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Background: We developed a fully automated quantitative immunoassay for the detection of prostaglandin E-major urinary metabolite (PGE-MUM). In this study, we evaluated the analytical performance of this assay., Methods: Sensitivity, within-run reproducibility, correlation with radioimmunoassay (RIA), cross-reactivity, dilution linearity, spike recovery performance, analyte stability, and effects of coexisting substances were evaluated. The assay was also used to measure PGE-MUM in 211 healthy people., Results: The limit of detection and quantification were 1.0 and 1.3 ng/mL, respectively. When the assay was performed six times in a single run, the coefficient of variation ranged from 1.4% to 2.2%. The coefficient of correlation with a preceding RIA method was 0.970 with a correlation slope of 0.88. There was no cross-reactivity with PGE-MUM analogs. Linearity of dilution was confirmed at up to 16-fold dilution with assay results within 100 ± 20% of the theoretical values calculated based on the undiluted sample. Spike recovery was good and ranged from 94% to 101%. Analyte stability was tested by storing samples at 25°C for 6 days, 10°C for 1 month, and by performing up to five freeze-thaw cycles. Assay results were all within 100 ± 10%, the values measured before storage and before the freeze-thaw process. Assay results in healthy people ranged from 3.1 to 162.7 ng/mL (mean: 35.8 ng/mL). After correction for creatinine, the 95% confidence interval was 8.68-42.25 μg/g creatinine., Conclusion: The assay precisely detects PGE-MUM., (© 2024 The Author(s). Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

We investigated the effect of hypocalcemia on plasma renin, aldosterone, and urine PGE 2 levels in children with vitamin D deficiency rickets (VDDR). In the study group, 25 patients with VDDR-induced hypocalcemia were treated with a single dose of 150,000-300,000 IU cholecalciferol and 50 mg/kg/day elemental Ca for 10 days. On any day between 21th and 30th days after the treatment, the patients' clinical, biochemical and radiologic findings were re-evaluated. The healthy children with the same sex and similar age as the study group comprised the control group. Plasma sodium (Na), potassium (K), calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), parathyroid hormone (PTH), 25- hydroxy vitamin D (25OHD), renin, aldosterone; and urinary Ca, creatinine (Cr) and prostaglandin E 2 (PGE 2 ) levels were measured in both the study (pre-treatment and post-treatment) and the control group. Plasma Ca, P, 25OHD and renin levels and urinary PGE 2 /Cr ratio in the post-treatment group were significantly higher than those in the pre-treatment group while K, ALP, and PTH concentrations were significantly lower. Plasma ALP and PTH levels in pre-treatment group were significantly higher than in the control group while Ca, P, 25OHD, aldosterone and renin concentrations and urinary PGE 2 /Cr ratio were significantly lower. Post-treatment plasma Ca level was significantly decreased in normal limits compared to the control group while other biochemical parameters were not different from the control group. Plasma Ca concentration was positively correlated with renin level and urinary PGE 2 /Cr ratio. The findings suggest that hypocalcemia may inhibit the production of renin, aldosterone and PGE 2 and a blunt aldosterone secretion may develop even after recovery from hypocalcemia., Competing Interests: Conflict of interest statement The authors have nothing to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Prostaglandin E-major urinary metabolite (PGE-MUM) and C-reactive protein (CRP) are useful biomarkers in patients with ulcerative colitis. However, whether changes in endoscopic scores over time are reflected in the values of these biomarkers has not been verified. This prospective observational study aimed to assess the relationship between changes in biomarker levels and endoscopic scores in patients with ulcerative colitis. A total of 100 colonoscopy intervals of patients with ulcerative colitis were enrolled. The relationship between variations in the Mayo endoscopic subscore over time and the accompanying changes in biomarker values were investigated. PGE-MUM levels showed a significant rise in the increased endoscopic score group (P = 0.007) and a decrease with reduced endoscopic score group (P = 0.023). CRP levels showed a significant decline with lower endoscopic values (P < 0.001); however, there was no corresponding increase with higher endoscopic scores (P = 0.141). Biomarker levels remained unchanged with stable endoscopic scores (P = 0.090 and P = 0.705). PGE-MUM levels varied significantly, and corresponded to the mucosal healing state (P = 0.019 and P = 0.009). The correlation between changes in PGE-MUM and the endoscopic score was stronger than that for CRP (r = 0.518, P < 0.001 vs. r = 0.444, P < 0.001, respectively). PGE-MUM reflected changes in endoscopic scores more accurately than CRP., (© 2021. The Author(s).)

