Urinary Prostaglandin Excretion Research Articles

Influence of the selective COX-2 inhibitor celecoxib on sex differences in blood pressure and albuminuria in spontaneously hypertensive rats

We previously reported that female spontaneously hypertensive rats (SHR) have greater cyclooxygenase-2 (COX-2) expression in the renal medulla and enhanced urinary excretion of prostaglandin (PG) E2 (PGE2) metabolites compared to male SHR. Based on the role of COX-2-derived prostanoids in the regulation of cardiovascular health, the aim of the current study was to test the hypothesis that blood pressure (BP) in female SHR is more sensitive to COX-2 inhibition than in males. Seven week old male and female SHR were implanted with telemetry transmitters for continuous BP recording. After one week of baseline BP recording, male and female SHR were randomized to receive the selective COX-2 inhibitor celecoxib (10 mg/kg/day) or vehicle for six weeks (from 9 to 14 weeks of age). Female SHR had lower BP and albuminuria compared to male SHR as well as enhanced urinary excretion of PGE metabolite (PGEM), 6-keto PGF1α and thromboxane B2, indicators of PGE2, PGI2 and TXA2, respectively. Treatment with celecoxib did not significantly alter BP or albuminuria in either female or male SHR. Celecoxib did not change PGs metabolites excretion in male SHR; however, excretion levels of PGEM and 6-keto PGF1α were reduced in female SHR. COX-2 derived PG can also induce oxidative stress. Markers of oxidative stress (thiobarbituric acid reactive substances (TBARs) and H2O2 excretion) were lesser in female SHR versus male SHR. Celecoxib treatment did not significantly change markers of oxidative stress in female SHR, however, urinary TBARs excretion was significantly reduced in male SHR after 6 weeks of treatment with celecoxib. Therefore, although celecoxib treatment appears to have distinct effects on prostanoids levels in female SHR vs. males, it is unlikely that COX-2 contributes to established sex differences in BP in SHR.

A severe phenotype of Gitelman syndrome with increased prostaglandin excretion and favorable response to indomethacin.

Our understanding of Gitelman syndrome (GS) and Bartter syndrome has continued to evolve with the use of genetic testing to more precisely define the tubular defects responsible. GS is caused by mutations in the SLC12A3 gene encoding the Na+–Cl− co-transporter of the distal convoluted tubule (NCCT) and tends to be associated with a milder salt-losing phenotype. We describe two female siblings presenting in infancy with a severe salt-losing tubulopathy and failure to thrive due to compound heterozygous mutations in the SLC12A3 gene encoding the NCCT. Both children were treated with indomethacin resulting in improved linear growth and polyuria. Some atypical biochemical findings in our cases are discussed including raised urinary prostaglandin (PGE2) excretion that normalized with intravenous fluid repletion.

Effect of n-3 Fatty Acid Supplementation on Urinary Risk Factors for Calcium Oxalate Stone Formation

Findings are inconsistent in a few studies of the effect of n-3 fatty acid supplementation on urinary calcium and oxalate excretion in stone formers. We evaluated the physiological effects of supplementation with eicosapentaenoic acid and docosahexaenoic acid on urinary risk factors for calcium oxalate stone formation under standardized conditions. We studied 15 healthy subjects initially while consuming a standardized diet for 5 days (control phase). During consecutive intervention phases 1-5-day standardized diet, 2-20-day free diet and 3-5-day standardized diet participants received 900 mg eicosapentaenoic acid and 600 mg docosahexaenoic acid daily. While ingesting the standardized diets, daily 24-hour urine samples were collected. After short-term supplementation with eicosapentaenoic acid and docosahexaenoic acid in phase 1 we noted no changes in urinary parameters compared to the control phase. After 30-day supplementation with eicosapentaenoic acid and docosahexaenoic acid in phase 3 relative supersaturation with calcium oxalate decreased significantly by 23% from a mean ± SD of 2.01 ± 1.26 to 1.55 ± 0.84 due to significantly decreased urinary oxalate excretion (p = 0.023). Other urinary variables were not affected by supplementation. Results show that 30-day n-3 fatty acid supplementation effectively decreases urinary oxalate excretion and the risk of calcium oxalate crystallization. The mechanism of the physiological effect may be decreased cellular oxalic acid exchange attributable to an altered fatty acid pattern of membrane phospholipids with concomitant changes in oxalate transporter activity. Calcium oxalate stone formers may benefit from long-term n-3 fatty acid supplementation.

