Renal PGE2 Research Articles

Effects of gluco- and antiglucocorticoids on renal and aortic prostaglandin synthesis.

The effects of glucocorticoid agonists RU 26988 (G) and dexamethasone (D) and antagonist RU 486 (AG) on aortic and renal prostaglandin (PG) production were studied in Wistar rats. Blood pressure increased in rats administered G (20 mg X kg-1 X day-1) during 1 or 3 days; such increase was prevented by AG (100 mg X kg-1 X day-1). Renal papillary PGE2 release was increased after a 3-day administration of G, and this was prevented by AG. Neither G nor AG altered basal 6-keto-PGF1 alpha aortic production. However, G inhibited and AG magnified the stimulatory effect of ionophore A 23187, added in vitro, on 6-keto-PGF1 alpha production; AG reversed G inhibition. In addition, AG alone (20 mg X kg-1 X day-1 X 3 days) enhanced the stimulatory effect of angiotensin II (10(-8) M), added in vitro, on 6-keto-PGF1 alpha release. In vitro studies were performed on renomedullary interstitial cells grown in culture; G and D depressed PGE2 production in a dose-dependent manner; AG at equimolar 10(-8) M concentration inhibited this effect. In conclusion, AG inhibits the effects of G on blood pressure and PG synthesis. G exerts strong depressor activity on in vitro PGE2 renal production, whereas in vivo effects are more complex. Endogenous G inhibits aortic prostacyclin production, an action unmasked by AG administration. Diminished stimulation of vascular prostacyclin synthesis may contribute to vascular hyperreactivity in G-induced hypertension.

Different excretion pattern of urinary PGE 2 and 6-keto-PGF 1α in two kidney-one clip goldblatt rats

Changes in blood pressure and 24 hour urinary excretion of PGE 2 and 6-keto-PGF 1α have been studied during ten weeks after renal artery clipping or sham operation in rats. From the second week on, systolic blood pressure was significantly increased in the two kidney-one clip rats as compared to controls. Maximal differences were reached in the 10th week after the operation (145 ± 8 vs 116 ± 3.2 mm Hg; p<0.001). Urinary PGE 2 levels showed markedly elevated values versus controls from the 6th week on (p<0.001). However, no significant changes in urinary 6-keto-PGF 1α excretion were observed between the groups during the whole experimental period. These findings suggest that renal PGE 2 may be involved in the pathophysiology of blood pressure control in the two kidney-one clip model, whereas, 6-keto-PGF 1α seems not to be altered after renal artery clipping.

The effect of sodium bicarbonate on the flow-dependency of urinary prostaglandin excretion in man.

The influence of oral water loading on the excretion rate of prostaglandin (PG) E was investigated in healthy human subjects in a control study where the urine was acidic (pH 5.7) and after oral sodium bicarbonate, which made the urine mildly alkaline (pH 7.2). PGE was immediately extracted from urine and measured by a radioimmunoassay technique. After sodium bicarbonate (5 g) the urinary PGE excretion rate was some three-fold higher (P less than 0.01) than in the control study, in the absence of any significant difference in the urine flow (approximately 80 ml/h). In the control study (urine pH 5.7) the urinary PGE excretion rate increased significantly (P less than 0.01) as the urine flow rose in response to the oral fluid load. However, after sodium bicarbonate, PGE excretion did not alter after the fluid load despite a 10-fold increase in urine flow. Since after bicarbonate administration PGE excretion is independent of urine flow, mildly alkaline urine may represent a condition under which renal PGE synthesis can be effectively assessed from measurements of urinary PGE excretion, in the presence of changes in urine flow. In addition, the results are compatible with the hypothesis that, in man, PGE may be passively reabsorbed in the distal nephron, and a reduction in this reabsorption could contribute to or be responsible for the dependency of the excretion rate of PGE on urine flow.

PGI2 synthesis and excretion in dog kidney: evidence for renal PG compartmentalization.