Background: Intraductal papillary mucinous neoplasms (IPMN) are precursors of pancreatic cancer. Potential biomarkers of IPMN progression have not been identified in urine. A few urinary biomarkers were reported to be predictive of pancreatic ductal adenocarcinoma (PDAC). Here, we seek to assess their ability to detect high-risk IPMN., Methods: Urine was collected from patients undergoing pancreatic resection and healthy controls. TIMP-1(Tissue Inhibitor of Metalloproteinase-1), LYVE-1(Lymphatic Vessel Endothelial Receptor 1), and PGEM(Prostaglandin E Metabolite) levels were determined by ELISA and analyzed by Kruskal-Wallis., Results: Median urinary TIMP-1 levels were significantly lower in healthy controls (n = 9; 0.32 ng/mg creatinine) compared to PDAC (n = 13; 1.95) but not significantly different between low/moderate-grade (n = 20; 0.71) and high-grade/invasive IPMN (n = 20; 1.12). No significant difference in urinary LYVE-1 was detected between IPMN low/moderate (n = 16; 0.37 ng/mg creatinine) and high/invasive grades (n = 21; 0.09). Urinary PGEM levels were not significantly different between groups., Conclusions: Urinary TIMP-1, LYVE-1, and PGEM do not correlate with malignant potential of pancreatic cysts., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Early definitive diagnosis of necrotizing enterocolitis (NEC) based on Bell's staging criteria is difficult because there are few observable changes on abdominal imaging and blood chemistry tests at the onset of the disease., Purpose: To investigate whether prostaglandin E-2 major urinary metabolite (PGE-MUM) can be a useful surrogate marker reflecting the disease state and severity of NEC in infants., Methods: Infants were enrolled in this study between January 2014 and December 2016. NEC diagnosis was based on Bell's staging criteria > Stage II or necrotic bowel observed at surgery. After diagnosis, PGE-MUM level was measured and compared with that of the other disease and healthy infant groups., Results: Median PGE-MUM value was highest in the NEC group (576 [65-3672] μg/g•Cre/BSA × 1000), followed by the other disease group (94 [57-296] μg/g•Cre/BSA × 1000) and the healthy infant group (19 [10-44] μg/g•Cre/BSA × 1000) (sensitivity: 92.3%, specificity: 81.5%, accuracy: 85.0%; p < 0.01). PGE-MUM level correlated with improved status of NEC, length of necrotic intestine, and Bell's staging criteria., Conclusions: PGE-MUM level may be a useful surrogate biomarker reflecting the disease state of NEC. The method of urine sample collection is also advantageous, being noninvasive for infants. This is the first study reporting PGE-MUM level in NEC., Type of Study: Study of diagnostic test., Level of Evidence: LEVEL II., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Ivacaftor has produced significant improvement in certain individuals with cystic fibrosis (CF), though the full metabolic effects of treatment remain unknown. Abnormalities in fatty acid metabolism have previously been shown to be a characteristic of CFTR dysfunction. We hypothesized that as a reflection of this clinical improvement, ivacaftor would improve plasma fatty acid levels and decrease urine prostaglandin E metabolite levels., Methods: This study analyzed plasma fatty acid levels and urine prostaglandin E metabolites (PGE-M) in 40 subjects with CF participating in the G551D observational (GOAL) study who demonstrated response to the medication by a significant decrease in sweat Cl levels. Paired samples were analyzed before and after 6months of ivacaftor treatment., Results: Linoleic acid and docosahexaenoic acid levels, which are typically low in individuals with CF, did not significantly increase with ivacaftor treatment. However, arachidonic acid levels did decrease with ivacaftor treatment and there was a significant decrease in the arachidonic acid metabolite PGE-M as measured in the urine [median: before treatment 17.03ng/mg Cr; after treatment 9.06ng/mg Cr; p<0.001]. Furthermore, there were fatty acid age differences observed, including pediatric participants having significantly greater linoleic acid levels at baseline., Conclusion: Ivacaftor reduces inflammatory PGE without fully correcting the plasma fatty acid abnormalities of CF. Age-related differences in fatty acid levels were observed, that may be a result of other clinical factors, such as diet, clinical care, or drug response., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: For the assessment of inflammatory status, we have developed a simple, reliable radioimmunoassay (RIA) of prostaglandin E-major urinary metabolite (PGE-MUM), which remains stable in urine after it is metabolized. Using this method, we conducted a screening study to compare standard values of PGE-MUM to serum C-reactive protein (CRP) levels in health check volunteers., Methods: PGE-MUM (micrograms per gram creatinine) was measured in normal urine samples obtained from 797 samples in volunteers for health check, using a newly developed RIA, and analyzed in relation to age, gender, smoking, and drinking habits. Results were compared to serum CRP., Results: PGE-MUM was significantly higher in males than in females. It was significantly higher in smoking males, compared to males who had never smoked (nonsmokers), particularly in those above 40 years of age. In nonsmokers, PGE-MUM declined in males with advancing age, while it rose in females. Although PGE-MUM reflected current smoking status, independent of smoking index (SI), serum CRP indicated both current and former smoking condition, rather dependent upon SI., Conclusions: PGE-MUM increases in smokers, as suggested by possible inflammatory injury of pulmonary tissue. This RIA method for PGE-MUM may be thus a sensitive and reliable biomarker for current inflammation, different from serum CRP., (© 2013 Wiley Periodicals, Inc.)

Compared with diets high in fat, low-fat diets are associated with reduced risk of cardiovascular disease. We hypothesized that a low-fat (LF) (20% fat) and an LF high-omega-3 (n-3) fatty acid diet (LFn3) (23% fat with 3% as α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid [DHA]) would enhance n-3 composition of plasma phospholipid fatty acid and reduce urinary prostaglandin E(2) (PGE(2)) relative to a high-fat diet (HF) (40% fat) and that these changes would be associated with alterations in δ5 desaturase (D5D) and δ6 desaturase (D6D) activity. Phospholipid fatty acids and urinary PGE(2) were measured, and D5D and D6D activity indices calculated in a crossover trial in 17 postmenopausal women fed each of 3 test diets (HF, LF, and LFn3) for 8-week feeding periods. Desaturase activity indices were calculated as D5D, 20:4n-6/20:3n-6, and D6D, 20:3n-6/18:2n-6. Plasma phospholipid fatty acid, α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid (DPA), DHA, and total n-3 fatty acids increased, whereas linoleic acid and arachidonic acid decreased with consumption of LFn3. The LF resulted in enhanced arachidonic acid and DHA. High fat reduced D6D, whereas both HF and LF increased D5D. Urinary PGE(2) was reduced in response to both the LF and LFn3 diets. Low-fat diets, with or without long-chain n-3 fatty acids, promote positive health effects due in part to favorable alteration of plasma phospholipid fatty acid profiles and modification in desaturase activity indices, suggesting that the type and amount of fat consumed are modifiable risk factors for the prevention of cardiovascular disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To investigate the association between the urinary levels of prostaglandins (PGE(2) and PGF(2α)), nerve growth factor (NGF) and substance P, and overactive bladder (OAB) symptoms in patients with suprapontine brain diseases., Materials and Methods: The subjects were 114 patients in the chronic phase of a brain disease and 27 healthy controls with no brain disease or lower urinary tract symptoms (LUTS). The OAB symptoms were assessed with the OAB symptom score and the subjects were then classified into 5 groups: healthy control, patients without LUTS, increased bladder sensation (IBS), OAB dry, and OAB wet. Urinary mediator concentrations were measured using enzyme-linked immunosorbent assay and normalized to the urinary creatinine concentration, and then compared among the 5 groups., Results: The urinary PGE(2) level was significantly higher in patients with brain diseases than in healthy controls, even in the patients without any OAB symptoms, and compared with patients without LUTS, a significant increase in the urinary PGE(2) was observed in patients with OAB dry or wet (P = .004 or .015, respectively). The PGF(2α) level showed a significant increase in OAB wet compared with patients without LUTS (P = .001). The urinary levels of NGF and substance P were not significantly associated with OAB as a result of this type of brain disease., Conclusion: The urinary PGE(2) level was putatively elevated in patients with suprapontine brain diseases and associated with the presence of OAB. The PGF(2α) level may also be associated with OAB., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Purpose: Oxidative stress was examined with use (N = 29) or nonuse (N = 25) of ibuprofen in ultramarathoners after the Western States Endurance Run., Methods: Oxidative stress was assessed by measuring plasma and urinary F2-isoprostanes, plasma nitrite, and plasma urate. A urinary prostaglandin E2 metabolite (PGE-M) was used as an end point to assess ibuprofen use. Ibuprofen users consumed 600 and 1200 mg of ibuprofen the day before and on race day, respectively, and nonusers avoided all antiinflammatory medications. Blood and urine were collected in the morning before the race and immediately after the race., Results: Use compared with nonuse of ibuprofen significantly increased plasma (P

