Urinary 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin-F1α in healthy post-menopausal and pre-menopausal women receiving aspirin 100 mg.

The prevalence of cardiovascular diseases in women increases sharply after menopause. In postmenopausal women, thromboxane production increases while prostacyclin decreases. Low dose aspirin reduces the production of both thromboxane and prostacyclin. The present study was an open-label clinical trial with two parallel groups of 15 premenopausal women and 15 postmenopausal women. Twenty-four hours urine was collected from each subject before and after aspirin 100 mg daily for 7 days. The concentration of thromboxane and prostacyclin was measured as their metabolites (11-dehydro-thromboxane B(2) and 2,3-dinor-6-keto-prostaglandin-F(1α)) in urine using enzyme immunoassay methods. This study showed that aspirin significantly reduced thromboxane in both groups with significantly larger percentage reduction in postmenopausal women compared to premenopausal women (73.32 vs. 61.13%, p = 0.021). This study also showed that aspirin reduced prostacyclin significantly in both groups, but the percentage reduction between the groups was not significantly different. The decrease in the ratio of 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) should be compared to assess aspirin efficacy as an antithrombotic. Calculation of the ratio of 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) before aspirin consumption was higher in postmenopausal women than in premenopausal women. The decrease in 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) ratio by aspirin was greater in postmenopausal women than in premenopausal women (1.91 vs. 0.17; p = 0.022). It was concluded that aspirin reduced thromboxane and prostacyclin significantly in each group with significant 11-dTXB(2) percentage reduction between groups and non-significant 2,3-dinor-6-keto-PGF(1α) percentage reduction between groups, but reduced the 11-dTXB(2)/2,3-dinor-6-keto-PGF(1α) ratio much larger in postmenopausal women compared to that in premenopausal women.

Disposition and metabolism of a novel prostanoid antiglaucoma medication, tafluprost, following ocular administration to rats.

The disposition and metabolism of tafluprost, an ester prodrug of the 15,15-difluoro-prostaglandin F(2alpha) antiglaucoma agent, have been studied in rats after ocular administration. Radioactivity was absorbed very rapidly into the eye and systemic circulation after a single ocular dose of 0.005% [(3)H]tafluprost ophthalmic solution, with maximum levels in plasma and most eye tissues occurring within 15 min. The absorption ratio of radioactivity was approximately 75%, suggesting the high availability of ocular administration of tafluprost. Approximately 10% of the dose was present in cornea at this time, and radioactivity concentrations in this tissue exceeded those in aqueous humor and iris/ciliary body throughout the 24-h study period. After repeated daily ocular doses, radioactivity levels remained greatest in cornea, followed by iris/ciliary body that replaced aqueous humor as the eye tissue containing the second highest radioactivity concentration. In female rats, radioactivity was excreted equally between urine and feces after a single ocular dose, whereas in male rats more was excreted in feces, reflecting the greater biliary excretion in males rats (50% dose) compared with females rats (33% dose). Tafluprost was extensively metabolized in the rat, such that intact prodrug was not detected in plasma, tissues, or excreta by radio-high-performance liquid chromatography. On the other hand, the active moiety, tafluprost acid, was the only noteworthy radioactive component in cornea, aqueous humor, and iris/ciliary body for at least 8 h after the ocular dose, and it was also a major plasma metabolite in early time points. The gender differences in conjugation reactions resulted in the differences in the excretion.

Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects.

