Urinary Prostaglandin E2 Excretion Research Articles

The Effect of Thiazide Diuretics on Urinary Prostaglandin E2 Excretion and Serum Sodium in the General Population.

Thiazide-induced hyponatremia is one of the most common forms of hyponatremia, but its pathogenesis is incompletely understood. Recent clinical data suggest links with prostaglandin E2 (PGE2) and a single nucleotide polymorphism (SNP) in the prostaglandin transporter gene (SLCO2A1), but it is unknown if these findings also apply to the general population. To study the associations between serum sodium, thiazide diuretics, urinary excretions of PGE2 and its metabolite (PGEM), and the rs34550074 SNP in SLCO2A1 in the general population. Prospective population-based cohort study (Rotterdam Study). General population. 2,178 participants (65% female, age 64 ± 8 years). None. Serum sodium levels. Higher urinary PGE2 excretion was associated with lower serum sodium: difference in serum sodium for each two-fold higher PGE2 -0.19 mmol/l (95%CI -0.31 to -0.06), PGEM -0.29 mmol/l (95%CI -0.41 to -0.17). This association was stronger in thiazide users (per two-fold higher PGE2 -0.73 vs. -0.12 mmol/l and PGEM -0.6 vs. -0.25 mmol/l, p for interaction < 0.05 for both). A propensity score matching analysis of thiazide vs. non-thiazide users yielded similar results. The SNP rs34550074 was not associated with lower serum sodium or higher urinary PGE2 or PGEM excretion in thiazide or non-thiazide users. Serum sodium is lower in people with higher urinary PGE2 and PGEM excretion and this association is stronger in thiazide users. This suggests that PGE2-mediated water reabsorption regulates serum sodium, which is relevant for the pathogenesis of hyponatremia in general and thiazide-induced hyponatremia in specific.

Urinary Prostaglandin E2 Excretion and the Risk of Cardiovascular and Kidney Disease.

Inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory drugs is associated with cardiovascular mortality and kidney disease. This study hypothesizes that urinary prostaglandin E2 (PGE2) and PGE2 metabolite (PGEM) excretions are markers of cardiovascular and kidney health, because they reflect both systemic and kidney-derived PGE2 production. PGE2 and PGEM were measured in spot urine samples from 2291 participants (≥55 years old)of the population-based Rotterdam Study. Urinary PGE2 and PGEM excretions were analyzed using linear regression analyses to identify cross-sectional associations with cardiovascular risk factors and baseline estimated glomerular filtration rate (eGFR). Longitudinal associations with cardiovascular mortality and kidney outcomes (eGFR <60 or <45 mL/min per 1.73 m2 and the composite outcome 40% eGFR loss or kidney failure) were assessed with Cox regression. Urinary PGE2 and PGEM excretions were higher with increasing age, lower eGFR, smoking, diabetes, and albuminuria. A 2-fold higher urinary PGE2 and PGEM excretion was associated with a higher risk of cardiovascular mortality (28 825 patient-years; 160 events; PGE2 hazard ratio [HR], 1.27, [95% CI, 1.06-1.54]; PGEM HR, 1.36 [95% CI, 1.10-1.67]). Higher PGE2 excretions were also associated with a higher risk of incident eGFR <60 mL/min per 1.73 m2 (31 530 person-years; 691 events; HR, 1.13 [95% CI, 1.02-1.25]) with similar HRs for the other kidney outcomes. Urinary PGE2 and PGEM excretions are novel markers for the presence and progression of cardiovascular and kidney disease. Future studies should address whether these associations are causal and can be targeted to improve cardiovascular and kidney outcomes.

Prostaglandin E2, osmoregulation and disease progression in autosomal dominant polycystic kidney disease.