Urinary Lipocalin-Type Prostaglandin D Synthase: A Potential Marker for Early Gentamicin-Induced Renal Damage?

Urinary excretion of lipocalin-type prostaglandin D synthase (L-PGDS) has been suggested to be a useful biomarker of early diabetic nephropathy. We studied whether L-PGDS is also a marker of gentamicin (GM)-induced renal damage in the "creatinine-blind" range. A prospective study was conducted in 6 patients who were given long-term intravenous administration of GM (18-42 days in combination with a beta-lactam/carbapenem antibiotic or vancomycin) for the treatment of infective endocarditis. Urinary excretions of L-PGDS, beta2-microglobulin, and N-acetyl-beta-D-glucosaminidase were measured in the early (within 10 days from commencement) and late (thereafter) phases of GM therapy. Systemic clearance of GM (CLGM) and creatinine clearance (CLcr) was also measured concomitantly. CLGM was reduced significantly (P < 0.05) by 10% from the early to late treatment phase, whereas urinary L-PGDS excretion showed a significant (P < 0.05) increase (from 7.3 +/- 4.6 to 8.7 +/- 5.0 mg/g creatinine, mean +/- SD) concomitantly. In contrast, no significant changes were observed for urinary beta2-microglobulin and N-acetyl-beta-D-glucosaminidase concentrations. In conclusion, urinary L-PGDS may be a promising biomarker for the early phase of GM-induced renal impairment.

Urinary Prostaglandins and the Effect of Indomethacin on Phosphate Excretion in Children With Hypophosphatemic Rickets

We recently reported the urinary prostaglandin E(2)/creatinine ratio (PGE(2)/Cr) was markedly elevated in Hyp mice, the animal model for X-linked hypophosphatemia, compared with control mice. We provided evidence for altered prostaglandin production mediating the phosphaturia and that indomethacin decreases urinary phosphate excretion in Hyp mice but not control mice. To determine the levels of urinary PGE(2)/Cr, the safety and efficacy of indomethacin on phosphate excretion in children with hypophosphatemic rickets (HPR), a prospective clinical trial was performed in 16 children with HPR and 16 age- and gender-matched healthy controls. Urinary PGE(2)/Cr excretion was determined on a 24 h timed urine collection. A randomized cross over, placebo versus indomethacin, clinical trial was performed in the 16 children with HPR. There was no difference in urinary PGE(2)/Cr excretion between controls and patients with HPR. In children with HPR, indomethacin treatment for 3 mo had no significant effect on serum phosphorus or urinary phosphate excretion. In conclusion, urinary prostaglandin excretion is similar in children with HPR compared with controls. Indomethacin had no significant effect on serum phosphorus or urinary phosphate excretion in children with HPR.

Endothelin A Receptor Blockade Reduces Diabetic Renal Injury via an Anti-Inflammatory Mechanism