Acetylation of platelet cyclooxygenase by oral aspirin is dose dependent and cumulative with repeated administration. However, no single dose of aspirin has been found to be completely selective of platelet thromboxane (TX) synthesis inhibition in man. We determined the dose dependence, cumulative nature and selectivity of aspirin effects on platelet TXB(2) and renal prostaglandin (PG) and prostacyclin (PGI(2)) production. We measured, by radioimmunoassay, serum TXB(2) levels after whole blood clotting and urinary excretion of PGE(2), PGF(2alpha), and 6-keto-PGF(1alpha), before and after single or repeated oral aspirin doses given to 46 healthy subjects. Single doses of 6-100 mg aspirin resulted in a linear (r = 0.92, P < 0.01) inhibition of platelet TXB(2) production, ranging from 12 to 95% after 24 h. A daily dose of 0.45 mg/kg given for 7 d produced a cumulative and virtually complete inhibition of platelet TXB(2) production, without significantly reducing the urinary excretion of PGE(2), PGF(2alpha), and 6-keto-PGF(1alpha) in both healthy men and women. The platelet inhibitory effect of this regimen was maintained unaltered throughout 1 mo of therapy, with no evidence of cumulative inhibition of renal PG-synthesis. Moreover, furosemide-induced renal PGI(2) synthesis and renin release were unaffected by chronic low-dose aspirin. Following cessation of aspirin therapy, platelet TXB(2) production returned toward control values at a similar rate as after a single higher dose. WE CONCLUDE THAT IN HEALTHY SUBJECTS: (a) aspirin causes a dose-dependent inhibition of platelet TXA(2) production, with no obvious sex-related difference; (b) the inhibitory effect of daily low-dose aspirin is cumulative on platelet TXA(2) but not on renal PG-synthesis; (c) during chronic low-dose aspirin therapy, renal PGI(2)-producing cells are readily activable by furosemide at a time of virtually complete suppression of platelet cyclooxygenase activity.

Functional significance of renal prostacyclin and thromboxane A2 production in patients with systemic lupus erythematosus.

We have examined the urinary excretion of stable immunoreactive eicosanoids in 23 female patients with systemic lupus erythematosus (SLE), 16 patients with chronic glomerular disease (CGD), and 20 healthy women. SLE patients had significantly higher urinary thromboxane B2 (TXB2) and prostaglandin (PG) E2 excretion and significantly lower 6-keto-PGF1 alpha than did healthy women. In contrast, CGD patients only differed from controls for having reduced 6-keto-PGF1 alpha excretion. The group of SLE patients with active renal lesions differed significantly from the group with inactive lesions for having a lower creatinine clearance and urinary 6-keto-PGF1 alpha and higher urinary TXB2. Higher urinary TXB2 excretion was associated with comparable platelet TXB2 production in whole blood, undetectable TXB2 in peripheral venous blood, and unchanged urinary excretion of 2,3-dinor-TXB2. A significant inverse correlation was found between urinary TXB2 and creatinine clearance rate (CCr). In contrast, the urinary excretion of 6-keto-PGF1 alpha showed a significant linear correlation with both CCr and para-aminohippurate clearance rate (CPAH). In four SLE and seven CGD patients, inhibition of renal cyclooxygenase activity by ibuprofen was associated with a significant reduction in urinary 6-keto-PGF1 alpha and TXB2 and in both CCr and CPAH. However, the average decrease in both clearances was 50% lower in SLE patients than in CGD patients, when fractionated by the reduction in urinary 6-keto-PGF1 alpha or PGE2 excretion. We conclude that the intrarenal synthesis of PGI2 and TXA2 is specifically altered in SLE. Such biochemical alterations are associated with changes in glomerular hemodynamics and may play a role in the progression of SLE nephropathy.

Attenuation of angiotensin II- and III-induced aldosterone release by prostaglandin synthesis inhibitors.

The effect of two prostaglandin synthesis inhibitors, indomethacin and meclofenamate, on angiotensin II (AII)- and III (AIII)-induced aldosterone release was studied in normal and sodium-depleted conscious rats and in adrenal capsular cell suspensions obtained from normal rats. In normal rats, in vivo AII and AIII were equipotent in causing dose-related increases in serum aldosterone concentrations. Indomethacin decreased the basal serum aldosterone levels by 50% and serum renin levels by 43%. In addition, the steroidogenic effects of AII and AIII were reduced by 45 and 63% with 3 mg/kg of indomethacin and 63 and 73% with 10 mg/kg, respectively. In contrast, meclofenamate failed to alter basal serum levels of aldosterone or AII-stimulated aldosterone release but inhibited serum renin levels by 27% and the aldosterone-stimulating effect of AIII by 99%. Indomethacin (3 mg/kg) and meclofenamate (2 mg/kg) inhibited urinary prostaglandin (PG)E(2) and PGF(2alpha) excretion by 63 and 52% and 37 and 31%, respectively. Both inhibitors significantly decreased the adrenal capsular PGE(2) and PGF(2alpha) content and the conversion of [(14)C]arachidonate to [(14)C]PGE(2) and [(14)C]PGF(2alpha). In sodium-depleted rats, indomethacin produced similar effects reducing the control serum aldosterone levels by 29%, AII-stimulated aldosterone by 47%, and completely suppressing the aldosterone response to AIII without altering serum renin activity. In adrenal cell suspensions, similar results were observed with indomethacin inhibiting basal and AII- and AIII-stimulated aldosterone release by 29, 81, and 93%, respectively. Meclofenamate failed to alter basal and AII-stimulated aldosterone release but inhibited that stimulated by AIII by 86%. The present findings suggest that prostaglandins modulate the effects of the renin-angiotensin system by stimulating the release of renin from the kidney and augmenting the steroidogenic effects of AII and AIII in the adrenal cortex.