Prostaglandin E2 (PGE2) plays a physiological role in osmoregulation, a process that is affected early in autosomal dominant polycystic kidney disease (ADPKD). PGE2 has also been implicated in the pathogenesis of ADPKD in pre-clinical models, but human data are limited. Here, we hypothesized that urinary PGE2 excretion is associated with impaired osmoregulation, disease severity and disease progression in patients with ADPKD. Urinary excretions of PGE2 and its metabolite (PGEM) were measured in a prospective cohort of patients with ADPKD. Linear regression was used for the cross-sectional analysis of the associations between urinary PGE2 and PGEM excretions, markers of osmoregulation and disease severity. Cox regression and linear mixed models were used for the longitudinal analysis of the associations between urinary PGE2 and PGEM excretions and disease progression. In two separate intervention studies we quantified the effect of starting tolvaptan and adding hydrochlorothiazide to tolvaptan on urinary PGE2 and PGEM excretions. In 562 patients with ADPKD (61% female, eGFR 63 ± 28 ml/min/1.73 m2) higher urinary PGE2 or PGEM excretions were independently associated with higher plasma copeptin, lower urine osmolality, lower eGFR and greater total kidney volume. Patients with higher baseline urinary PGE2 and PGEM excretions had an increased risk of 40% eGFR loss or kidney failure (HR 1.28 and 1.47 for each doubling in urinary PGE2 or PGEM excretions) and a faster change in eGFR over time (-0.39 and -0.53 ml/min/1.73 m2/year for each doubling in urinary PGE2 or PGEM excretions). In the intervention studies, inducing polyuria by tolvaptan significantly increased urinary PGEM excretion, while reducing polyuria by adding hydrochlorothiazide to tolvaptan significantly increased urinary PGE2 excretion. Higher urinary PGE2 and PGEM excretions in patients with ADPKD are associated with parameters of osmoregulation, disease severity and progression.

2-Methoxyestradiol Ameliorates Angiotensin II-Induced Hypertension by Inhibiting Cytosolic Phospholipase A2α Activity in Female Mice.

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Abstract 078: Nephron-Specific Deletion of Intraflagellar Transport 88 Alters Renal Electrolyte Excretion in the Absence of Cystic Kidney Disease in a Sex-Specific Manner

Defects in primary cilia in the nephron can cause cystic kidney disease, however, the physiological role of nephron primary cilia is largely unknown. To address this, nephron primary cilia were disrupted by targeting the intraflagellar transport 88 ( IFT88 ) gene. IFT88 f/f mice containing loxP-flanked exons 4-6 of the IFT88 gene were bred with doxycycline-inducible Pax8-rtTA/tetO7-CMV*-Cre knockin mice. Inactivation of IFT88 (KO) was induced with 2 mg/ml doxycycline in drinking water supplemented with 2% sucrose for 12 days at 2 months of age; controls were the same genotype but without doxycycline treatment; mice were studied 2-4 months after doxycycline treatment. Renal IFT88 gene recombination was observed in KO mice associated with an 88±5% decrease in whole kidney IFT88 mRNA. Metabolic cage studies were conducted under a normal-Na + (0.3% Na + , 5 days), a low-Na + (0.03% Na + , 7 days), and a high-Na + (3.2% Na + , 7 days) diet (N=10 males and 10 females per group). No significant differences were found in food intake, water intake, urine volume (UV), urinary Na + excretion (UNaV), or urinary K + excretion (UKV) between KO and control mice under either a normal-Na + or a low-Na + diet. In contrast, water intake, UV, UNaV, and UKV were higher on days 2-7 of high-Na + diet in male, but not female, KO compared with control mice (p&lt;0.05); no differences in food intake were noted. Plasma renin concentration was similar between high-Na + diet-treated KO and control mice. Both urinary nitrite/nitrate excretion (UNOxV) and urinary prostaglandin E2 excretion (UPGE2V) were increased in high-Na + diet-treated male, but not female, KO mice (p&lt;0.05). No cysts or tubule dilation were evident in KO mice at the end of experiments. In summary, nephron-specific deletion of IFT88 increases urinary fluid and electrolyte excretion during high salt intake associated with increases in UNOxV and UPGE2V; these differences are evident in male, but not female, mice. These data suggest that primary cilia regulate nephron function independent of cystogenesis and in a sex-specific manner.