Endothelin (ET) receptor blockade delays the progression of diabetic nephropathy; however, the mechanism of this protection is unknown. Therefore, the aim of this study was to test the hypothesis that ET(A) receptor blockade attenuates superoxide production and inflammation in the kidney of diabetic rats. Diabetes was induced by streptozotocin (diabetic rats with partial insulin replacement to maintain modest hyperglycemia [HG]), and sham rats received vehicle treatments. Some rats also received the ETA antagonist ABT-627 (sham+ABT and HG+ABT; 5 mg/kg per d; n = 8 to 10/group). During the 10-wk study, urinary microalbumin was increased in HG rats, and this effect was prevented by ET(A) receptor blockade. Indices of oxidative stress, urinary excretion of thiobarbituric acid reactive substances, 8-hydroxy--deoxyguanosine, and H2O2 and plasma thiobarbituric acid reactive substances were significantly greater in HG rats than in sham rats. These effects were not prevented by ABT-627. In addition, renal cortical expression of 8-hydroxy--deoxyguanosine and NADPH oxidase subunits was not different between HG and HG+ABT rats. ETA receptor blockade attenuated increases in macrophage infiltration and urinary excretion of TGF-beta and prostaglandin E2 metabolites in HG rats. Although ABT-627 did not alleviate oxidative stress in HG rats, inflammation and production of inflammatory mediators were reduced in association with prevention of microalbuminuria. These observations indicate that ETA receptor activation mediates renal inflammation and TGF-beta production in diabetes and are consistent with the postulate that ETA blockade slows progression of diabetic nephropathy via an anti-inflammatory mechanism.

Increase in heme oxygenase-1 levels ameliorates renovascular hypertension

The heme oxygenase system (HO-1 and HO-2) catalyzes the conversion of heme to free iron, carbon monoxide (CO), a vasodepressor, and biliverdin, which is further converted to bilirubin, an antioxidant. HO-1 induction has been shown to suppress arachidonic acid metabolism by cytochrome P450 (CYP450) monooxygenases and cyclooxygenases (COX), and to decrease blood pressure in spontaneously hypertensive rats (SHR). The Goldblatt 2K1C model is a model of renovascular hypertension in which there is increased expression of COX-2 in the macula densa and increased renin release from the juxtaglomerular apparatus of the clipped kidney. We examined whether HO-1 overexpression, as a prophylactic approach, would attenuate renovascular hypertension and evaluated potential mechanisms that may account for its effect. 2K1C rats were treated with cobalt protoporphyrin (CoPP) or tin mesoporphyrin (SnMP) one day before surgery and weekly for three weeks thereafter. We measured systolic blood pressure, HO activity, HO-1, HO-2, COX-1 and COX-2 protein expression, heme content, and nitrotyrosine levels as indices of oxidative stress. Urinary prostaglandin excretion (PGE2), plasma renin activity (PRA), and plasma aldosterone levels were also measured. CoPP administration induced renal HO-1 expression by 20-fold and HO activity by 6-fold. This was associated with a reduction in heme content, nitrotyrosine levels, COX-2 expression and urinary PGE2 excretion, and attenuation of the development of hypertension in the 2K1C rats. There was no decrease in plasma renin activity; however, plasma aldosterone levels were significantly lower. In the 2K1C SnMP-treated rats, blood pressure was significantly higher than that of untreated 2K1C rats throughout the study, and the difference in the size of the smaller left clipped kidney compared to the nonclipped right kidney was significantly increased. These findings define an action of prolonged HO-1 induction to interrupt and counteract the influence of the renin-angiotensin-aldosterone system (RAAS) to increase in blood pressure in the 2K1C model of renovascular hypertension. Multiple mechanisms include a decrease in oxidative stress as indicated by the decrease in cellular heme and nitrotyrosine levels, an anti-inflammatory action as evidenced by a decrease in COX-2 and PGE2, interference with the action of angiontensin II (Ang II) as evidenced by an increase in PRA in the face of a decrease in PGE2 and aldosterone, as well as the inhibition of aldosterone synthesis.

Reply:

We thank Drs. Campbell and Makar for their interest in our paper.1 We also thank them for their comments recognizing the tightly controlled conditions of our study and the relevance of our conclusions indicating that naproxen, but not celecoxib, administered during a short period of time adversely affects renal function and the renal response to furosemide in patients with cirrhosis and ascites and increased activity of the renin-angiotensin system. We agree with these authors that our investigation did not offer information about the safety of celecoxib administered for therapeutic purposes in patients with decompensated cirrhosis and that further studies using selective cyclooxygenase-2 inhibitors for a longer period of time and providing data at the patient level are required to warrant the safety of these drugs in clinical practice. The exclusion from analysis of 7 patients found to have hepatorenal syndrome (HRS) at baseline, despite a normal serum creatinine value (<1.5 mg/dL), reflects the difficulties in performing renal physiological studies in patients with decompensated cirrhosis. HRS is defined as a glomerular filtration rate (GFR) lower than 40 mL/min,2 and we found a GFR below this level in all 7 patients as measured by the technetium 99m-diethylenetriaminepentaacetic acid clearance, which is a sensitive technique for assessing GFR. Three major reasons justified the exclusion of these patients. First, HRS is considered to be secondary to an imbalance between an increased activity of endogenous vasoconstrictors systems (renin-angiotensin and sympathetic nervous systems) and a deficient renal synthesis of prostaglandins (PGs).3 Contrary to what occurs in patients without renal failure, in whom GFR and renal plasma flow are critically dependent on renal synthesis of PGs, patients with HRS have extremely low urinary excretion of PGs.3 Therefore, testing the renal effects of anti-inflammatory drugs in patients who already have a renal impairment in PG excretion is not a good approach. Second, since the diagnosis of HRS based on GFR was not done at randomization (it was based on serum creatinine concentration), keeping the patients with GFR lower than 40 mL/min within the study might have introduced bias in the homogeneity of the groups. Finally, PG inhibition by short-term administration of anti-inflammatory drugs produces between a 20% and 30% decrease in GFR.3 If baseline values of GFR are very low, as occurs in HRS, the clearance technique is not sensitive enough to detect small changes in GFR. In our study, no patient treated with celecoxib developed a significant (greater than 20%) decrease in GFR. We have no explanation for the differences between our results and those of Guevara et al.4 Although they administered celecoxib for a longer period of time (1.5 days more) than us, we do not think this accounts for the observed differences. However, the study of Guevara et al.4 was a pilot study, whereas ours was a randomized, double-blind, placebo, naproxen investigation. Joan Clària*, Vicente Arroyo*, * Liver Unit-Institut de Malalties Digestives, Hospital Clínic, Barcelona, Spain

Effects of cyclooxygenase-2 (COX-2) inhibition on plasma and renal renin in diabetes

COX-2-derived prostaglandins (PG) have been suggested to be important modulators of renin release and expression. However, the role of COX-2 in various high-renin states is still being debated. In the present studies we explored the role of COX-2-derived PG on basal and angiotensin converting enzyme inhibitor (ACEI)-stimulated plasma and renal renin concentrations (PRC and RRC, RIA), and mRNA expression (RmRNA, RNAse protection assay) in experimental diabetes (DM). Groups of moderately hyperglycemic (n = 5, ~350 mg/dl), streptozotocin-diabetic rats (D) after 3 weeks of DM were treated with a selective COX-2 inhibitor, MF-tricyclic (MF, 5 mg/kg/day for 10 days in food), the combination of MF and the ACEI enalapril (3 mg/kg/day), enalapril alone, or vehicle (MF-free chow), for 10 days. Non-diabetic control rats, fed MF-free chow, were also studied. All groups of diabetic rats demonstrated similar glycemic control. Treatment with ACEI resulted in significant elevations in PRC, RRC and RmRNA as compared to non-ACEI treated groups of diabetic and control rats. A similar rise in these parameters was observed in the rats treated with the combination of ACEI and MF. Furthermore, in diabetic rats treated with MF alone, PRC and RRC were similar to vehicle-treated animals. Diabetic rats demonstrated higher urinary PG as compared to controls. MF-treated rats demonstrated a significant reduction in urinary PG excretion. In summary, selective COX-2 inhibition influenced neither basal renin status nor ACEI-induced renin release and expression in diabetic rats. These findings do not support a significant role for COX-2 in mediating renin status in diabetes. (J Lab Clin Med 2002;140:351-7)

Development and Evaluation of a Practical ELISA for Human Urinary Lipocalin-Type Prostaglandin D Synthase