Purpose: Increased levels of cyclooxygenase-2 and prostaglandin E2 (PGE2) have been observed in tobacco-related malignancies of the upper aerodigestive tract. Moreover, exposure to tobacco smoke can stimulate the synthesis of PGE2. Recent evidence suggests that urinary PGE metabolite (PGE-M) can be used as an index of systemic PGE2 production. In this study, we investigated whether levels of urinary PGE-M were increased in smokers and in patients with head and neck squamous cell carcinoma (HNSCC)., Experimental Design: Fifty-eight HNSCC cases and 29 age- and gender-matched healthy controls were prospectively enrolled in the study. A detailed smoking history and single void urine specimen were obtained from each participant. Levels of urinary PGE-M were quantified in a blinded fashion using mass spectrometry and compared with smoking history and tumor status., Results: Adjusted for case-control matching, median urinary PGE-M levels were significantly higher in ever smokers (15.7 ng/mg creatinine) compared with never smokers (9.9 ng/mg creatinine) for the entire study population (n = 87, P = 0.005). Concentrations of urinary PGE-M were nearly doubled in ever smokers (15.2 ng/mg creatinine) versus never smokers (7.8 ng/mg creatinine) among healthy controls (P = 0.001). Higher PGE-M levels were observed in current versus former smokers and in those with greater pack-year exposure. A significant difference in amounts of PGE-M was not observed in patients with HNSCC versus healthy controls., Conclusions: Increased levels of urinary PGE-M were observed in smokers. Urinary PGE-M may have use as a noninvasive biomarker of the effects of tobacco smoke exposure.

Patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome typically have renal salt wasting, hypercalciuria with nephrocalcinosis, and secondary hyperaldosteronism. Antenatally, these patients have fetal polyuria, leading to polyhydramnios and premature birth. Hyperprostaglandin E syndrome/antenatal Bartter syndrome is accompanied by a pathologically elevated synthesis of prostaglandin E(2), thought to be responsible for aggravation of clinical symptoms such as salt and water loss, vomiting, diarrhea, and failure to thrive. In this study administration of the cyclooxygenase-2 (COX-2) specific inhibitor nimesulide to patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome blocked renal prostaglandin E(2) formation and relieved the key parameters hyperprostaglandinuria, secondary hyperaldosteronism, and hypercalciuria. Partial suppression of serum thromboxane B(2) synthesis resulting from platelet COX-1 activity and complete inhibition of urinary 6-keto-prostaglandin F(1alpha), reflecting endothelial COX-2 activity, indicate preferential inhibition of COX-2 by nimesulide. Amelioration of the clinical symptoms by use of nimesulide indicates that COX-2 may play an important pathogenetic role in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Moreover, on the basis of our data we postulate that COX-2-derived prostaglandin E(2) is an important mediator for stimulation of the renin-angiotensin-aldosterone system in the kidney.

The objective of this study was to evaluate the effect of conventional and long-chain polyunsaturated fatty acids (LCP)-enriched preterm formula on prostanoid formation in preterm infants during their first weeks of life. In a prospective, randomized, double-blind study, healthy infants received either formula enriched with LCP (n = 10), standard preterm formula (n = 10), or (expressed) breast milk (n = 10). Urine was sampled, and anthropometric measurements were taken at study entry and after the study period of 3 wk. In vivo formation of prostaglandin E2, thromboxane A2, and prostacyclin was evaluated by measuring the urinary excretion of the respective index metabolities by gas chromatography-mass spectrometry. There were no significant differences in urinary prostanoid excretion and anthropometric data between the groups at the end of the study period. We conclude that neither conventional formula nor supplementation of a preterm formula with LCP for a period of 3 wk substantially influence prostanoid formation in healthy preterm infants.

Pre-pubertal body growth was followed in eight children with the hyperprostaglandin E syndrome (neonatal Bartter syndrome) treated with indomethacin over a period of 5-12 years. When corrected for prematurity, the general growth pattern was normal, with the exception of a child with delayed therapy. From the first observation (usually at birth) to the start of indomethacin, the mean height standard deviation score (SDS) corrected for prematurity changed from -0.2 to -2.8. During the first 2 years of therapy rapid catch-up growth occurred, followed by a slow adaptation of the growth pattern to that of healthy children born at term. At last observation the mean corrected height SDS was -0.5 (range -1.9 to +0.9) and the mean target height -0.9 SDS (range -1.8 to +0.1). Weight, body mass index and bone maturation also reached the normal range. No correlation was found between height SDS per year and serum potassium levels or calcium excretion. We conclude that under indomethacin treatment long-term skeletal growth of children with the hyperprostaglandin E syndrome is similar to that of other preterm children.