EHD4 Regulates Prostaglandin E2 Synthesis in Renal Collecting Duct Principal Cells: Potential Implications for AQP2

Eps15 homology domain‐containing protein 4 (EHD4) regulates endocytic recycling. We previously reported that global EHD4 knockout (EHD4‐KO) mice have a higher urine flow and lower urine osmolality than wild‐type (WT) mice. Further, the diuretic phenotype in EHD4‐KO mice is associated with a reduced accumulation of aquaporin 2 (AQP2) in the apical membrane of principal cells of EHD4‐KO mice. However, the mechanism by which EHD4 regulates AQP2 localization is not known. EHD4 and AQP2 share common protein interacting partners, therefore we hypothesized that EHD4 interacts with AQP2, thereby regulating its trafficking. To test this hypothesis, we transfected mouse cortical collecting duct principal (mpkCCD) cells with a GFP‐tagged EHD4 plasmid and visualized the localization of EHD4 and AQP2. EHD4 was found to co‐localize with AQP2 in mpkCCD cells. To assess the interaction between EHD4 and AQP2, co‐immunoprecipitation of AQP2 was performed and the presence of EHD4 in the immunecomplex was measured by Western blotting. EHD4 was not detected in the immune‐complex containing AQP2, suggesting that these two proteins may not interact directly. Pointing to a potential indirect mechanism of regulation, evidence from the literature suggests that the paralog EHD1 binds to cytosolic phospholipase A2α, a key enzyme for eicosanoid synthesis. Prostaglandin E2 (PGE2) is a known negative regulator of AQP2 trafficking. Therefore, we hypothesize that EHD4 deletion increases PGE2 synthesis in principal cells, thereby contributing to the reduced membrane accumulation of AQP2. To test our hypothesis we examined urinary PGE2 excretion by female mice and found it to be significantly higher in EHD4‐KO mice (3595 ± 581 pg/day, n = 6) compared to WT mice (1042 ± 131 pg/day, n = 4; P = 0.008). To exclude a role for flow‐mediated stimulation of PGE2 synthesis, we examined the role of EHD4 in PGE2 synthesis in the mpkCCD cell line. PGE2 concentrations in the surrounding media of EHD4‐siRNA treated mpkCCD cells was significantly higher than of scrambled siRNA‐treated cells (84 ± 7 versus 53 ± 5 pg/ml respectively; n = 6; P = 0.0002). Together, these data suggest that EHD4 regulates collecting duct PGE2 production, providing a possible mechanism by which EHD4 regulates AQP2 localization and urine excretion in vivo.Support or Funding InformationAmerican Heart Association Grant‐In‐Aid 17GRNT33661008This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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.

Oral Contraceptives and Renal Water Handling: A diurnal study in young women.

To test the hypothesis that use of oral contraceptives (OC) changes diurnal variation in fluid balance mechanisms including blood pressure, secretion of vasopressin and oxytocin, and renal water and electrolyte excretion. Fifteen naturally cycling (NC) women in mid‐follicular phase and 11 long‐term OC users were included in a 24‐h standardized inpatient study for measurements of vasopressin, oxytocin, sodium, and osmolality in plasma as well as urinary excretion of electrolytes, aquaporin‐2, and prostaglandin E2. Blood pressure and heart rate were monitored noninvasively. Plasma vasopressin showed circadian rhythm (P = 0.02) and were similar in both groups (P = 0.18) including nighttime increases (P < 0.001). There was no circadian rhythm in plasma oxytocin within (P = 0.84) or between groups (P = 0.22). OC users had significantly lower plasma osmolality (Δosm: 3.05 ± 0.29 mosm/kg, P = 0.04) and lower plasma sodium (ΔNa+: 0.91 ± 0.09 mmol/l, P = 0.05). The two groups showed similar nighttime decreases in diuresis (1.08 ± 0.04 mL/(kg·h), P < 0.001) and increases in urine osmolality (109 ± 9 mosm/kg, P = 0.02), but similar rates of excretion of Aquaporin‐2, prostaglandin E2 and sodium. Nighttime decreases in mean arterial pressure of approximately 13% were significant in both groups (P < 0.001), but 24‐h average mean arterial pressure was significantly higher in OC users than in controls (+4.7 ± 0.4 mmHg, P = 0.02). Packed cell volumes were similar between groups (P = 0.54). OC does not change the diurnal patterns of renal fluid excretion, but resets the osmoreceptors for vasopressin release and leads to a significant increase in arterial blood pressure.

Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia.

Thiazide diuretics are among the most widely used treatments for hypertension, but thiazide-induced hyponatremia (TIH), a clinically significant adverse effect, is poorly understood. Here, we have studied the phenotypic and genetic characteristics of patients hospitalized with TIH. In a cohort of 109 TIH patients, those with severe TIH displayed an extended phenotype of intravascular volume expansion, increased free water reabsorption, urinary prostaglandin E2 excretion, and reduced excretion of serum chloride, magnesium, zinc, and antidiuretic hormone. GWAS in a separate cohort of 48 TIH patients and 2,922 controls from the 1958 British birth cohort identified an additional 14 regions associated with TIH. We identified a suggestive association with a variant in SLCO2A1, which encodes a prostaglandin transporter in the distal nephron. Resequencing of SLCO2A1 revealed a nonsynonymous variant, rs34550074 (p.A396T), and association with this SNP was replicated in a second cohort of TIH cases. TIH patients with the p.A396T variant demonstrated increased urinary excretion of prostaglandin E2 and metabolites. Moreover, the SLCO2A1 phospho-mimic p.A396E showed loss of transporter function in vitro. These findings indicate that the phenotype of TIH involves a more extensive metabolic derangement than previously recognized. We propose one mechanism underlying TIH development in a subgroup of patients in which SLCO2A1 regulation is altered.

Lithium‐induced NDI, Hypercalcemia and Urinary PGE2 Excretion Develop Independently in Mice

Lithium is the mainstay treatment for bipolar disorder. However, it leads to nephrogenic diabetes insipidus (NDI) and hypercalcemia in 10-20% of patients. Lithium-induced NDI is caused by the inability of the renal collecting duct to reabsorb water and correlates in C57BL/6 mice with the level of excreted prostaglandin E2 (PGE2). Lithium-induced hypercalcemia is ascribed to a decreased sensitivity of the parathyroid gland to blood Ca2+ levels. As lithium-induced NDI and hypercalcemia only occur in a subset of patients, we investigated whether these processes are linked by analyzing their development in 15 different inbred mouse strains. Starting at 10 weeks of age, female mice had access to normal chow or lithium diet (40mmol/kg). At day 8 and 26 mice were housed for 48 hours in metabolic cages to collect urine and at day 10 and 28 blood was isolated. Lithium treatment significantly elevated the urine production of several strains while other strains were not affected. Interestingly, in none of the strains lithium significantly affected urinary PGE2 levels. Furthermore, lithium did not significantly alter blood pH, while urinary proton excretion was elevated in several strains. Lithium-induced hypercalcemia was observed in 4 strains, and did not correlate with the effect of lithium on urine production. Our results demonstrate that development of lithium-induced NDI, hypercalcemia and excretion of PGE2 varies among inbred strains, indicating an independent development of these lithium-related features. Moreover, the diversity in response reveals that inclusion of additional strains may allow identification of susceptibility genes for these lithium-induced disorders.

Physiological mechanisms for the increase in renal solute‐free water clearance by a glucagon‐like peptide‐1 mimetic

The aim of the present study was to clarify the mechanisms mediating the effect of a glucagon-like peptide-1 (GLP-1) mimetic on solute-free water excretion in rats. The GLP-1 mimetic exenatide (0.05-5.0nmol/kg, i.m.), alone and in combination with either a vasopressin V2 receptor antagonist (15nmol/kg, i.p.) or vasopressin (0.01nmol/kg, i.m.), was injected into control and water-loaded (water 10-50mL/kg, p.o., or 50mL/kg of 0.6% NaCl, i.p.) rats to evaluate the role of collecting duct water permeability in the hydrouretic effect. Urinary prostaglandin (PG) E2 excretion and the effects of diclofenac (5mg/kg, i.m.) and GLP-1 receptor antagonist (0.15μmol/kg, i.p.) on exenatide action were assessed. The hydrouretic effect of exenatide was equivalent following oral or intraperitoneal water loading, and was proportional to the volume of water administered. Injection of exenatide, under conditions of a maximal decrease in collecting duct water permeability (V2 receptor antagonist administration in water-loaded rats), additionally stimulated solute-free water formation. The GLP-1 receptor antagonist weakened the hydrouretic action of exenatide. Urinary PGE2 excretion increased following water loading (47±6 vs 24±4ng/kg over a 30min period) and was enhanced as a result of additional exenatide injection (69±10ng/kg). Diclofenac and vasopressin delayed the hydrouretic effect of exenatide. The effect of exenatide on solute-free water clearance in water-loaded rats is presumably mediated by stimulation of PGE2 secretion and reinforcement of tubular fluid influx from the proximal tubule to the distal segment of the nephron and collecting duct.

Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice

In addition to its role as an essential neurotransmitter, dopamine serves important physiologic functions in organs such as the kidney. Although the kidney synthesizes dopamine through the actions of aromatic amino acid decarboxylase (AADC) in the proximal tubule, previous studies have not discriminated between the roles of extrarenal and intrarenal dopamine in the overall regulation of renal function. To address this issue, we generated mice with selective deletion of AADC in the kidney proximal tubules (referred to herein as ptAadc-/- mice), which led to selective decreases in kidney and urinary dopamine. The ptAadc-/- mice exhibited increased expression of nephron sodium transporters, decreased natriuresis and diuresis in response to l-dihydroxyphenylalanine, and decreased medullary COX-2 expression and urinary prostaglandin E2 excretion and developed salt-sensitive hypertension. They had increased renin expression and altered renal Ang II receptor (AT) expression, with increased AT1b and decreased AT2 and Mas expression, associated with increased renal injury in response to Ang II. They also exhibited a substantially shorter life span compared with that of wild-type mice. These results demonstrate the importance of the intrarenal dopaminergic system in salt and water homeostasis and blood pressure control. Decreasing intrarenal dopamine subjects the kidney to unbuffered responses to Ang II and results in the development of hypertension and a dramatic decrease in longevity.

Renal Responses to Magnesium Lithospermate B

Renal responses to magnesium lithospermate B isolated from Salviae miltiorrhizae radix were examined in normal rats. Urinary sodium, potassium, prostaglandin E2 and kallikrein excretion was significantly increased after magnesium lithospermate B administration, whereas excretion of urinary 6-keto-prostaglandin F1 alpha and thromboxane B2 was unchanged. Rats administered with the drug also revealed a slight elevation of plasma renin activity and the levels of angiotensins I and II. Plasma aldosterone was decreased slightly. No significant changes were observed in angiotensin-converting enzyme or blood pressure.

Cisplatin decreases renal cyclooxygenase-2 expression and activity in rats

Cisplatin (CP) induced acute renal failure (ARF) has previously been associated with decreased urinary prostaglandin E2 (PGE2) excretion and reduced aquaporin 2 (AQP2) expression in kidney collecting duct. In this study we examined the expression of cyclooxygenase (COX)-1 and -2 as well as AQP2 and the Na-K-2Cl cotransporter in kidneys from rats with CP induced ARF. Rats were treated with either CP or saline and followed for 5 days. Kidneys were dissected into three zones and prepared for immunoblotting, quantitative polymerase chain reaction (QPCR) and immunohistochemistry. Renal content and urinary PGE2 excretion was measured. Cisplatin treatment was associated with polyuria and a significant decreased creatinine clearance. Inner medullary PGE2 content and urinary PGE2 excretion was decreased in CP-treated rats. QPCR and semiquatitative immunoblotting demonstrated that CP treatment reduced COX-2, AQP2 and Na-K-2Cl cotransporter abundance in the different kidney zones, whereas no change in COX-1 was observed. Results were confirmed by immunohistochemistry. Cyclooxygenase-2 expression is decreased in inner medulla and cortex. Consistent with this urinary PGE2 levels were reduced. These data suggest that downregulation of COX-2 is responsible for impaired de novo generation of vasodilatory prostaglandins which may play an important role for the CP induced renal vasoconstriction and development of nephropathy.