Role of renal prostaglandins in sympathetically mediated renin relase in the rat.

Renal prostaglandins (PG) appear to mediate renin release due to stimulation of the intrarenal baroreceptor, but not that due to activation of the macula densa. However, as the role of PG in sympathetically mediated renin release remains unclear, a possible interrelationship between these factors was examined in conscious rats. Hydralazine increased the serum renin levels from 3.1+/-0.8 to 16.7+/-3.0 ng/ml per h at a dose of 1 mg/kg. Indomethacin (5 mg/kg) suppressed urinary PGE(2) and PGF(2alpha) excretion by 89 and 74%, respectively, arachidonate hypotension by 82%, and inhibited the elevated renin levels from hydralazine by 100% without altering the hypotensive effect of the drug. Another PG synthetase inhibitor, meclofenamate, was also effective in attenuating hydralazine-induced renin release, urinary PGE(2) and PGF(2alpha) excretion, and arachidonate hypotension. Isoproterenol, a nonselective beta-adrenergic agonist, increased heart rate, lowered blood pressure, and also stimulated the release of renin when administered intraperitoneally. However, intrarenal infusion of the drug only resulted in increased renin release. Indomethacin inhibited isoproterenol-induced renin release by 66 and 67%, respectively, without altering the hemodynamic effects associated with the intraperitoneal administration of the drug. The selective beta(1) agonist, H133/22, increased the release of renin and heart rate in a dose-related manner without altering blood pressure. H133/22-induced renin release was inhibited by 80% by indomethacin pretreatment. Finally, intrarenal infusions of dibutyryl cyclic AMP (3 mg/kg per min) increased the serum activity from 4.1+/-0.2 to 20.4+/-3.9 ng/ml per h without altering mean arterial pressure. Indomethacin inhibited this renin response to dibutyryl cyclic AMP by 96%. Thus, renal PG appear to be important mediators of sympathetically stimulated renin release acting as a site distal to the beta-adrenergic receptor.

Modulating role for thromboxane in the tubuloglomerular feedback response in the rat.

Some studies have indicated that PGs can modulate the single nephron tubuloglomerular feedback (TGF) response. The aim of this study was to define the specific role of the vasoconstrictor PG, TX, by administration to rats of either vehicle (group 1; n = 20) or drugs that inhibit either cyclooxygenase (indomethacin [indo], 5 mg.kg-1, group 2, n = 17), TX synthetase (UK-38,485 [UK], 100 mg.kg-1, group 3, n = 19), or TX receptors (SQ-29,548 [SQ], 8 mg.kg-1, group 4, n = 14, or L-641,953 [L], 50 mg.kg-1, group 5, n = 8). Indo reduced excretion of the prostacyclin derivative 6-keto-PGF1 alpha and TXB2 and lowered whole kidney GFR and renal plasma flow, whereas UK lowered excretion of TXB2 only and did not change basal renal hemodynamics. The TGF response (assessed from reduction in proximal tubule stop-flow pressure (Psf, mmHg) during increases in perfusion of the loop of Henle (LH) from 0 to 40 nl.min-1) was unchanged after vehicle (9.8 +/- 0.5-10.9 +/- 1.0, NS) but blunted (P less than 0.001) by 40-65% in rats of groups 2-5 (indo, 11.1 +/- 1.0-4.4 +/- 0.7; UK, 9.0 +/- 0.8-4.8 +/- 0.7; SQ, 10.3 +/- 0.6-4.8 +/- 0.6; L, 10.7 +/- 0.5-6.7 +/- 1.3). This blunting was due to lower values for Psf at zero LH flow after indo, SQ, and L, and higher values of Psf at 40 nl.min-1 LH flow after indo and UK. The fall in single nephron GFR (SNGFR, nl.min-1) with increasing LH perfusion was unchanged after vehicle (10.9 +/- 2.8-11.2 +/- 0.8) but was blunted (P less than 0.05) by 45-55% in rats given indo (13.9 +/- 1.2-6.2 +/- 2.2) or UK (12.8 +/- 2.1-7.0 +/- 1.5). UK produced dose-dependent reductions in TXB2 excretion (IC50, 15 mg.kg-1) and inhibition of the TGF response (IC50: 30 mg.kg-1). After blockade of TX receptors by SQ, UK had no further affect on the TGF response. The fall in Psf at high LH flow was blunted (P less than 0.05) by indo and UK, whereas the rise in Psf at zero LH flow was blunted by indo, SQ, and L. In conclusion, endogenous TX generation can modulate the reductions in Psf and SNGFR during increased delivery of NaCl to the LH.