1. Twelve healthy volunteers maintained on a 100 mmol/day Na+ diet, were given an intravenous infusion of 2L saline (0.9%) between 10.00 h on 2 study days at least 1 week apart. Urine collections (90 min) were made from 08.30 to 16.00 h. Either carbidopa 100 mg or indomethacin 50 mg was given orally at 07.45 h on one study day and placebo was given on the other (in random order). 2. On the placebo day, saline infusion caused significant decreases in plasma albumin concentration, plasma renin activity (PRA), plasma aldosterone concentration and urinary aldosterone excretion, with 2 to 3-fold increases in plasma atrial natriuretic peptide (ANP) concentration and urinary dopamine: noradrenaline ratio (DA:NA), whereas mean urinary kallikrein and prostaglandin E2 (PGE2) excretion rates were unchanged. Carbidopa decreased urinary DA:NA and indomethacin decreased urinary PGE2 excretion, compared with the placebo day. Excretion of sodium (Na+) decreased below baseline in two out of six carbidopa-treated subjects and in three out of six indomethacin-treated subjects, but showed little or no change in the remainder. 3. These preliminary observations suggest that some subjects in the early phase of natriuresis after an intravenous Na+ load can be identified as having prostaglandin-dependent or dopamine-dependent mechanisms for Na+ excretion.

Metabolic investigations, including the use of stable isotopes of calcium, were used to study calcium kinetics in three children with the hyperprostaglandin E syndrome. The studies were performed both during indomethacin treatment and in the absence of therapy. Off therapy, each child had hypercalciuria (mean urinary calcium excretion 0.478 mM/kg/d), hyperprostaglandinuria, and elevated serum calcitriol concentration. All had diminished bone density and were euparathyroid. Indomethacin treatment was associated with a marked reduction in serum calcitriol concentration, as well as decreased prostaglandin E excretion. Mean urinary calcium excretion fell to 0.135 mM/kg/d. The stable isotope studies defined two components to the hypercalciuria of this disease: an indomethacin-sensitive dietary contribution and a relatively indomethacin-resistant bone resorptive element. Bone densitometry confirmed the presence of the resorptive element by demonstrating skeletal demineralization.

To determine the influence of prostaglandin (PG) synthesis inhibition on the renal function in renal transplant recipients, we carried out a crossover, double-blind, placebo controlled study of 18 ambulatory patients. Glomerular filtration rate (GFR) was measured using 51-Cr EDTA, before and after indomethacin (50 mgr. three times a day for three days), and placebo. Overnight urinary PGE excretion decreased 88.9 +/- SEM 4.81% after indomethacin, but remained unchanged following placebo. GFR decreased 15.3 +/- SEM 3.94% (p = 0.0139) after indomethacin. There was no correlation between PGE urinary excretion and GFR changes. Pre-existing renal functional impairment was not a significant risk factor. Caution should be exercised when using non-steroidal anti-inflammatory drugs in renal transplant patients.

Eighteen patients with senile pyelonephritis and nephrogenic arterial hypertension were examined for the effect of trental monotherapy (600 mg/day) on intrarenal hemodynamics, the rate of glomerular filtration (effective renal blood flow, the intensity of blood flow in the medullary layer of the kidney), activity of the renin-angiotensin-aldosterone system (plasma renin activity, plasma and urine aldosterone), prostaglandin synthetic capacity of the kidneys (PGE and PGF2 alpha), water-electrolyte balance (circulating blood volume, sodium content in the serum and its excretion with urine), and on arterial pressure and general vascular peripheral resistance. Prolonged administration of the drug (from 3 weeks to 6 months) led to a significant improvement of the medullary blood flow, increase (p less than or equal to 0.05) of excretion of natriuretic PGE [correction of RGE] and lowering (p less than or equal to 0.05) of diurnal excretion of PGF2 alpha, which was accompanied by a rise of natriuresis (p less than or equal to 0.05) and diuresis.

There has been no useful treatments for chronic vascular rejection (CVR) after kidney transplantation until now. Recently, however, some reports have suggested that the thromboxane A2 synthetase inhibitor, OKY-046, is useful in reducing proteinuria in nephrotic syndrome and preventing progression of CVR. Five patients with CVR (serum creatinine range: 1.7-2.6 mg/dl) were treated with OKY-046 for over one year and the effect of OKY-046 was evaluated. One patient developed acute rejection and another renal hypertension during this study. Except for the cases of acute rejection and renal hypertension, serum creatinine slightly decreased in 1 case and remained unchanged in 2 cases. Urinary excretion of protein and thromboxane B2 decreased significantly but prostaglandin E2 did not change in the treatment of the deterioration with OKY-046. We concluded that OKY-046 was effective in preventing graft function and decreasing urinary protein excretion in kidney transplant recipients with CVR.

The authors describe the history of a nine year old girl, with a disease that seemed to be hyperprostaglandin-E syndrome. They give a survey of the literature about the pathophysiological cause of the disease, the clinical and laboratory findings and the effect of indomethacin, which can inhibit the synthesis of prostaglandins. Prolonged treatment with indomethacin can decrease the urinary excretion of prostaglandine, polyuria and hypercalciuria and it can moderate the growth retardation. They found the same but milder clinical and laboratory features at the four year old brother of the patient too.