791 CHRONIC HYPERLIPIDEMIA CAUSES DETRUSOR OVERACTIVITY AND INCREASE IN URINARY PROSTAGLANDIN E2 RELEASE IN RABBITS

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Basic Research1 Apr 2011791 CHRONIC HYPERLIPIDEMIA CAUSES DETRUSOR OVERACTIVITY AND INCREASE IN URINARY PROSTAGLANDIN E2 RELEASE IN RABBITS Masaki Yoshida, Koichi Masunaga, Takashi Nagata, Akito Inadome, Yutaka Miyamoto, Tomomi Haba, and Junzo Kudoh Masaki YoshidaMasaki Yoshida Kumamoto, Japan More articles by this author , Koichi MasunagaKoichi Masunaga Tokyo, Japan More articles by this author , Takashi NagataTakashi Nagata Saitama, Japan More articles by this author , Akito InadomeAkito Inadome Kumamoto, Japan More articles by this author , Yutaka MiyamotoYutaka Miyamoto Kumamoto, Japan More articles by this author , Tomomi HabaTomomi Haba Kumamoto, Japan More articles by this author , and Junzo KudohJunzo Kudoh Kumamoto, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.609AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recently, we demonstrated that chronic hyperlipidemia caused bladder dysfunction including detrusor overactivity in heritable hyperlipidemic rabbits (WHHLMI rabbits). Various pathologic conditions cause prostaglandins synthesis in both bladder smooth muscle and mucosa, resulting in bladder dysfunction. To evaluate the effects of hyperlipidemia on lower urinary tract function, we examined the relationship between hyperlipidemia-induced bladder dysfunction and urinary prostaglandin E2 (PGE2) level in WHHLMI rabbits. METHODS WHHLMI rabbits and the age and sex-matched Japanese white rabbits (control group) were prepared. In all rabbits, the urinary volume and frequency were recorded for three days, and 24-h urine samples of all rabbits were collected. Cystometrograms were performed under anesthesia using constant infusion of saline into the bladder to elicit voiding, and voided volume, residual urine, micturition pressure, and micturition interval were evaluated. 24-h urinary PGE2 levels were assayed by enzyme immunoassay (EIA) by using PGE2 EIA kit-Monoclonal. In addition, immunohistochemical staining of COX-2 of bladder tissue of WHHLMI and control rabbits was performed, using mouse monoclonal anti-COX-2 antibody. RESULTS The number of micturition per day was higher in WHHLMI rabbits (4.24±1.07 times/day) than in control rabbits (1.8±0.3 times/day), and the voided volume was lower in WHHLMI rabbits (14.81±4.60 ml) than in control rabbits (43.8±5.1 ml). In cystometrograms, WHHLMI rabbits showed detrusor overactivity, higher frequency of micturition (7.55±1.25 times/20 min) and lower voided volume (6.92±1.5 ml) than in control rabbits (1.44 ± 2.51 times/20 min and 20.8±3.2 ml, respectively). The urinary excretion of PGE2 was significantly higher in WHHLMI rabbits (6.44±1.87 ng/ml) than in control rabbits (0.91±0.14 ng/ml). Analysis of relationship between parameters of bladder function and urinary PGE2 level in WHHLMI rabbits indicated a significantly negative correlation (r=0.81) between urinary PGE2 level and voided volume, and a significant positive correlation between urinary PGE2 level and the number of micturition (r=0.86). Immunohistochemical staining of COX-2 showed a significant higher immunoreactivity in bladder mucosa of WHHLMI rabbits, as compared to control. CONCLUSIONS The present study suggested that chronic hyperlipidemia caused increase of COX-2 activity in bladder mucosa, which might cause the enhanced PGE2 release, resulting in activation of sensory input and detrusor overactivity. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e318 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Masaki Yoshida Kumamoto, Japan More articles by this author Koichi Masunaga Tokyo, Japan More articles by this author Takashi Nagata Saitama, Japan More articles by this author Akito Inadome Kumamoto, Japan More articles by this author Yutaka Miyamoto Kumamoto, Japan More articles by this author Tomomi Haba Kumamoto, Japan More articles by this author Junzo Kudoh Kumamoto, Japan More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Dietary fatty acid composition alters magnesium metabolism, distribution, and marginal deficiency response in rats*