Angiotensin II-induced hypertension in the rat. Effects on the plasma concentration, renal excretion, and tissue release of prostaglandins.

We examined in rats the effects of intraperitoneal angiotensin II (AII) infusion for 12 d on urinary excretion, plasma concentration, and in vitro release of prostaglandin (PG) E2 and 6-keto-PGF1 alpha, a PGI2 metabolite. AII at 200 ng/min increased systolic blood pressure (SBP) progressively from 125 +/- 3 to 170 +/- 9 mmHg (P less than 0.01) and elevated fluid intake and urine volume. Urinary 6-keto-PGF1 alpha excretion increased from 38 +/- 6 to 55 +/- 5 and 51 +/- 7 ng/d (P less than 0.05) on days 8 and 11, respectively, of AII infusion, but urinary PGE2 excretion did not change. Relative to a control value of 129 +/- 12 pg/ml in vehicle-infused (V) rats, arterial plasma 6-keto-PGF1 alpha concentration increased by 133% (P less than 0.01) with AII infusion. Aortic rings from AII-infused rats released more 6-keto-PGF1 alpha (68 +/- 7 ng/mg) during 15-min incubation in Krebs solution than did rings from V rats (40 +/- 3 ng/mg); release of PGE2, which was less than 1% of that of 6-keto-PGF1 alpha, was also increased. Slices of inner renal medulla from AII-infused rats released more 6-keto-PGF1 alpha (14 +/- 1 ng/mg) during incubation than did slices from V rats (8 +/- 1 ng/mg, P less than 0.05), but PGE2 release was not altered. In contrast, AII infusion did not alter release of 6-keto-PGF1 alpha or PGE2 from inferior vena cava segments or from renal cortex slices. Infusion of AII at 125 ng/min also increased SBP, plasma 6-keto-PGF1 alpha concentration, and in vitro release of 6-keto-PGF1 alpha from rings of aorta and renal inner medulla slices; at 75 ng/min AII had no effect. SBP on AII infusion day 11 correlated positively with both 6-keto-PGF1 alpha plasma concentration (r = 0.54) and net aortic ring release (r = 0.70) when data from all rats were combined. We conclude that augmentation of PGI2 production is a feature of AII-induced hypertension. The enhancement of PGI2 production may be an expression of nonspecific alteration in vascular structure and metabolic functions during AII-induced hypertension, as well as the result of a specific effect of the peptide on the arachidonate-prostaglandin system.

The identification of 5beta,7alpha-dihydroxy-11-oxotetranor-prostane-1,16-dioic acid as a urinary metabolite of prostaglandin F2alpha in the rat.

5beta,7alpha-Dihydroxy-11-oxotetranor-prostane-1,16-dioic acid has been identified by gas chromatography-mass spectrometry as a urinary metabolite of [9beta-3H]prostaglandin F2alpha in the rat. This tetranor prostaglandin F derivative, which is the 5beta epimer of the major urinary metabolite of prostaglandin F2alpha, accounted for at least 2% of the total dose. Absence from the metabolite of tritium label at the C-5 position indicated the existence of a minor, previously unknown metabolic pathway by which prostaglandin Falpha derivatives may be converted by oxido-reduction into prostaglandins of Fbeta stereochemistry.

Prostaglandins E3 and F3 alpha are excreted in human urine after ingestion of n - 3 polyunsaturated fatty acids.