We investigated the relationship between urinary prostaglandin E2 (UPGE2), kallikrein (UKal), graft function and complications after renal transplantation in 11 patients. Grafts of 9 patients were from living-related donors (LRD), and other 2 patients were from a cadaveric donor (CAD). UPGE2 was measured by the radio immunoassay, and UKal was measured by the amidolytic method using Pro-Phe-Arg-MCA. The results were as follows. 1. In 5 of 6 patients from LRD without acute rejection episode (ARE), both UPGE2 and UKAL were within normal and/or slightly less than normal. UKal values of the other patient were high in his donor. 2. In 2 of 3 recipients from LRD who experienced ARE, UKal increased prior to ARE. UPGE2 also increased at the time of ARE, but it showed a periodic rise in the stable condition. 3. In 1 of 2 recipients from CAD, UKal exhibited a transient elevation at the time of acute tubular necrosis (ATN) and pyelonephritis while UPGE2 was low. In another recipient, UKal was almost within normal range at the time of ATN, and UPGE2 showed a periodic rise. 4. A significant correlation was seen between UKal, UPGE2 and UAld in the recipients from LRD without ARE (except 1 patient who showed high UKal values). However, the correlation was blurred inclusive of values in the patients who experienced ARE or other complications. There was no relationship between UKal, UPGE2, creatinine clearance, urine volume and urinary sodium. 5. Soybean trypsin inhibitor (STI) was used for the confirmation of specificity of the amidolytic method.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship of renal prostaglandins to antidiuretic hormone action and water diuresis was examined in 13 normal subjects and 2 subjects with diabetes insipidus. Following overnight water deprivation, a oral water load caused a prompt and sustained rise in the rate of urinary PGE2 excretion from 7.7 +/- 1.2 to 81.6 +/- 26.4 ng/hr (P less than 0.0001) in 7 normal subjects. Because the simultaneous increase in urinary excretion of urea was only 17% of the rise in urinary PGE2, passive wash-out of renal PGE2 probably accounts for only a small fraction of the increment in PGE2 excretion. Administration of the antidiuretic hormone analogue DDAVP to 6 normal subjects during sustained water diuresis resulted in a decrease in PGE2 excretion and urine flow rate comparable to that of dehydrated subjects. Thus, PGE2 excretion varied directly with urine flow rate over a wide range of states of hydration in all 13 normal subjects. One patient with central diabetes insipidus and one with nephrogenic diabetes insipidus demonstrated a similar positive correlation of PGE2 excretion rate and urinary flow rate in states of hydration, dehydration, and after administration of DDAVP. In the patient with nephrogenic diabetes insipidus, this relationship of PGE2 excretion rate to urine flow rate was unaffedted by DDAVP over a broad range of urine flow rates. Inhibition of prostaglandin synthesis with indomethacin in 6 normal subjects resulted in a significant decline in free water clearance (7.7 +/- 1.0 to 4.7 +/- 0.9 ml/min. P less than 0.001) and an increase in the minimal UOsm (61 +/- 4 to 93 +/- 19 mOsm/kg. P less than 0.01) achieved during water diuresis without a change in creatinine or osmolar clearances. Furthermore, the tightly linked relationship of PGE2 excretion rate to urine flow rate was reduced in 5 of 6 subjects during indomethacin treatment. We conclude that urinary PGE2 excretion varies directly with urine flow rate and is not directly dependent on ADH activity or state of hydration in man. The rise in PGE2 excretion during water diuresis may enhance the excretion of free water since indomethacin treatment blunted free water clearance while suppressing the rise in PGE2 excretion.

The renal response to arginine vasopressin was investigated with and without the simultaneous administration of the kallikrein inhibitor, aprotinin, in conscious Brattleboro homozygous rats with hereditary diabetes insipidus. Arginine vasopressin caused a marked antidiuretic response (urinary osmolality increased from 118 to 739 mosmol/l) which was accompanied by a significant increase in urinary prostaglandin excretion (prostaglandin E2 and F2 alpha excretion increased by 182 and 441%, respectively). Kallikrein excretion remained unchanged after arginine vasopressin infusion. The infusion of aprotinin diminished urinary kallikrein activity to undetectable levels, decreased potassium excretion significantly and caused a slight fall in urinary prostaglandin excretion. However, aprotinin failed to modify the arginine vasopressin-induced enhancement in prostaglandin excretion (prostaglandin E2 and F2 alpha excretion increased by 168 and 442%, respectively), and the antidiuretic response was also similar to that observed under control conditions. These results indicate that the kallikrein-kinin system is not involved in the renal response to vasopressin in the Brattleboro rat.

The adrenal and renal responses to similar increases in plasma angiotensin II (AII) were studied in chronically catheterized fetal lambs (112-131 days gestation: term 145 days) and adult nonpregnant sheep. The rate of AII infusion was adjusted to compare the effect of similar rises in plasma AII concentration between fetuses and adult ewes. Increases in plasma AII were associated with a decrease in plasma renin activity (PRA) in both fetuses (5.55 +/- 1.53 to 2.11 +/- 0.59 ng/ml per hr, P less than 0.05) and adult ewes (1.28 +/- 0.34 to 0.62 +/- 0.16 ng/ml per hr, P less than 0.05), but the percent changes in PRA for similar increases in plasma AII were not different when fetuses were compared to adult ewes. Contrary to the effect of AII on PRA, the increase in plasma AII did not produce parallel changes in plasma aldosterone concentration when fetuses were compared to adult ewes. The percent changes in plasma aldosterone concentration for similar increases in AII concentration were significantly higher in adult ewes (+165 +/- 37%) than in fetuses (+58 +/- 15%)(P less than 0.01). Finally, there were no significant changes in fetal urinary excretion of PGE and PGF2alpha when a significant rise (P less than 0.05) was observed in adult ewes at the highest level of plasma AII concentration. In summary, the present results tend to suggest that there are differences between fetuses and adult ewes in the response to AII, the response being smaller in fetuses.

1. The role of endogenous prostaglandins in the antihypertensive mechanism of the angiotensin converting enzyme inhibitor, captopril, was investigated. 2. An unequivocal reduction in blood pressure and significant increase in plasma renin activity and urinary prostaglandin E excretion were found after the captopril administration. 3. The changes in blood pressure, plasma renin activity and urinary prostaglandin E excretion induced by captopril were reversed after the inhibition of endogenous prostaglandin synthesis by indomethacin. However, the responses in low renin hypertension were different from those in normal renin hypertension. 4. In low renin hypertensive patients who responded to captopril, the hypotensive effect was abolished after th addition of indomethacin, whereas no marked change in blood pressure was induced by indomethacin in normal renin hypertensive patients. In contrast, plasma renin activity was markedly increased after captopril administration in normal renin hypertension, and no significant change was found in low renin hypertension. 5. Potentiation of the prostaglandin system seems to be a principal factor in the antihypertensive mechanism of captopril in low renin hypertension, and inhibition of the renin-angiotensin system is important in normal renin hypertensives. 6. The increase in renin release after the administration of captopril was inhibited by indomethacin, suggesting that an endogenous prostaglandin system may contribute to the short feedback mechanism of renin release.