Based on dietary intake recommendations, magnesium deficiency commonly occurs throughout the world. However, widespread pathological conditions induced by dietary magnesium deficiency have not been identified. This discrepancy may be caused by other dietary factors ameliorating or exacerbating the response to a marginal magnesium deficiency and/or the length of the deficiency. Thus, a study was performed to determine whether the n-6/n-3 fatty acid composition of the diet affects the response to marginal magnesium deprivation, and whether the effect was dependent upon the length of deprivation. Weanling female rats were fed diets containing 250 mg/kg magnesium in a factorial arrangement with dietary variables of supplemental magnesium at 0 or 250 mg/kg (total of 250 or 500 mg/kg) and fat sources of 75 g/kg corn oil or 65 g/kg fish (menhaden) oil plus 10 g/kg linoleic acid. After 8 and 12 weeks on their respective diets, each rat was placed in a metabolic cage for a 16-hour collection of urine. After 13 weeks, the rats were anesthetized with ether for the collection of plasma and organs. Marginal magnesium deficiency was confirmed by decreased urinary excretion and femur, tibia and vertebrae concentrations of magnesium. Dietary oil influenced the effect of marginal magnesium deficiency on magnesium metabolism, distribution and oxidative stress indicators. Fish oil, but not corn oil, significantly decreased urinary magnesium excretion and increased kidney magnesium concentration. Femur magnesium was significantly decreased by marginal magnesium deficiency in rats fed fish oil but not in rats fed corn oil, and liver magnesium concentration was decreased by fish oil. Marginal magnesium deficiency increased plasma extracellular superoxide dismutase and cysteine (component of glutathione) in rats fed corn oil but not in rats fed fish oil. Urinary prostaglandin E₂ excretion was significantly decreased by marginal magnesium deficiency at 8 weeks, but not at 12 weeks; an increase between weeks 8 and 12 in marginally magnesium-deficient rats fed fish oil caused this change in significance. The findings show that the dietary fatty acid composition affects the response of rats to marginal magnesium deprivation. The findings also indicate that dietary or physiological factors affecting oxidative stress could affect the response to marginal magnesium deficiency, and that a response to a dietary change that takes time to develop, such as an increase in dietary n-3 fatty acids, may result in signs of marginal deficiency being different over time.

Evening Primrose Oil Supplementation Increases Citraturia and Decreases Other Urinary Risk Factors for Calcium Oxalate Urolithiasis

We investigated the effects of gamma-linolenic acid (an omega-6 polyunsaturated fatty acid) in the form of evening primrose oil on calcium oxalate urinary stone risk factors in 2 ethnic groups. Eight black and 8 white healthy male subjects ingested 1,000 mg evening primrose oil (Natrodale, Kuils River, South Africa) daily for 20 days while following a free diet. Arachidonic acid content was determined by a dietary questionnaire. On days 0, 10 and 20, and 4 days after protocol 24-hour urine samples were collected. Samples were analyzed using routine assays. Citraturia increased significantly in each group. Urinary oxalate showed a tendency to decrease in black subjects. Calciuria and the Tiselius risk index decreased significantly in each group. Carryover effects were observed. To our knowledge increased citraturia has not been previously reported for any essential fatty acid. We hypothesize that evening primrose oil inhibits lipogenesis, thereby decreasing citrate consumption. For the decrease in oxaluria we suggest that evening primrose oil alters membrane fatty acid composition, thereby inhibiting the modulation of protein kinases that lead to hyperoxaluria. In regard to decreased calciuria we suggest that evening primrose oil modulates delta-5 and/or delta-6-desaturase, thereby inhibiting the production of arachidonic acid and prostaglandin E2, which influence calciuria. The different response in the 2 groups with respect to oxaluria confirms previously reported differences in sensitivity toward supplemental ingestion. Data suggest that evening primrose oil supplementation should be investigated as a possible conservative treatment for calcium oxalate urolithiasis.