Prostaglandins E3 and F3 alpha, presumably of renal origin, were characterized for the first time in urine of volunteers after ingestion of n - 3 polyunsaturated fatty acids by combined gas chromatography-mass spectrometry. Quantitation of prostaglandins E3, E2, F3 alpha and F2 alpha using deuterated internal standards showed low levels of the 3 series prostaglandins in the control period. Levels of prostaglandins E3 and F3 alpha rose about 10-fold by the 12th week of the dietary trial and were still elevated 4-fold after a wash-out period of 20 weeks. Excretion of prostaglandins E2 and F2 alpha tended to be depressed in the 12th week of the dietary trial and rose again to control values after the wash-out period. Our data indicate that n - 3 polyunsaturated fatty acids are incorporated into the human kidney and are retained there for a long time. Prostaglandins E3 and F3 alpha may contribute to the observed favorable effects of marine oils rich in n - 3 polyunsaturated fatty acids on certain renal diseases.

Identification of the major metabolite of prostacyclin and 6-ketoprostaglandin F1 alpha in man.

Human volunteers were infused with 3H- and 2H-labeled prostacyclin or 3H-labeled 6-ketoprostaglandin F1 alpha and, in separate experiments, with the unlabeled prostanoids. The urine was purified by different chromatographic steps and finally separated into several fractions by high-performance liquid chromatography. The major fractions contained 20.5 and 23.0% of the eluted readioactivity for the metabolites of prostacyclin and 6-ketoprostaglandin F1 alpha, respectively. The structure of both metabolites was identified by gas-liquid chromatography-mass spectrometry as dinor-6-ketoprostaglandin F1 alpha. It is concluded that the major metabolite of prostacyclin and 6-ketoprostaglandin F1 alpha in man is dinor-6-ketoprostaglandin F1 alpha.

Estradiol is responsible for reduced renal prostaglandin dehydrogenase activity in female rats.

The contribution of sex steroids to sex-related differences in renal prostaglandin dehydrogenase activity and urinary prostaglandin excretion was examined in 7-8-week-old male and female rats subjected to sham-operation or gonadectomy at 3 weeks of age. Rats were injected subcutaneously twice over a 6-day interval with vehicle (peanut oil, 0.5 mg/kg) or with depot forms of testosterone (10 mg/kg), estradiol (0.1 mg/kg), progesterone (5 mg/kg), or with estradiol and progesterone combined (0.1 and 5 mg/kg). After the second injection, 24-h urine samples were collected for prostaglandin measurement by radioimmunoassay; the rats were killed, and renal and pulmonary prostaglandin dehydrogenase activities were determined by radiochemical assay. Renal prostaglandin dehydrogenase activity was 10-times higher in intact male rats than in intact females. Gonadectomy increased renal prostaglandin dehydrogenase activity 4-fold in females, but had no effect in males; estradiol, alone or combined with progesterone, markedly suppressed renal prostaglandin dehydrogenase activity in both sexes, while testosterone or progesterone alone had no effect. Pulmonary prostaglandin dehydrogenase did not differ between the sexes and was unaffected by gonadectomy or sex-steroid treatment. Intact female sham-operated rats excreted 70-100% more prostaglandin E2, prostaglandin F2 alpha, and 6-keto-prostaglandin F1 alpha in urine than did males; gonadectomy abolished the difference in urinary prostaglandin E2 excretion. Estradiol decreased urinary prostaglandin E2 in females but not in males; treatment with other sex steroids did not alter urinary prostaglandin excretion.

Salsalate exacerbation of chronic renal insufficiency. Relation to inhibition of prostaglandin synthesis.

Nonacetylated salicylates have not been reported to cause the hemodynamically mediated acute renal failure associated with nonsteroidal anti-inflammatory drug therapy. A 73-year-old woman with a creatinine clearance of 0.33 mL/s (20 mL/min), hypertension, and arteriosclerotic cardiovascular disease developed reversible renal insufficiency when her dose of salsalate was increased to 4.5 g/d (serum salicylate concentration, 2.22 mmol/L [30.7 mg/dL]). Under close observation the patient was re-treated with lower doses of salsalate while renal function and the urinary excretions of prostaglandins were monitored. The excretion of prostaglandin E2 decreased abruptly while the excretion of 6-keto-prostaglandin F1 alpha decreased more gradually as the dose of salsalate was increased. Renal function appeared to decline in parallel with the decrease in 6-keto-prostaglandin F1 alpha and recovered rapidly after discontinuation of salsalate therapy. Nonacetylated salicylates can cause a hemodynamically mediated acute renal failure in patients at risk for this nephropathy.