In a double-blind cross-over trial 15 captopril (daily dose 600 mg) treated patients, received in addition to the converting-enzyme inhibitor, placebo or bendrofluazide (7.5 mg). Bendrofluazide lowered blood pressure, while body weight decreased slightly. During captopril-bendrofluazide treatment, the plasma renin-angiotensin-aldosterone system was stimulated, while no effect on the urinary excretion of prostaglandin E2 and F2 alpha was found.

Mean blood pressure (MBP) was found to be lower, while renal plasma flow (RPF), glomerular filtration rats (GFR), sodium excretion rate (U(Na)V), potassium excretion rate (U(k)V) and urinary prostaglandin E (PGE) concentration were higher in 15 normotensive subjects (15NS) compared with the values obtained in 15 essential hypertensive patients (15EHP) of the same mean age. After volume expansion of the 15HP with isotonic saline infusion, RPF, U(Na)V, U(k)V, urine volume (UV) and urinary PGE increased significantly while plasma renin activity (PRA) decreased significantly. Urinary aldosterone concentration and MBP decreased also but not significantly. After oral administration of 75 mg of indomethacin, in the same loaded group of 15 EHP, urinary PGE, urinary aldosterone and PRA decreased significantly while RPF, GRF, U(Na)V remained unaltered and MBP increased. When these values obtained in saline loaded and indomethacin treated 15EHP were compared to those obtained in the same group before volume expansion, it was found that RPF, U(NaV, U(k)V and UV were higher after indomethacin-saline administration while MBP, GRF and urinary PGE did not differ significantly and PRA and urinary aldosterone were significantly lower. These findings argue against the suggestion that PGE increases sodium reabsorption at the distal tubule and indicate that the unaltered sodium excretion rate in saline loaded and indomethacin treated unanaesthetized subjects, results from the simultaneous decrease of renomedullary PGE, Renin and aldosterone secretion.

Pre-irradiation administration of the radioprotectant drug WR-2721 to rats resulted in a significant reduction in radiation-induced increases in excretion rates of prostaglandins (PGE and PGF2 alpha) and thromboxane (TxB2). In animals not irradiated. WR-2721 did not significantly alter these excretion rates. Dramatic reductions in the levels of urinary PGE and TxB2 were observed following exposure to 9.0 Gy of whole-body, unilateral gamma-radiation in WR-2721-treated animals, whereas changes in PGF2 alpha levels were less pronounced. Radiation-induced diuresis was also significantly depressed in animals given WR-2721 before irradiation. Reduced prostaglandin excretion rates may reflect the general radioprotective capacity of the chemoprotector WR-2721 on the release of prostaglandins from radiation-damaged tissue. The decrease in diuresis may be related to the observed prostaglandin decreases.

Using a double-blind procedure, 29 patients with a recent myocardial infarction were randomly allocated to a placebo group (n = 14) and to a group receiving aspirin, 300 mg three times a day (n = 15) over 7 days. No change in renal function was observed in either treatment group. Compared with the placebo group, the 24-h urinary excretion of prostaglandin E2 (PGE2) was significantly suppressed in the aspirin group, but the urinary kallikrein activity was unchanged. These results contrast with our previous study of similar patients, in which sulfinpyrazone decreased renal function, as well as the urinary PGE2 and kallikrein excretions. These divergent effects of aspirin and sulfinpyrazone on urinary kallikrein activity could explain the different trends in renal function observed early after myocardial infarction.

Urinary excretion of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha), plasma concentrations of renin, aldosterone, norepinephrine (NE) and epinephrine (E) were determined during pregnancy, 5 days, 3, and 6 months after delivery in preeclampsia, normotensive pregnant, and nonpregnant control subjects. The PGE2 was higher in normotensive pregnant control subjects than in nonpregnant subjects. In preeclampsia, PGE2 was reduced to nonpregnant level. PGF2 alpha was the same in preeclampsia and in normotensive pregnancy, but elevated when compared to the normotensive nonpregnant control group. Plasma concentrations of renin and aldosterone were increased during pregnancy, but considerably less in preeclampsia than during normotensive pregnancy. NE and E were the same as in nonpregnant subjects during both hypertensive and normotensive pregnancy. All parameters were normal 3 months after delivery. There were no correlations between PGE2, PGF2 alpha, plasma concentrations of renin, aldosterone, NE, or E and blood pressure level in third trimester either in preeclampsia or in normotensive pregnancy. PGE2 was positively correlated to plasma concentrations of renin. It is suggested that the lack of renal PGE2 in preeclampsia might be responsible for the decrease in renal blood flow and sodium excretion. It is hypothesized that preeclampsia is a state of prostaglandin deficiency. The changes in the renin-aldosterone system may be secondary to changes in prostaglandin concentration both in preeclampsia and normotensive pregnancy.

Continued PG synthesis in the early stages of essential hypertension might reflect an activation of the renal antihypertensive function in respect to neurogenic and/or hormonal pression stimuli, subsequently a deficiency of renal PG synthesis related to irreversible changes with the kidney would lead to the prepoderance of a pressure mechanism, resulting to a further increase of blood pressure.