Urinary excretion of lipocalin-type prostaglandin D synthase (L-PGDS) is significantly increased in patients with chronic renal failure, but its diagnostic potential in less advanced stages of renal diseases remains to be elucidated. Six mouse monoclonal antibodies (MAbs) were raised against recombinant human L-PGDS. We constructed a sandwich ELISA with two MAbs that recognized different epitopes with high affinities and assessed its assay performance and clinical utility with urine samples from healthy controls, diabetic patients, and patients with various renal diseases. Western blot analyses with NH(2)-terminus-truncated L-PGDS mapped the epitopes to Ala(23)-Val(28) (MAb-7F5 and -10A3), Ser(52)-Ala(73) (MAb-9A6), Tyr(107)-Val(120) (MAb-1B7 and -6F5), and Gly(140)-Pro(155) (MAb-6B9). A sandwich ELISA was constructed with MAb-1B7 and -7F5, the K(d) values of which were 3.6 and 3.9 nmol/L, respectively, for native L-PGDS. Recoveries were 91-111%, and intra- and interassay CVs were <6% and <9%, respectively. The ELISA showed parallelism of standard and urine samples and no significant interference by a variety of urinary constituents. Urinary L-PGDS excretion was significantly increased in patients with diabetic nephropathy, IgA nephropathy, and chronic glomerulonephritis even when serum creatinine was not increased. In patients with renal diseases, urinary L-PGDS was correlated with urinary albumin (r = 0.64; P <0.0001), N-acetyl-beta-D-glucosaminidase (r = 0.43; P <0.001), and serum creatinine (r = 0.66; P <0.0001). At a cutoff value of 284 mg/mol creatinine, the assay had sensitivities of 74% for diabetic nephropathy and 83% for chronic glomerulonephritis and a specificity of 93%. This ELISA system is suitable for measurement of urinary L-PGDS in a routine clinical assay and may be useful to detect less advanced stages of renal diseases.

Blood Sugar Control Reverses the Increase in Urinary Excretion of Prostaglandin D Synthase in Diabetic Patients

Background/Aims: We investigated basal levels of serum and urinary lipocalin-type prostaglandin D synthase/β-trace (L-PGDS) in type-2 diabetic patients and explored whether glycemic control affects L-PGDS status in another 55 diabetic inpatients with normoalbuminuria. Methods: Fifty-five type-2 diabetic outpatients (HbA1c, 9.14 ± 0.20%; creatinine (Cr), 85.1 ± 2.4 µmol/l), and 55 age-matched healthy control subjects were recruited. Serum and urinary levels of L-PGDS were determined with respect to the stage of diabetic nephropathy. The L-PGDS was localized by immunohistochemistry. Results: The urinary L-PGDS index increased in diabetic patients, compared with the controls (234.8 ± 27.4 vs. 73.8 ± 7.8 µg/mmol Cr, p < 0.001). Even in normoalbuminuric patients as well as in microalbuminuric patients, urinary L-PGDS indexes were higher than the controls (166.0 ± 21.1, p < 0.0001 and 338.6 ± 62.5 µg/mmol Cr, p < 0.0001, respectively), although the serum L-PGDS level was equal to that in the control subjects. Multiple regression analysis revealed that the urinary L-PGDS index was predicted solely by glucose levels and type-IV collagen index, whereas the serum L-PGDS was determined mainly by age and serum Cr. Glycemic control reduced the urinary L-PGDS index towards the normal range in diabetic patients with normoalbuminuria (172.3 ± 6.6 vs. 118.1 ± 2.6 (SE) µg/mmol Cr, p < 0.0001). Immunohistochemistry showed that L-PGDS was uniquely present in the renal tubules in diabetes while in nondiabetics, L-PGDS occurred solely in the peritubular interstitium, not in the tubular cells. Conclusion: Inadequate glycemic control is responsible for urinary L-PGDS excretion in the diabetic patients. Urinary L-PGDS is useful to predict subclinical renal injury associated with type-2 diabetes.