Dexamethasone does not inhibit antidiuretic hormone-stimulated prostaglandin production in vivo.

Glucocorticoids are potent inhibitors of prostaglandin (PG) release in vitro, but they fail to influence basal PG production in vivo. To test one possible explanation for this apparent discrepancy in the present study we investigated the effect of dexamethasone (DEX) on basal and antidiuretic hormone-stimulated renal PG synthesis in vivo. In long term experiments, Brattleboro diabetes insipidus rats were treated with DEX (250 micrograms kg-1 day-1) for 7 days, and the effects of deamino-8-D-arginine vasopressin were investigated on the fifth day of DEX treatment. Administration of deamino-8-D-arginine vasopressin was accompanied by a marked increase in PGE2 and PGF2 alpha excretion in both control and DEX-treated animals, but the response was significantly higher during DEX treatment. Furthermore, DEX, by itself, caused a significant increase in the excretion of both PGs. In short term experiments, diabetes insipidus rats received a 24-h iv infusion of DEX (1 mg kg-1 day-1), then renal PG synthesis was stimulated acutely by the infusion of arginine vasopressin (AVP) for 40 min. DEX treatment failed to inhibit basal PG excretion, and the AVP-induced enhancement of PGE2 and PGF2 alpha production was also identical in control and DEX-treated animals. DEX was ineffective in altering the hydroosmotic effect of AVP, confirming that intrarenal PG synthesis was not inhibited. We conclude that glucocorticoids in vivo do not inhibit anti-diuretic hormone-stimulated PG production, and thus, a differential effect of glucocorticoids on basal vs. stimulated PG synthesis cannot account for the discrepancy between in vivo and in vitro studies.

Biphasic effect of dexamethasone on urinary prostaglandins in rats: relation to alterations in renal medulla triglycerides and prostaglandin metabolism.

This study was designed to characterize the time course of the effects of dexamethasone (2.5 mg kg-1 week-1, sc) on the renal arachidonate-prostaglandin (PG) system and to define the effect of the steroid on the interstitial cells of the renal inner medulla (RIC). The RIC are rich in triglycerides, which, due to their high content of arachidonic acid, may be a source of arachidonate for PG synthesis during conditions of phospholipase inhibition. After 1 day of dexamethasone treatment, the urinary excretion of PGE2 and PGF2 alpha was reduced to about 50% of the control value (P less than 0.05), and angiotensin II-induced release of arachidonic acid and PGs from renal medulla slices was blunted (P less than 0.05). In contrast, dexamethasone treatment did not affect ionophore A23187-induced release of PGs and arachidonic acid from renal medulla slices. By day 3 of dexamethasone treatment, urinary excretion of PGE2 and PGF2 alpha had returned to control levels, and by days 5 and 14 the excretion rates of both were clearly increased (P less than 0.05). The rise in urinary PG excretion was accompanied by a reduction of renal 15-hydroxyprostaglandin dehydrogenase activity, augmentation of renal medulla microsomal PG synthetase activity, and diminution of renal medulla triglycerides, the latter associated with a reduction in the number of RIC and of RIC osmiophilic granules. This study demonstrates that the effects of dexamethasone on urinary PG are biphasic; this may reflect the changing balance between the opposing actions of the steroid on renal PG-synthesizing and catabolizing enzymes and the inhibitory effect on the synthesis of renal PG that is linked to activation of specific renal lipases by endogenous factors such as angiotensin II.

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.

Preeclampsia -- a state of prostaglandin deficiency? Urinary prostaglandin excretion, the renin-aldosterone system, and circulating catecholamines in preeclampsia.

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.

Initial mechanisms in hypertension after bilateral renal ischemia in the rat.