To assess the concept of compartmentalization of renal prostaglandins (PG), we compared entry of PGE2 and the PGI2 metabolite 6-keto-PGF1 alpha into the renal vascular and tubular compartments, in sodium pentobarbital-anesthetized dogs. Renal arterial 6-keto-PGF1 alpha infusion increased both renal venous and urinary 6-keto-PGF1 alpha outflow. In contrast, renal arterial infusion of arachidonic acid (AA) or bradykinin (BK) increased renal venous 6-keto-PGF1 alpha outflow but had no effect on its urinary outflow. Both urinary and renal venous PGE2 outflows increased during AA or BK infusion. Ureteral stopped-flow studies revealed no postglomerular 6-keto-PGF1 alpha entry into tubular fluid. During renal arterial infusion of [3H]PGI2 and inulin, first-pass 3H clearance was 40% of inulin clearance; 35% of urinary 3H was 6-keto-PGF1 alpha, and two other urinary metabolites were found. During renal arterial infusion of [3H]6-keto-PGF1 alpha and inulin, first-pass 3H clearance was 150% of inulin clearance; 75% of urinary 3H was 6-keto-PGF1 alpha, and only one other metabolite was found. We conclude that in the dog PGE2 synthesized in the kidney enters directly into both the renal vascular and tubular compartments, but 6-keto-PGF1 alpha of renal origin enters directly into only the renal vascular compartment.

Prostaglandin and thromboxane formation in glomeruli from rats with reduced renal mass.

In vitro formation of prostaglandins (PG) E2, F2 alpha, 6-keto-F1 alpha, and thromboxane B2 (TxB2) by glomeruli from rats with reduced renal mass (RRM) were evaluated by radioimmunoassay. Four weeks following ablation of renal mass, PGE2, PGF2 alpha, and TxB2 production by glomeruli from RRM rats was significantly greater, when compared with glomerular PG and TxB2 production of sham-operated control (C) rats. The effect of cyclooxygenase inhibition with indomethacin and the selective inhibition of thromboxane formation with UK 38485 on glomerular filtration rate (GFR) was investigated in experiments in vivo. In RRM rats indomethacin reduced GFR from 212 +/- 17 to 138 +/- 14 microliter/100 g/body weight (p less than 0.05) without effect on C rats. Thromboxane synthesis inhibition with UK 38485, however, increased GFR significantly in RRM rats (221 +/- 26 to 303 +/- 21; p less than 0.05). The data suggest that vasodilatory PGs and TxB2 modulate GFR in rats with ablation of renal mass.

Redistribution of renal blood flow in patients with liver cirrhosis: The role of renal PGE 2

Cirrhotic patients frequently show a decrease in renal blood flow and redistribution of the flow from the outer cortex to the juxtamedullary cortex. The cause of the maintenance of juxtamedullary perfusion is not presently known. Prostaglandin E2 (PGE2) has its vasodilating effect on medullary and juxtamedullary vessels where it is synthesized. Therefore, its increased production, frequently shown in cirrhotics, could be responsible for the relative preservation of juxtamedullary blood flow. To verify this hypothesis we examined 13 cirrhotic patients. In these patients we determined mean renal blood flow (MRBF), blood flow in the 1st compartment (ICBF) and in the 2nd compartment (IICBF) with the 133-Xenon washout technique and PGE2 plasma levels in the renal veins (PGE2V). MRBF and ICBF were significantly reduced as compared to control subjects (P less than 0.01); IICBF resulted unaltered. Significant correlation was found between IICBF and PGE2V (P less than 0.01). Our data confirm the decrease in renal blood flow and the redistribution of intrarenal blood flow in cirrhotic patients. The maintenance of IICBF is likely to be a consequence of PGE2 renal production.

Congenital hypokalemia with hypercalciuria in preterm infants: A hyperprostaglandinuric tubular syndrome different from Bartter syndrome

A congenital hypokalemic tubular disorder is described with many features resembling Bartter syndrome. Additional features include prenatal onset with polyhydramnios and premature labor; failure to thrive; episodes of fever, vomiting, diarrhea, and renal electrolyte and water wastage; hypercalciuria; nephrocalcinosis; and osteopenia. Unlike Bartter syndrome, there is no defect in tubular reabsorption of chloride. Urinary levels of prostaglandin E2 and 7 alpha-hydroxy-5,11-diketotetranorprosta-1,16-dioic acid are selectively elevated, indicating marked stimulation of renal and systemic PGE2 production. Chronic suppression of PGE2 activity by indomethacin corrects most of the abnormalities, and there is an immediate decompensation of the disease on indomethacin withdrawal. We conclude that these preterm infants have a distinct variety of hypokalemic tubular disorders rather than a variant of Bartter syndrome, because renal and systemic hyperprostaglandinism ranks high in the pathogenic chain of events, and the suppression of PGE2 hyperactivity is associated with significant improvement in the development (and probably in the prognosis) of the affected children.