Cyclooxygenase isozyme expression and intimal hyperplasia in a rat model of balloon angioplasty.

Prostaglandin formation is enhanced in vascular disease, in part through induction of cyclooxygenase (COX-2) in vascular smooth muscle cells. Because COX regulates cell growth and migration, we examined whether the COX expression plays a role in the development of intimal hyperplasia after vascular injury. Rats undergoing balloon angioplasty of the carotid artery were randomized to receive a selective COX-2 inhibitor (SC-236), a selective COX-1 inhibitor (SC-560) or a combination of the two. Normal, uninjured vessels showed COX-1, but no COX-2 expression. Fourteen days after balloon injury, both COX-1 and COX-2 were expressed in the neointima. Balloon angioplasty resulted in a marked increase in the urinary excretion of prostaglandin (PG) E(2,) PGF(2alpha), and thromboxane (TX) B(2). Both the COX-1 inhibitor SC-560 and the COX-2 inhibitor SC-236 suppressed the generation of PGE(2) and PGF(2alpha), particularly when combined, suggesting a role for both isozymes in the generation of prostaglandins in this model. In contrast, TXA(2) was markedly suppressed by the COX-1 inhibitor SC-560. COX-2 inhibition with SC-236 had no effect on intimal hyperplasia at day 14 (0 versus 8.5%; n = 7 in controls). In contrast, intimal hyperplasia was reduced by SC-560 when administered alone (by 42%; n = 7, p < 0.05) or in combination with SC-236 (by 40%; n = 7, p < 0.05). COX-1 may play a role in the development of intimal hyperplasia, potentially through the inhibition of platelet TXA(2). Despite being expressed in the neointima, COX-2 does not play a role in the development of intimal hyperplasia after vascular injury.

Urinary prostaglandin excretion in pregnancy: the effect of dietary sodium restriction

Introduction: Dietary sodium restriction results in activation of the renin-angiotensin-aldosterone-system. In the non-pregnant situation renin release in response to a low sodium diet is mediated by prostaglandins. We studied the effect of dietary sodium restriction on urinary prostaglandin metabolism in pregnancy.Patients and methods: In a randomized, longitudinal study the excretion of urinary metabolites of prostacyclin (6-keto-PGF1 αand 2,3-dinor-6-keto-PGF1 α) and thromboxane A2(TxB2and 2,3-dinor-TxB2) was determined throughout pregnancy and post partum in 12 women on a low sodium diet and in 12 controls.Results: In pregnancy the excretion of all urinary prostaglandins is increased. The 6-keto-PGF1 α/ TxB2-ratio as well as the 2,3-dinor-6-keto-PGF1α/ 2,3-dinor-TxB2-ratio did not significantly change in pregnancy.Conclusion:Prostacyclin and thromboxane do not seem to play an important role in sodium balance during pregnancy.

Neonatal urinary prostanoid excretion

Urinary excretion of prostanoids prostaglandin E 2 (PGE 2), PGE-M (7α-hydroxy-5,11-diketo- 2,3,4,5,20-penta-19-carboxyprostanoic acid), 6-keto-PGF 1α, 2,3-dinor-6-keto-PGF 1α, thromboxane B 2 (TxB 2) 2,3-dinor-TxB 2 and 11-dehydro-TxB 2 was determined by gas chromatography/mass spectrometry in preterm and term infants to show that there is an age-dependent excretion rate of the above prostanoids in infants this young. Group I included premature children with normal postnatal development, Groups II and III included term children who were admitted in the neonatal period for observation because of feeding problems but who were subsequently found to be completely healthy. We present normal data of three primary prostanoids and four prostanoid metabolites. In Group I, excretion rates of 2,3-dinor-TxB 2 were significantly lower than in Group II ( P = 0.04) and in Group III ( P = 0.05). Furthermore, the excretion rate of 11-dehydro-TxB 2 in group I was significantly lower than in Group II ( P = 0.05). We found no significant age-dependent differences between the three groups in excretion rates of PGE 2, PGE-M, 6-keto-PGF 1α, 2,3-dinor-6-keto-PGF 1α, and TxB 2.