Cumulative water- and electrolyte balance, plasma creatinine (PC), plasma renin activity (PRA), urinary prostaglandins (PGs) E2, and F2alpha and kallikrein (K) were studied in 40 male Wistar CHbb THOM rats (250 +/- 4 g SE). A solid silver clip (0.25 mm lumen) was applied to both renal arteries in 18 animals; 13 rats were sham-operated and nine remained intact. The analyses were performed during a control period and up to 10 days after surgery. Blood pressure (BP) recorded on the 10th and 12th day of the study increased significantly in clipped rats with respect to sham rats (p less than 0.001);PC and PRA measured on the 11th day were not significantly different. A positive cumulative water "balance" )p less than 0.01) and sodium balance (p less than 0.02) was found in clipped rats when compared with sham rats in the first 5 days of the experimental period. Significantly higher values of PGE2 urinary excretion were observed in sham rats vs clipped rats on the 2nd and 5th day after surgery (p less than 0.02). On the 2nd day after surgery, K urinary excretion was significantly lower in clipped rats than in sham rats (p less than 0.02). No significant changes were observed in PGF2alpha excretion. The absence of significant difference in PRA 10 days after bilateral renal artery stenosis points to a lack of any fundamental role of circulating angiotensin II at this stage of the development of hypertension. The significant water- and salt retention in the first 5 days after clipping suggests that it might be involved in the pathogenesis of this model. Early changes in PGs E2 and F2alpha and K appear to be related more to intrarenal adjustments soon after surgery than to the increase in BP.

Effects of sulindac and indomethacin on renal prostaglandin synthesis.

We compared the effects of sulindac and indomethacin, the effects of two nonsteroidal anti-inflammatory drugs, on renal prostaglandin synthesis and renal function. Sulindac, 200 mg twice daily, indomethacin, 25 mg four times a day, or placebo were taken by 15 normal female subjects (five in each of three treatment groups). Indomethacin decreased renal excretion of prostaglandins PGE2, PGF2 alpha, and 6-keto-PGF1 alpha, but sulindac and placebo had no effect on renal prostaglandin excretion. Concomitant with the reduction of renal prostaglandin synthesis in the indomethacin group, sodium and chloride excretion decreased; sulindac and placebo had no discernible effects on urine electrolytes. Extrarenal cyclooxygenase activity, as assessed by platelet thromboxane beta 2 release, was inhibited by both sulindac and indomethacin. Plasma renin activity and plasma aldosterone levels fell in all groups as a result of positive sodium balance, but the decrements of aldosterone were greater after indomethacin and sulindac. None of the treatments altered glomerular filtration rate or renal plasma flow in these normal women. We conclude that in normal women renal prostaglandin synthesis and prostaglandin-dependent tubular functions such as Na and Cl reabsorption are relatively unaffected by doses of sulindac (200 mg twice daily) that inhibit nonrenal cyclooxygenase. This may reflect the capacity of oxidative enzymes in the kidney to convert the active sulfide metabolite of sulindac to the inactive prodrug sulindac sulfoxide.

Sulindac is not renal sparing in man.

We investigated the claimed renal-sparing effect of the cyclooxygenase inhibitor sulindac. Fifteen normal women following a diet of 50 mEq salt a day were randomly assigned to 5 days of either placebo, sulindac, 200 mg b.i.d., or indomethacin, 25 mg q.i.d., after first serving as their own controls. Renal effects were assessed by the excretion rate of prostaglandin (PG) E2 (an index of renal PG synthesis), sodium balance, plasma renin activity (PRA), and the response to furosemide. Systemic effects were assessed by collagen-induced platelet aggregation and thromboxane B2 formation and by the urinary excretion of a systemically formed metabolite of PGF2 alpha (PGF-M). Both sulindac and indomethacin resulted in a positive sodium balance and a reduction in 24-hour urinary PGE2 excretion (range -49% to -86%). Basal PRA was decreased by indomethacin only, but the increases in PRA and in urinary PGE2 excretion in response to furosemide were inhibited by both sulindac and indomethacin. Sulindac reduced the natriuresis induced by furosemide, and indomethacin reduced the rise in inulin clearance after furosemide. Thus the two nonsteroidal anti-inflammatory drugs had similar effects on the kidney. Indomethacin had a greater effect than sulindac on the inhibition of collagen-induced platelet aggregation and thromboxane synthesis and the two drugs had equivalent effects on the reduction of PGF-M excretion. Peak plasma drug concentration of indomethacin (1.9 +/- 0.4 microgram/ml) and sulindac sulfide (7.7 +/- 1.9 microgram/ml) were those associated with clinical efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)