- 0.4 and 0.32 +/- 0.08 (P less than 0.05), respectively, without a fall in mean arterial pressure. At 50 minutes, renal cortical generation rates of PGE2 (1075 +/- 108 pg/mg tissue), 6 keto PGF1 alpha (221 +/- 41 pg/mg), and TxB2 (106 +/- 12 pg/mg) were significantly higher than those of vehicle-treated control rats (N = 10, PGE2 = 466 +/- 107, 6 keto PGF1 alpha = 94 +/- 3, and TxB2 = 35 +/- 3 pg/mg), and morphologic examination revealed normal histology with notable absence of leukocytes and platelets. Pretreatment of a third group of nine rats with TxA2 synthetase inhibitor UK-37.248 (dazoxiben, 10 mg/kg) selectively abolished the LPS-induced rise in TxB2 (29 +/- 3 pg/mg), but not PGE2 (837 +/- 62 pg/mg) or 6 keto PGF1 alpha (179 +/- 5 pg/mg), prevented the fall in RBF at 50 minutes (6.3 +/- 0.4 ml/min), and allowed for significant preservation of GFR (0.67 +/- 0.08 ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Animals; Chromones; Dinoprostone; Endotoxins; Epoprostenol; Escherichia coli; Glomerular Filtration Rate; Imidazoles; Kidney; Male; Prostaglandins E; Rats; Rats, Inbred Strains; SRS-A; Thromboxane A2; Vascular Resistance

Since prostacyclin (PGI2) is known to regulate renal cortical blood flow and since ischemia stimulates thromboxane (Tx) A2 synthesis, the role of these prostanoids in moderating the response to renal ischemia was studied in the rat. At baseline, plasma TxB2 concentration in untreated animals (n = 13) was 357 pg/ml. The left renal pedicle was clamped for 45 minutes after a right nephrectomy (n = 16), which led after 5 minutes of reperfusion to a rise in TxB2 to 2825 pg/ml (p less than 0.001), but there was no change in 6-keto-PGF1 alpha. After 24 hours creatinine levels rose from 0.4 to 3.0 mg/dl (p less than 0.001), and left renal weight rose from 94% to 117% (p less than 0.001) relative to the weight of the right kidney. In nephrectomized but nonischemic sham control rats (n = 7), creatinine level was 0.9 mg/dl and kidney weight 91% after 24 hours. Pretreatment with OKY 046 (n = 13) (2 mg/kg administered intravenously) blocked ischemia-induced TxB2 synthesis, while 6-keto-PGF1 alpha levels rose from 96 to 302 pg/ml (p less than 0.001). There was no increase in creatinine levels or kidney weight relative to the sham group. Pretreatment with ibuprofen (n = 10) (12 mg/kg) or OKY 046 and ibuprofen (n = 9) inhibited TxB2 and 6-keto-PGF1 alpha synthesis, but creatinine levels and renal weight rose (p less than 0.001). Renal histology in OKY 046-pretreated animals was equal to that in nephrectomized controls, while all other ischemic groups showed tubular necrosis. Results indicate that a high PGI2/TxA2 ratio protects against renal ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Epoprostenol; Ibuprofen; Ischemia; Male; Methacrylates; Premedication; Rats; Renal Circulation; Thromboxane A2; Thromboxane B2; Thromboxanes

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

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

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

Platelet aggregation and thromboxane B2 production, in response to adenosine diphosphate, were significantly impaired in 7 undialyzed or inadequately dialyzed patients with renal failure when compared to adequately dialyzed individuals or normal subjects. In 1 patient, platelet aggregation and thromboxane synthesis were corrected after adequate hemodialysis. The defect in both platelet aggregation and thromboxane production was induced in normal platelets incubated with uremic platelet-poor plasma. These findings suggest that the uremic platelet defect may be due, in part, to a plasma factor that inhibitors platelet thromboxane synthesis. Further, adequate dialytic therapy may reverse this defect.

Topics: Acute Kidney Injury; Adult; Aged; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Aggregation; Renal Dialysis; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: Acute Kidney Injury; Angiotensin II; Animals; Arachidonic Acids; Biological Assay; Bradykinin; Glycerol; Kidney; Male; Rabbits; Rats; Thromboxane A2; Thromboxanes

The hemodynamic alterations occuring in glycerol induced renal failure are controversial. To date no single humoral substance can fully explain the change in renal resistance observed in this hemodynamic model of acute renal failure. To assess the capacity of the rabbit kidney to produce thromboxane A2, a potent vasoconstrictor, the following experiments were carried out. Rabbits received 14 ml/kg of 50% glycerol subcutaneously 24 hrs before the study. After 24 hrs., the kidneys were removed and perfused ex vivo in superfusion bioassay cascade. Kidneys from rabbits which developed renal failure, as assessed by elevated serum creatinines, released a substance which produced contraction of rabbit aorta (RCS) in response to bradykinin (BK) and angiotensin II. Microsomes prepared from these kidneys when incubated with [14C]-arachidonic acid produced a peak of radioactivity which comigrated with thromboxane B2 on the thin layer chromatography and was inhibited by the thromboxane synthetase inhibitor imidazole. Furthermore, an inverse linear relation was found between the BK dose required to release RCS from perfused kidney and the serum creatinine levels. A direct linear relation was found between the percent of TxB2 produced by renal microsome preparations and the serum creatinine. These studies demonstrate an increased renal capacity of the glycerol-model of acute renal failure to produce TxA2. The production of TxA2 a potent vasoconstrictor should therefore be further evaluated as a potential endogenous mediator of the hemodynamic changes occurring in acute renal failure.

Topics: Acute Kidney Injury; Animals; Creatinine; Glycerol; Hemodynamics; In Vitro Techniques; Kidney; Male; Microsomes; Perfusion; Rabbits; Thromboxane A2; Thromboxanes