Acetaminophen inhibits spinal prostaglandin E2 release after peripheral noxious stimulation.

Prostaglandin play a pivotal role in spinal nociceptive processing. At therapeutic concentrations, acetaminophen is not a cyclooxygenase inhibitor. inhibitor. Thus, it is antinociceptive without having antiinflammatory or gastrointestinal toxic effects. This study evaluated the role of spinal prostaglandin E2 (PGE2) in antinociception produced by intraperitoneally administered acetaminophen. The PGE2 concentrations in the dorsal horn of the spinal cord were measured after formalin was injected into the hind paw of rats. The effect of antinociceptive doses of acetaminophen (100, 200, and 300 mg/kg given intraperitoneally) on PGE2 levels and flinching behavior was monitored Spinal PGE2 and acetaminophen concentrations were obtained by microdialysis using a probe that was implanted transversely through the dorsal horn of the spinal cord at L4. Furthermore, the effects of acetaminophen on urinary prostaglandin excretion were determined. Intraperitoneal administration of acetaminophen resulted in a significant decrease in spinal PGE2 release that was associated with a significant reduction in the flinching behavior in the formalin test Acetaminophen was distributed rapidly into the spinal cord with maximum dialysate concentrations 4560 min after intraperitoneal administration. Urinary excretion of prostanoids (PGE2, PGF2alpha, and 6-keto-PGF1alpha) was not significantly altered after acetaminophen administration. The data confirm the importance of PGE2 in spinal nociceptive processing. The results suggest that antinociception after acetaminophen administration is mediated, at least in part, by inhibition of spinal PGE2 release. The mechanism, however, remains unknown. The finding that urinary excretion of prostaglandins was not affected might explain why acetaminophen is antinociceptive but does not compromise renal safety.

Selective inhibition of cyclooxygenase 2 spares renal function and prostaglandin synthesis in cirrhotic rats with ascites

Background & Aims: The critical role of cyclooxygenase (COX) products in maintenance of renal function in cirrhosis with ascites discourages the use of nonsteroidal anti-inflammatory drugs in this disease. The recent development of selective COX-2 inhibitors opens new avenues for the use of these compounds in decompensated cirrhosis. The current study evaluates the effects of a selective COX-2 inhibitor (SC-236) on renal function in cirrhotic rats with ascites. Methods: In protocol 1, urine volume, urinary excretion of sodium and prostaglandins, glomerular filtration rate, and renal plasma flow were measured before and after administration of SC-236 (n = 12) or ketorolac (n = 10) to rats with cirrhosis. Protocol 2 was aimed at assessing the effects of COX inhibitors on renal water metabolism in 28 cirrhotic rats. Results: Administration of SC-236 to cirrhotic animals did not produce significant renal effects, whereas administration of the nonselective COX-1/COX-2 inhibitor, ketorolac, resulted in a marked reduction in urine volume, urinary excretion of prostaglandins, and glomerular filtration rate and in a significant impairment in renal water metabolism. Conclusions: These findings indicate that SC-236 does not significantly impair renal function in rats with cirrhosis. GASTROENTEROLOGY 1999;116:1167-1175

Renal hemodynamic effects of nabumetone, sulindac, and placebo in patients with osteoarthritis

We assessed the effects of nabumetone, sulindac, and placebo on renal function and renal excretion of vasodilatory prostaglandins in older female patients (age >50 years) with osteoarthritis and normal renal function. Using a prospective, crossover design, we compared the effects of nabumetone 2000 mg/d and sulindac 400 mg/d with placebo on glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary excretion of prostaglandin E 2 and 6-keto-prostaglandin F 1α in 12 patients. Urinary excretion of vasodilatory prostaglandins was not decreased after 14 days of treatment with either nabumetone or sulindac. Likewise, treatment with nabumetone or sulindac did not significantly alter renal function compared with placebo. There were no differences in mean changes in GFR or RPF from baseline after treatment with nabumetone or sulindac compared with placebo. The mean (± SD) changes in GFR from baseline were 0% ± 8% in patients receiving nabumetone, −8% ± 15% in patients receiving sulindac, and −7% 5% in patients receiving placebo. The results of this study demonstrate that treatment with nabumetone or sulindac caused no deterioration in renal function in older female patients with osteoarthritis and normal renal function.

