Renal Prostaglandin Synthesis Research Articles

Prostaglandins and the kidney

This review provides a summary and assessment of research involving renal prostaglandins. Arachidonic acid released from phospholipids is converted by prostaglandin cyclo-oxygenase in the kidney to PGF2, PGF2alpha, PGD2, and, possibly, to PGI2 and thromboxane A2. Production of PGE2 and PGF2alpha is predominately but not exclusively in the medulla, whereas degradative enzymes are present in both cortex and medulla. Prostaglandins enter the tubular lumen by facilitated transport and are partially reabsorbed from the urine in the distal nephron. Urine prostaglandins probably reflect renal synthesis. PGE2 and endoperoxides stimulate and PGF2alpha and indomethacin inhibit renal renin synthesis. In response to ischemia, vasoconstriction, or angiotensin II the kidney increases prostaglandin synthesis to modulate renal vascular resistance. In conscious animals or man no role has been established for prostaglandins in the maintenance of basal renal blood flow or renal sodium excretion. PGE influences renal water excretion by inhibiting the action vasopressin. Despite conflicting data there is evidence that renal prostaglandins are involved either primarily or secondarily in many types of hypertension. Inhibitors of prostaglandin cyclooxygenase have been used with success in Bartter's syndrome. Conflicting results in many areas of investigation may be resolved by the use of more accurate and reliable assays, careful handling of samples, and the use of urine to further investigate renal prostaglandin synthesis.

The effect of prostaglandin synthesis inhibitors on renal blood flow distribution in conscious rabbits.

1. We have studied the effects of two prostaglandin synthesis inhibitors on renal cortical blood flow distribution in conscious rabbits. 2. Renal blood flow distribution was estimated by means of radioactive microspheres injected into chronically implanted left atrial cannulae. Cardiac output was measured by a thermodilution technique. 3. Measurements were made in groups of animals treated with either indomethacin, meclofenamate or control injections of phosphate buffer. 4. A method of microtome slicing of the renal cortex was developed to standardize measurements. Microtome sections were grouped into inner, middle and outer zones. After both indomethacin and meclofenamate there was a reduction in total renal blood flow with a redistribution of flow from inner to outer cortex. 5. Estimated renal vascular resistance rose in all three cortical zones. 6. The data support the hypothesis that renal prostaglandin synthesis is necessary for maintaining flow to the deep cortex. It is suggested that renal prostaglandins may also influence flow in more superficial zones. 7. Estimated total systemic vascular resistance was increased both with meclofenamate and indomethacin, suggesting an inhibiting effect of prostaglandins on arteriolar tone throughout a major part of the systemic circulartion.

Unmasking of thromboxane A2 synthesis by ureteral obstruction in the rabbit kidney.

THE rabbit kidney has a high capacity for prostaglandin biosynthesis. The major renal prostaglandin released in response to various stimuli is PGE2, a vasodepressor prostaglandin1 thought to have a role in the regulation of intrarenal blood flow2. Although renal prostaglandin synthesis may initiate a reduction in vascular resistance of the kidney in response to reduced perfusion pressure, it has not been possible to establish a functional role for renal prostaglandins as mediators of increased vascular resistance evoked by augmented renal perfusion pressure. An increase in renal resistance, if related to changes in the rate of synthesis of endogenous substances, implies the biosynthesis of a vasoconstrictor or suppression of the basal production of a vasodepressor material. Unilateral ureteral obstruction (model of hydronephrosis) in the dog, rat and rabbit is initially associated with a decrease in renal resistance which is followed by a fall in GFR and renal blood flow3,4 by 24 h post-occlusion. The initial renal vasodilator phase may be associated with enhanced renal basal PGE2 synthesis and markedly facilitated PG release in response to hormone stimulation5. Here we report the observation that the ureter-obstructed kidney may be producing a natural vasoconstrictor material.

In vivo effect of indomethacin to potentiate the renal medullary cyclic AMP response to vasopressin.