Renal vein prostaglandins in renovascular hypertensive patients

To investigate the role of intrarenal prostaglandins in the pathophysiology of renovascular hypertension, we measured bilateral renal vein prostaglandins (PGE 2, 6-keto-PGF lα) and plasma renin activity (PRA) of nine patients with renovascular hypertension caused by fibromuscular dysplasia. Both PGE 2 and PRA on the stenotic side were significantly higher than those on the non-stenotic side. The difference in 6-keto-PGF lα levels between the stenotic and the nonstenotic sides was not significant. PGE 2 ratio of the stenotic and the non-stenotic sides was significantly correlated with PRA ratio of the stenotic and contralateral sides. These results suggest that renal PGE 2 plays an important role in the maintenance of renal blood flow through modulation against vasoconstriction in the renal vasculature and that renal PGE 2 may be closely associated with renal renin secretion in the renovascular hypertension.

Effect of potassium loading on prostaglandin E 2 and F 2α excretion in the brattleboro rat

In order to assess the relative roles played by potassium (K) and the antidiuretic hormone (ADH) on the renal production of prostaglandins (PG) E 2 and F 2α,the 24 hour urinary excretion of these substances was measured in Brattleboro rats (devoid of ADH) and in control Long Evans heterozygote rats. Rats of each strain received either a normal K intake or a K load for 8 days. Urinary PGE 2 and PGF 2α were measured by radioimmunoassay in three consecutive 24 h urine collections obtained after the above periods. K loading induced an increase in PGF 2α (p<0.01),PGE 2 showing a non significant trend to decrease. The E/F ratio was decreased in K loaded animals. The changes were qualitatively similar in presence or absence of ADH, but animals with diabetes insipidus had lower levels of PGs than control animals. The results suggest the possibility that K loading induces an increase in the activity of the renal enzyme PGE 2α-9-ketoreductase. The resulting increase in PGF 2α could play a role in K excretion and this response is probably independent of ADH.

Estradiol stimulates rat renopapillary prostaglandin E2 (PGE2), but not PGF2 alpha biosynthesis.

The effects of estrogen on renal prostaglandin (PG) and renin-angiotensin were investigated in rats in relation to sodium metabolism and blood pressure regulation. Regardless of estrous cycle phase, PGE2 urinary excretion in females was 2-3 times higher than that in males and was associated with higher sodium excretion. A positive correlation was observed between urinary PGE2 and free estradiol concentrations. Reno-papillary PGE2 synthesis in vitro after slice incubation was higher in estrous females than in males. Ovariectomy resulted in a marked decrease in PGE2 renal synthesis and excretion, and estradiol administration (50 micrograms, im) restored these to levels comparable to those in cycling females. This estradiol treatment also was associated with a 3-fold rise in PRA without alteration in blood pressure. In estrogen-primed ovariectomized rats, infusion of the angiotensin antagonist Sar1-Ala8-angiotensin II at a rate of 30 micrograms/microliter X h resulted in a further rise in PRA as well as a significant decrease in renal PGE2 synthesis and excretion toward values observed in the ovariectomized animals. In contrast, renal synthesis and excretion of PGF2 showed no fluctuations during identical variations in estrogenic states. The results suggest that estradiol stimulates renal PGE2, but not PGF2 alpha, synthesis not only via a direct stimulatory action, but also through augmentation of the renin-angiotensin II axis. This increase in vasodilatory PGE2 may function to offset the prohypertensive effects of the estrogen-stimulated renin-angiotensin axis.