A 34-year-old female complaining of numbness and weakness of the extremities was examined. Consanguineous marriage was contracted between mother and father. She was of short stature (149 cm), and her blood pressure was normal (118/60 mmHg). Her serum potassium concentration had decreased to a level between 2.5 and 3.2 mEq/L, and hypokalemic alkalosis was present. Potassium clearance had increased and urinary concentrating capacity was impaired. Plasma renin activity was high at 25 ng/ml/hr but plasma aldosterone concentration was normal. Hypertensive response to angiotensin II (50 ng/kg/min) was weak but improved to nearly the normal value after the administration of indomethacin for 17 days at a dose of 50 mg/day. A slight elevation in blood pressure was observed during the infusion of norepinephrine (250 ng/kg/min). A decrease in blood pressure was observed during the infusion of 1-sarcosine, 8-isoleucine angiotensin II (600 ng/kg/min) with concomitant increase of plasma renin activity. Twenty-four hour urinary excretion of prostaglandin E decreased somewhat (225 approximately 252 ng/day), and hyperplasia of the juxtaglomerular cells and increased JG index were demonstrated in the biopsy specimens of the right kidney. From the findings, the present case were diagnosed as Bartter's syndrome. Although mild enlargement of the sella turcica was found in skull x-ray films, no abnormalities in pituitary function were demonstrated. Other unusual complications, i.e. hyperlipidemia (type II, beta-dominant) and abnormal configuration of peripheral erythrocytes, were demonstrated. Phospholipid composition of the erythrocyte membrane was normal. The fluidity of plasma VLDL examined by electron spin resonance was increased. Hypokalemia and hyperreninemia were improved through the administration of indomethacin. However, because of headache as an adverse effect, further administration could not be accepted. The patient's complaints were resolved by the rectal application of indomethacin with oral administrations of spironolactone and triamterene. Changes in serum lipid levels did not occur with the above mentioned treatment. alpha-tocopheryl nicotinate lowered the levels of serum lipids and normalized the configuration of peripheral erythrocytes. But increased fluidity of plasma VLDL remained, and phospholipid composition of erythrocyte membrane was also unchanged. The relationship between the rare complications mentioned above and the pathophysiology of Bartter's syndrome is still obscure.

We report that the inhibition of the angiotensin converting enzyme is an effective short-term treatment of low-renin hypertension in acute glomerulonephritis (AGN). We treated 9 patients who had AGN with moderate to severe hypertension and suppressed plasma renin activity with 25-50 mg of captopril per os every 6-8 hours. Control of blood pressure was achieved in 1-2 hours and maintained thereafter. Captopril therapy was associated with an increase in plasma renin activity, a decrease in plasma aldosterone and an increase in the urinary excretion of prostaglandin E2 and kallikrein, independent of changes in urine output. Creatinine clearance increased 39.6 +/- SE 15.2% with captopril and decreased in the postcaptopril period, suggesting that captopril exerted a reversible effect on glomerular filtration rate, possibly modifying intrarenal vasoconstriction. Our study shows that rapid control of hypertension in AGN may be obtained with oral inhibition of the angiotension converting enzyme. Stimulation of PGE2 and kinins, as well as angiotensin II blockade appear to contribute to the hypotensive effect of the drug; by inference, the suppressed activity of vasodilator systems seems to play a significant role in the hypertension of AGN.

The onset of infection is associated with increases in renal blood flow and sodium excretion. Our studies provide evidence that the natriuresis is mediated by stimulation of renal prostaglandin production by the cytokine, interleukin-1. A dose-dependent natriuresis and diuresis was elicited in conscious rats with bolus intravenous injections of human recombinant interleukin-1-beta (hrIL-1). Injection of 1.5, 3 and 24 micrograms hrIL-1 increased sodium excretion by 2.4 +/- 0.9 microEq/min, 4.0 +/- 0.8 microEq/min and 5.4 +/- 0.3 microEq/min, respectively. The natriuresis was preceded by a corresponding increase in urinary PGE excretion (80%, 110% and 296%, respectively). The natriuresis elicited by 3 micrograms hrIL-1 was independent of changes in glomerular filtration rate or effective renal plasma flow. IL-1 induced an increase in rectal temperature, (0.6 +/- 0.2 degrees C) and a modest increase in mean arterial pressure (12 +/- 3 mm Hg) within 10 minutes of injection. However, during the period of maximal natriuresis (40 to 100 min), blood pressure and rectal temperature were not significantly different from control. Pretreatment with the cyclooxygenase inhibitor, ibuprofen, significantly attenuated the natriuretic response and indomethacin completely abolished the natriuresis. These results identify IL-1 as a factor which stimulates renal PGE synthesis, and increases sodium excretion, independent of changes in glomerular filtration rate. We propose that IL-1-induced natriuresis may be a component of the overall acute phase response which is actively mounted by the host during infection.

There is evidence that neither activation of the renin-angiotensin system nor changes in sodium balance can fully explain the maintenance of blood pressure in Goldblatt hypertension. Thus, in Goldblatt two-kidney, one clip hypertension in the rat sodium balance is negative and in hypertension of a few months' duration plasma renin initially elevated has returned to normal. When hypertension is reversed by removal of the constricting clip from the renal artery, blood pressure falls within a matter of hours even when hypertension has been present for many months, suggesting that the effect of structural changes in vascular resistance vessels has been overcome. In addition, blockade of the renin-angiotensin system during renal artery declipping does not influence the pattern of the blood pressure fall. We investigated the role of the renomedullary vasodepressor system by inducing medullary necrosis with 2-bromo-ethylamine hydrobromide. This causes a moderate blood pressure increase in normal rats, and partly inhibits the fall of blood pressure in Goldblatt two-kidney, one clip hypertension when the renal clip is removed. Chemical medullectomy is associated with a slightly negative sodium balance, plasma volume contraction, a reduction in plasma renin activity and urinary PGE2, and a minimal elevation in plasma vasopressin. Blood pressure elevation appears to be attributable to inhibition of a vasodepressor system based on the renal medulla. Chemical medullectomy offers a valuable tool for investigating the role of this medullary vasodepressor system.

The urinary excretion of prostaglandins (PG) E2 and F2 alpha was measured by radioimmunoassay in 15 patients with essential hypertension, before and after 2 and 4 weeks of treatment with the selective beta 1-adrenergic blocker, atenolol. Systolic and diastolic blood pressure, pulse rate and plasma renin activity decreased significantly during the treatment. No change was observed in renal function and electrolyte balance. The 24-hour excretion of PGE2 and PGF2 alpha was also unaffected by the antihypertensive treatment. The above findings, in contrast with those previously observed with another beta-blocker, propranolol, suggest that tubular beta-receptors are not involved in the synthesis of PGs. The different hemodynamic effects of the two drugs are the most likely explanation for the different responses in prostaglandin excretion.