Impact of Calcitonin on Urinary Excretion of Prostaglandins during Menopause

The aim of this study was to investigate the effects of calcitonin as an antiresorptive agent in postmenopausal osteoporosis in prostaglandin metabolism. Urinary prostaglandin E₂ (PGE₂) concentrations were determined by PGE₂ (¹²⁵I) RIA kit in a total number of 37 patients in postmenopause; 27 in study group with established osteoporosis (WEO) and 10 in another group without osteoporosis (WO). An additional group of 12 patients in the premenopausal period were selected as controls (PreM). Data were given as mean ± SD and statistical analysis was performed by Student’s t test for paired and unpaired values. A significant decrease in urinary PGE₂ concentrations was observed in WEO (7.91 ± 3.08 vs. 3.79 ± 3.01 ng/l) (p < 0.001), WO (9.06 ± 6.76 vs. 6.06 ± 3.90 ng/l) (p < 0.05) and PreM (7.14 ± 1.68 vs. 5.16 ± 1.91 ng/l) (p < 0.01). As a conclusion, calcitonin seems to exert a negative effect on prostaglandin metabolism resulting in reduced new prostaglandin formation.

Glomerular thromboxane contributes to pressor response in deoxycorticosterone acetate-salt hypertension

To assess the role of renal thromboxane in a salt sensitive pressor response in hypertension, urinary excretion of thromboxane and its release from isolated glomeruli and renal papillae were examined in deoxycorticosterone acetate treated rats with normal (0.6%, n = 12) and high (4%, n = 12) salt diets for 8 weeks. Mean blood pressure, measured directly by an implanted aortic catheter, was higher in the high salt diet group than in the normal salt diet group (146 ± 2 vs 119 ± 2 mmHg, P < 0.01). Urinary excretion of thromboxane B 2 and 6-keto-prostaglandin F 1α in the high salt group were significantly higher than those in the normal salt diet group, but there was no difference in urinary excretion of prostaglandin E 2 between the two groups. Release of thromboxane B 2, 6-keto-prostaglandin F 1α, and prostaglandin E 2 from isolated glomeruli in the high salt diet group increased significantly by 104%, 55%, and 74%, respectively, compared with the normal salt diet group. Stepwise multiple linear regression analysis showed that significant contributory factors for mean blood pressure in deoxycorticosterone acetate treated rats were urinary excretion of sodium (F=14.187, P < 0.01) and release of thromboxane B 2 from isolated glomeruli (F=4.135, P < 0.05). The unstandardized coefficient (R) calculated from the regression function using these two factors was 0.875 and R 2 was 0.765. The manifest synthesis of thromboxane in renal glomeruli has an important role on salt sensitive pressor response in deoxycorticosterone acetate-salt hypertension of rats.

Parathormone, 1,25 dihydroxyvitamin D and prostaglandin E 2 correlation in children with idiopathic hypercalciuria

As urinary prostaglandin excretion might be involved in idiopathic hypercalciuria, we studied the excretion of prostaglandin E 2 and calcium together with serum prostaglandin E 2, parathormone and 1,25 dihydroxyvitamin D in 20 patients and 11 controls Idiopathic hypercalciuric patients showed increased levels of urinary prostaglandin E 2-like activity, which is correlated with calcium excretion. Although no change was observed in serum parathormone level in control and hypercalciuric patients, there was a positive correlation between serum 1,25 dihydroxyvitamin D and prostaglandin E 2-like activity. These findings suggest that prostaglandin E 2 could play a role in the hypercalciuria syndrome, possibly by increasing 1,25 dihydroxyvitamin D synthesis.