Role of renal prostaglandins in the fall in urine osmolality after papillary micropuncture

The effect of micropuncture of the renal papilla through an intact ureter on urinary concetrating ability of rats was examined. Micropuncture of the renal papilla caused a fall in urine osmolality in the punctured kidney from 1718 ± 106 to 1035 ± 79 mosmol/kg·H 2O. In order to investigate the role of renal prostaglandins in this process, PGE 2 excretion was measured and found to increase from 63.4 ± 14.0 to 205.5 ± 57.1 pg/min. Urine osmolality and PGE 2 excretion from the contralateral kidney were not significantly altered. In animals given meclofenamate (2 mg/kg·hr), renal PGE 2 excretion was reduced to 22.3 ± 5.1 pg/min prior to micropuncture and it remained low at 8.9 ± 1.8pg/min after papillary micropuncture. Meclofenamate also blocked the fall in urine osmolality caused by micropuncture of the renal papilla, with urine osmolality averaging 1940 ± 122 before and 1782 ± 96 mosmol/kg·H 2O after the micropuncture. These results indicated that papillary micropuncture through an intact ureter increased renal PGE 2 excretion and that a rise in renal production of PGE 2 or some other prostanoid is associated with a fall in urine concentrating ability.

Haemodynamic conditions for renal PGE2 and renin release during alpha- and beta-adrenergic stimulation in dogs.

Constriction of the renal artery and infusion of an alpha-adrenergic agonist induce autoregulated vasodilation and increase prostaglandin E2 (PGE2) and renin release. The enhancement of renin release during autoregulated vasodilation might be mediated by prostaglandins. To examine this hypothesis, experiments were performed in three groups of anaesthetized dogs. In six dogs constriction of the renal artery to a perfusion pressure below the range of autoregulation raised renin release from 2 +/- 1 to 27 +/- 6 micrograms AI X min-1 and PGE2 release from 1 +/- 1 to 10 +/- 2 pmol X min-1. After administration of indomethacin (10 mg X kg-1 b.wt), PGE2 release was effectively blocked and constriction of the renal artery raised renin release only from 0.1 +/- 0.1 to 6 +/- 1 micrograms AI X min-1. During subsequent continuous infusion of a beta-adrenergic agonist, isoproterenol (0.2 micrograms X kg-1 X min-1), constriction of the renal artery raised renin release from 0.1 +/- 0.1 to 52 +/- 11 micrograms AI X min-1, although there was no rise in PGE2 release. In six dogs, intrarenal infusion of phenylephrine, an alpha- adrenergic agonist, increased PGE2 and renin release before, but not after, indomethacin administration. In six other dogs, phenylephrine infused during isoproterenol infusion increased renin release equally before and after indomethacin administration. Thus the enhancing effect of constricting the renal artery or infusing an alpha-adrenergic agonist is not dependent upon prostaglandins. We propose that autoregulated dilation enhances renin release whether the stimulatory agent is a prostaglandin or a beta-adrenergic agonist.

Reduced prostaglandin synthesis by renal and aortic tissues from adult rats fed essential fatty acid-deficient diet after food deprivation

Studies were conducted to determine the efficacy of a dietary technique for reducing prostaglandin (PG) synthesis in adult rats. Rats weighing 280–318 g were fed either essential fatty acid (EFA)-deficient or EFA-adequate diets for 10–17 days after a period of food deprivation. Synthesis of renal papillary PGE 2 and aortic PGI2 from endogenous precursor in vitro were estimated by liquid chromatographic and bioassay/radioimmunoassay techniques, respectively, as indices of the capacity of the technique to induce EFA deficiency. PGE synthesis and PGI2 synthesis by isolated tissues from rats fed the EFA-deficient diet were significantly decreased (ca. 50%) relative to control rats fed an EFA-adequate diet. Body and renal papillary weights were not significantly altered by the EFA-deficient diet.

1620 EARLY EFFECTS OF STHEPIOZOTOCIM DIABETES (SD) ON RAT GLOMERULAR FILTRATIOM RATE (GFR) AND PROSTAGLANDIN E2 SYNTHESIS (PGE2)