Intrarenal Dopamine Attenuates Deoxycorticosterone Acetate/High Salt–Induced Blood Pressure Elevation in Part Through Activation of a Medullary Cyclooxygenase 2 Pathway

Locally produced dopamine in the renal proximal tubule inhibits salt and fluid reabsorption, and a dysfunctional intrarenal dopaminergic system has been reported in essential hypertension and experimental hypertension models. Using catechol-O-methyl-transferase knockout (COMT(-/-)) mice, which have increased renal dopamine because of deletion of the major renal dopamine-metabolizing enzyme, we investigated the effect of intrarenal dopamine on the development of hypertension in the deoxycorticosterone acetate/high-salt (DOCA/HS) model. DOCA/HS led to significant increases in systolic blood pressure in wild-type mice (from 115+/-2 to 153+/-4 mm Hg), which was significantly attenuated in COMT(-/-) mice (from 114+/-2 to 135+/-3 mm Hg). In DOCA/HS COMT(-/-) mice, the D1-like receptor antagonist SCH-23390 increased systolic blood pressure (156+/-2 mm Hg). DOCA/HS COMT(-/-) mice also exhibited more urinary sodium excretion (COMT(-/-) versus wild-type: 3038+/-430 versus 659+/-102 micromol/L per 24 hours; P<0.01). Furthermore, DOCA/HS-induced renal oxidative stress was significantly attenuated in COMT(-/-) mice. COX-2-derived prostaglandins in the renal medulla promote sodium excretion, and dopamine stimulates medullary prostaglandin production. Renal medullary COX-2 expression and urinary prostaglandin E2 excretion were significantly higher in COMT(-/-) than in wild-type mice after DOCA/HS treatment. In DOCA/HS-treated COMT(-/-) mice, the COX-2 inhibitor SC-58236 reduced urinary sodium and prostaglandin E(2) excretion and increased systolic blood pressure (153+/-2 mm Hg). These studies indicate that an activated renal dopaminergic system attenuates the development of hypertension, at least in large part through activating medullary COX-2 expression/activity, and also decreases oxidative stress resulting from DOCA/HS.

Effects of essential fatty acids on water balance and urinary excretion of prostaglandin E2 and vasopressin in rats.

Effects of Essential Fatty Acids on Water Balance and Urinary Excretion of Prostaglandin E2 and Vasopressin in Rats Get access Nutrition Reviews, Volume 40, Issue 9, September 1982, Pages 281–283, https://doi.org/10.1111/j.1753-4887.1982.tb05340.x Published: 01 September 1982

The influence of high and low levels of estrogen on diurnal urine regulation in young women

BackgroundSex hormones have a pronounced effect on arginine vasopressin (AVP), and therefore on the diurnal water homeostasis. Low and high levels of plasma-estradiol as seen in the follicular phase of the menstrual cycle may therefore alter the diurnal regulation of urine production. Furthermore the structural resemblance of oxytocin to vasopressin has led to speculations about the possible antidiuretic properties of oxytocin under normal physiological conditions. To elucidate the influence of high and low p-estradiol on the regulation of the diurnal urine production, 15 normal menstruating women (21–33 y) underwent two circadian in-patient investigations, both situated in follicular phase.MethodsAdmitting the participants solely in the follicular phase resulted in high and low plasma-estradiol whereas plasma-progesterone was similar. Urine and blood samples were taken at predetermined time points to determine plasma AVP, plasma oxytocin, plasma aldosterone, plasma natriuretic peptide (ANP), urinary solute excretions, and urinary excretions of prostaglandin E2 (PGE-2) and aquaporin-2 (AQP-2). Blood pressure was measured every hour.ResultsPlasma AVP, plasma aldosterone and plasma ANP were unaffected by the different levels of estradiol. All had marked circadian variations whereas oxytocin did not display any circadian rhythm. High estradiol resulted in lower p-osmolality and p-sodium reflecting the downward resetting of the osmoreceptors. Oxytocin did not correlate with either diuresis or urine osmolality. The diurnal urine production was similar in the two groups as were urine osmolality, excretion of PGE-2 and AQP-2. AQP-2 does not have a circadian rhythm and is not significantly correlated to either AVP or oxytocin under normal physiological conditions.ConclusionHigh and low level of estradiol has no influence on the circadian rhythm of AVP or the subsequent urine production. High p-estradiol resets the osmoreceptors for AVP release. Furthermore it appears that oxytocin under normal physiological conditions do not contribute to the overall antidiuretic effect.