We tested whether vasodilatory prostaglandins (PGs) mediate the adaptation of the maternal renal circulation to pregnancy by assessing production of PGs by kidney tissues in vitro. We reasoned that if PGs are crucial, then local synthetic rates of these hormones would most likely be increased. Glomeruli harvested from gravid rats of gestational days 6, 12, and 20 did not demonstrate greater basal or stimulated syntheses of PGF2 alpha, PGE2, or 6-keto-PGF1 alpha than those from virgin controls. Production of PGE2 and 6-keto-PGF1 alpha by renal cortical slices obtained from pregnant rats was not greater than that of virgins either. Urine 24-h excretory rates of PGE2 and 6-keto-PGF1 alpha, but not PGF2 alpha, were significantly increased during pregnancy (all P less than 0.05 from prepregnant levels). During midgestation, when urinary excretion of PGE2 and 6-keto-PGF1 alpha was greatest, medullary syntheses of these PGs were found to be comparable between virgin and gravid animals. The present study, which fails to show augmented synthesis of PGs by renal tissues derived from gravid rats, is consistent with our previous investigation in which cyclooxygenase inhibition did not reduce the gestational increase of renal hemodynamics or restore the attenuated renal pressor responsiveness to exogenous angiotensin II. Taken together, we conclude that in rats, PGs most likely do not mediate the alterations in the renal circulation observed during pregnancy.

Hypercalcemic conditions are commonly associated with hypertension and with abnormal magnesium homeostasis. The mechanism by which the hypertension of hypercalcemia is mediated is not clear, and the role that magnesium may play in its generation has not been examined. We review here the available clinical and experimental data and propose a role for abnormal magnesium metabolism in the mediation and generation of the hypertension of hypercalcemia.

The excretion of urinary immunoreactive prostaglandin E (iPGE), sodium, potassium, creatinine and volume was studied in 4 hr collections in normal women at normal activity. iPGE exhibited a circadian rhythm with an amplitude of 29% and peak excretion at 4:55 P. M. There were also significant circadian rhythms for sodium, potassium, creatinine, and volume, all peaking in late afternoon. There were no significant changes either in the total excretion or in the circadian rhythms of iPGE, potassium, or creatinine excretion when the subjects remained in bed for an entire day while the circadian rhythms of sodium and volume were significantly modified in amplitude and phase, respectively. Urinary aldosterone excretion decreased significantly when the subjects were at bed rest. iPGE excretion increased 33% when subjects were first recumbent and then erect for consecutive 4 hr period on the same day (but when subjects were erect 1 day for a 4 hr period, iPGE excretion was lower by 32% than for the same 4 hr period the preceding day when they were recumbent). These data indicate that: 1) the sympathetic nervous system and renin-angiotensin-aldosterone system do not affect the circadian rhythms of urinary iPGE, and 2) short-term experiments of prostaglandin E excretion must be designed to avoid misleading results due to the circadian rhythm.

A polyuric state is often observed after cis-dichlorodiammine platinum (cisplatin). To study the mechanism of this polyuria we gave 5-6 mg/kg cisplatin to conscious rats and observed polydipsia and a polyuric form of mild acute renal failure. A defect in renal concentrating ability was observed 1 and 8 days after cisplatin. Animals demonstrated diminished postdehydration plasma vasopressin at 1 but not at 8 days after cisplatin, and exogenous vasopressin corrected the renal concentration defect at 1 but not at 8 days after cisplatin. To assess the role of polydipsia in the concentration defect, water intake in cisplatin-treated animals was matched to pair-fed controls. Prevention of polydipsia improved the polyuria but not the concentration defect seen 8 days after cisplatin. To assess intrarenal factors in the renal concentration defect, postdehydration interstitial solute was measured and was significantly lower in cisplatin-treated than in control animals. To determine whether the diminished interstitial solute was due to vascular mechanisms, inner medullary plasma flow was measured and was identical in cisplatin-treated and control rats. Treatment with cisplatin also resulted in decreased excretion of a water load. We conclude that either impaired synthesis or release of vasopressin is the cause of the impaired renal concentration seen 1 day after cisplatin. Eight days after cisplatin, the renal concentration defect is due in part to decreased interstitial tonicity.

Dose-related alterations in the levels of prostaglandins (PGF2 alpha and PGE) and thromboxane B2 (TxB2) were observed in the urine of unanesthetized rats following whole-body gamma radiation. Exposure doses of 100 and 900 rads resulted in significant changes in urinary levels of these cyclooxygenase products. These findings suggest the potential use of radioimmunoassay measurement of urinary prostaglandins and thromboxane as a noninvasive indicator of radiation exposure.

It has been postulated that renal prostaglandins (PGs) function as negative feedback inhibitors of the action of antidiuretic hormone (ADH), implying a correlation between levels of ADH and the rate of renal PG synthesis. These studies have evaluated the relationship between renal PG synthesis and hormone levels in rats with hereditary diabetes insipidus, a species devoid of circulating ADH. Since vasoconstrictor agents can stimulate renal PG synthesis by mechanisms unrelated to antidiuretic activity, deamino-8-D-arginine vasopressin (dDAVP) was utilized for replacement therapy instead of arginine vasopressin, which has considerable pressor activity. dDAVP was administered by S.C. implanted osmotic minipumps to obtain steady states of dDAVP at different dose levels. As indices of renal PG synthesis, urinary excretion of PGE2 and PGF2 alpha were measured by gas chromatography-mass spectrometry. PGE2 excretion, although increased by dDAVP treatment, was not correlated with dose of dDAVP. However, PGF2 alpha excretion was highly correlated with dose of dDAVP (r = 0.97, P less than .01). The sum (PGE2 + PGF2 alpha), which may more accurately reflect total medullary PG synthesis, was also significantly correlated with dose of dDAVP (r = 0.98, P less than .001). It is concluded that dDAVP stimulates renal PG synthesis in a dose-related fashion. This occurs at doses which bring urine osmolality into the normal physiological range. Furthermore, it is shown that stimulation of renal PG synthesis by arginine vasopressin is not due primarily to its pressor action. These experiments also provide evidence that urinary PGE2 and PGF2 alpha excretion can vary independently.