In SD the development of moderate hyperglycemia is closely associated with increases in GER that way be mediated by altered production of or reactivity to vasoactive substances. In the present studies renal cortical and medullary PGE2 synthesis and whole kidney GFR (CIN) were tamrinri 8 days after induction of SD (45 mg/kg i.v.) in young rats (139±1.7 g) treated with either daily aspirin (ASA) 300 mg/kg/day or ASA vehicle. PGE2 synthesis from 14C-arachidonic acid was determined in cortical and medullary microsones by thin layer chromatography. Mean values (± 1SE) for body weight (BW), blood pressure (bp), plasma glucose (Pglu, mg/dl), CIN (ml/min/g KW), and PGE2 synthesis (ng/mg/30 min) are shown below: *p<0.05, compared to group above; †p<0.05, compared to control (C).Weight gain in SD and SD/ASA rats was less than in C and C/ASA. After 8 days of SD PGE2 synthesis and GFR were increased compared to control values. Eight days of PG inhibition reduced PGE2 synthesis by 40% and GSR by 25% in SD/ASA compared to SD rats. ASA given to control rats reduced PGE2 synthesis but had no effect on GFR. These data suggest that hyperfiltration observed in moderately hyperglycemic SD rats may be mediated by elevated rates of prostaglandin synthesis. Whether chronic alterations in prostaglandin synthesis influence the onset and progression of glomerular histologic changes remain unknown.

Renal prostaglandin E 2 and the renin-angiotensin system in hypertensive disorders in man

We studied renalvein concentrations of prostaglandin E 2(PGE 2) and activity of the renin-angiotensin system i 9 normotensive young men (NT), 17 hypertensive patients with unilateral renal artery stenosis (URS), and 26 patients with essential hypertension (EH) of whom 12 had low renin essential hypertension (LRH). The PGE 2 concentration, plasma renin activity (PRA), and angiotensin II (A II) were measured in the inferior vena cava and were compared with the mean concentration for both renal veins under basal conditions and without pharmacological interference. The renal vein PGE 2 concentrations were higher in NT (p<0.01) and URS (p<0.05) than in LRH. However, there were no significant differences in A II concentrations between the groups, nor were there any correlations to PGE 2 concentrations. The positive correlation between PRA and PGE 2 (r=0.29, p<0.02) indicates that PGE 2 may contribute to the activation of the renin-angiotensin system or that there may be a common mechanism for stimulation of both hormonal systems. Our results are not compatible with the hypothesis that a reduction of PGE 2 production is a specific feature of patients with EH.

1632 THE ROLE OF PROSTAGLANDIN E2 (PGE2) IN A CONGENITAL HYPOKALEMIC TUBULAR DISORDER WITH HYPERCALCIURIA AND PREMATURITY

A congenital subtype of hypokalemic tubular disorders in 5 children (age 8 m to 4 ys) is described with many features resembling Bartter's syndrome. Additional features are: Prenatal onset with polyhydramnios and premature labor; failure to thrive; life threatening crises of fever, diarrhea, renal electrolyte and water wasting (however with normal renal chloride reabsorption); hypercalciuria, nephrocalcinosis and osteopenia. Renal PGE2 activity was monitored by mass spectrometric determination of urinary PGE2, and systemic PGE2 activity by a major urinary metabolite (PGE-M). The pathogenetic role of PGE2 is supported by withdrawal of PG synthesis inhibitors (PGSI) indomethacin or aspirin.Prolonged indomethacin treatment significantly improved the affected children's general condition. We conclude that renal as well as systemic PGE2 hyperactivity ranks high in the pathogenetic chain of events in this complex tubular disorder.

The role of prostaglandins in human hypertension.

A large body of evidence supports the concept that prostaglandins (PG) are importantly involved in arterial pressure regulation. Various PGs, especially PGE2 and prostacyclin (PGI2) may influence blood pressure through control of vascular tone, sodium excretion, and renin release. Inhibition of PG synthesis by nonsteroidal antiinflammatory drugs (NSAID) augments the vasoconstrictor response to exogenous pressors such as angiotensin II, arginine vasopressin (AVP), and fludrocortisone. The acute administration of NSAID to either normotensive or untreated hypertensive subjects results in an increase in arterial pressure and peripheral resistance; long-term administration, however, is associated with little or no change in blood pressure, possibly because of a reduction in cardiac output. Although NSAID have little influence on blood pressure in normotensive subjects or untreated hypertensives, inhibition of PG synthesis blunts or abolishes the antihypertensive effect of most antihypertensive agents. NSAID antagonize the vasodepressor action of diuretics, beta-adrenoreceptor antagonists, vasodilators, and converting enzyme inhibitors. Consequently, potent NSAID should be used with caution, if at all, during treatment of hypertensive patients. Numerous studies have examined renal PG production in essential hypertension (EH). The majority have demonstrated reduced basal and stimulated urinary PGE2 excretion in EH compared to normotensive subjects, but there is substantial overlap. Nevertheless, renal PGE2 synthesis is significantly decreased in approximately one-third of patients with EH. A recent innovative approach to arterial pressure regulation has focused on dietary supplementation with polyunsaturated fatty acids (PUFA), especially linoleic acid and eicosapentaenoic acid. Several groups have demonstrated that long-term dietary supplementation with PUFA reduces blood pressure in both normotensive individuals and in patients with EH.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of iron overload on urinary excretion of immunoreactive prostaglandin E 2

The effect of in vivo lipid peroxidation on the excretion of immunoreactive prostaglandin E 2 (PGE 2) in the urine of rats was studied. Weanling, male Sprague-Dawley rats were fed a vitamin E-deficient diet containing 10% tocopherol-stripped corn oil (CO) or 5% cod liver oil (CLO) with or without 40 mg dl-α-tocopheryl acetate/kg. To induce a high, sustained level of lipid peroxidation, some rats were injected intraperitoneally with 100 mg of iron as iron dextran after 10 days of feeding. Iron overload stimulated in vivo lipid peroxidation in rats, as measured by the increase in expired ethane and pentane. Dietary vitamin E reversed this effect. Rats fed the CLO diet excreted 9.5-fold more urinary thiobarbituric acid-reactive substances (TBARS) than did rats fed the CO diet. Iron overload increased the excretion of TBARS in the urine of rats fed the CO diet, but not in urine of rats fed the CLO diet. Dietary vitamin E decreased TBARS in the urine of rats fed either the CO or the CLO diet. Iron overload decreased by 40% the urinary excretion of PGE 2 by rats fed the CO diet, and dietary vitamin E did not reverse this effect. Iron overload had no statistically significant effect on urinary excretion of PGE 2 by rats fed the CLO diet. A high level of lipid peroxidation occurred in iron-treated rats, as evidenced by an increase in alkane production and in TBARS in urine in this study, and by an increase in alkane production by slices of kidney from iron-treated rats in a previous study [ V. C. Gavino, C. J. Dillard, and A. L. Tappel (1984) Arch. Biochem. Biophys., 233, 741–747]. Since PGE 2 excretion in urine was not correlated with these effects, lipid peroxidation appears not to be a major factor in renal PGE 2 flux.

Aminoglycoside treatment and renal prostaglandin excretion in premature infants.

During prospective studies of indomethacin treatment of symptomatic patent ductus arteriosus, the question arose whether aminoglycosides alter renal prostaglandin metabolism. Adopting the matched-pair method, we retrospectively analyzed creatinine clearances, urine output and renal PGE2 and PGF2 alpha excretion in preterm infants with and without aminoglycosides. No consistent differences of any of these parameters within the matched pairs could be demonstrated. Indomethacin induced comparable reductions of creatinine clearances in patients with and without aminoglycoside pretreatment. Discrepancies with animal studies and clinical implications of these results are discussed.

Selective inhibition of renal thromboxane biosynthesis increased sodium excretion rate in normal and saline-loaded rats.

The excretion rates of renal thromboxane B2 (TXB2) and 6-ketoPGF1 alpha, the stable chemical metabolites of thromboxane A2 (TXA2) and prostaglandin I2 (PGI2) respectively, PGE2 and sodium were determined in normal and saline-loaded rats treated with the thromboxane synthetase inhibitor imidazole. In normal rats the administration of imidazole in doses which did not affect renal 6-keto-PGF1 alpha and PGE2 excretion but selectively inhibited renal TXB2 excretion, significantly increased the sodium excretion rate. Volume expansion with saline increased renal PGE2 and 6-ketoPGF1 alpha excretion but did not alter renal TXB2 excretion. The increase in renal prostaglandin excretion was accompanied by an increased sodium excretion rate. The administration of imidazole to saline-loaded animals also decreased renal TXB2 excretion but did not alter the increased excretion of renal PGE2 and 6-ketoPGF1 alpha. This reduction in renal thromboxane biosynthesis by imidazole further increased the sodium excretion rate. We suggest that TXA2 is a potent antinatriuretic factor as well as the most potent vasoconstrictor agent known.