In a previous study we demonstrated that indomethacin potentiated the hydro-osmotic action of vasopressin in vivo. It was hypothesized that this action of indomethacin was due to its ability to suppress renal medullary prostaglandin synthesis, since in vitro studies have suggested that prostaglandins interfere with the ability of vasopressin to stimulate production of its intracellular mediator, cyclic AMP. In the present study this hypothesis was tested in vivo. Anesthetized rats undergoing a water diuresis were studied. In a control group, bolus injections of 200 muU of vasopressin caused a rise in urinary osmolality (Uosm) from 124 +/- 6 to 253 +/- 20 mosmol/kg H2O (P less than 0.005). In a group treated with 2 mg/kg of indomethacin the same dose of vasopressin caused a significantly greater (P less than 0.001) rise in Uosm from 124 +/- 7 to 428 +/- 19 mosmol/kg H2O. Medullary tissue cyclic AMP rose from 9.4 +/- 0.9 to 13.4 +/- 1.7 (P less than 0.05) pmol/mg tissue protein after vasopressin administration in animals receiving no indomethacin, while in indomethacin-treated animals there was a significantly greater rise (P less than 0.001) in medullary cyclic AMP from 10.4 +/- 0.9 to 21.6 +/- 2.1 pmol/mg tissue protein in response to the vasopressin injections. In neither control animals nor indomethacin-treated animals were there significant changes in renal hemodynamics, as measured by clearance techniques. Indomethacin, when given alone, had no effect on Uosm or medullary tissue cyclic AMP. Indomethacin did, however, reduce medullary prostaglandin E content from 84.7 +/- 15.0 to 15.6 +/- 4.3 pg/mg tissue. This study has shown that indomethacin, in a dose which suppresses medullary prostaglandin content, potentiates the ability of vasopressin to increase the tissue content of its intracellular mediator, cyclic AMP. Indomethacin caused no demonstrable inhibition of cyclic AMP phosphodiesterase. Therefore, it seems likely that indomethacin enhanced the ability of vasopressin to increase medullary cyclic AMP levels by causing an increased production rather than decreased destruction of the nucleotide. We conclude that this action of indomethacin contributes to its ability to potentiate the hydro-osmotic action of vasopressin in vivo. A corollary to this conclusion is that endogenous medullary prostaglandin E's may be significant physiological modulators of the renal response to vasopressin.

Effect of indomethacin and sodium meclofenamate on the renal concentrating defect in experimental enterococcal pyelonephritis in rats.

The present studies have confirmed a severe urinary concentrating defect early in the course of experimental enterococcal pyelonephritis. This defect in maximum concentrating ability was almost completely reversed immediately following indomethacin or sodium meclofenamate intravenously. This effect of indomethacin and sodium meclofenamate was transient and was not associated with a fall in numbers of enterococci per gram of kidney. Injection of indomethacin or sodium meclofenamate in noninfected rats had no effect on maximum renal concentrating ability. The potential mechanisms by which indomethacin and sodium meclofenamate, inhibitors of renal prostaglandin synthesis, could reverse a defect in maximum urinary concentration are discussed.

Renal prostaglandin synthesis in the spontaneously hypertensive rat.

The precise role of the kidney in spontaneous experimental hypertension is unknown. We have analyzed the rates of renal prostaglandin synthesis by utilizing a spontaneously hypertensive rat model. The synthetic rate of prostaglandin E2, prostaglandin F2alpha, and prostaglandin A2-like products was measured in vitro with renal microsomes. In the rabbit and rat there is a steep gradient of microsomal prostaglandin synthetase from papilla to cortex with highest activities in the papilla. Comparison of the activity of prostaglandin synthetase in medullary microsomes form normotensive and hypertensive rats showed accelerated synthesis in the spontaneously hypertensive rat. These differences appeared after several months of age, were statistically significant from 3 mo of age and, on the average, represented at least a twofold increase of in vitro activity. All classes of prostaglandins were involved with increased synthesis of prostaglandin E2, prostaglandin F2alpha and prostaglandin A2-like material. These data reenforce and extend previous work showing alterations of granularity and presumably prostaglandin synthesis in renal medullary intersitital cells in various experimental hypertensions. We also measured renal tissue content of prostaglandin E and prostaglandin A-prostaglandin B by radioimmunoassay. Swift and careful handling of the tissue was necessary to avoid extensive postmortem synthesis of prostaglandins. In rapidly-frozen medullary tissue only prostaglandin E was detectable in concentrations ranging from 10 to 200 pg/mg tissue. No significant differences were found in the medullary content of prostaglandin E in the control and hypertensive rats despite the increased rates of enzymatic synthesis. We conclude that renal prostaglandin synthesis is increased in renal medullary microsomes obtained from spontaneously hypertensive rat. This apparently occurs in response to the progressive development of hypertension since young animals did not show an increase Renal tissue prostaglandin E content did not increase and therefore appears to be a poor index of enhanced prostaglandin synthesis.

Bartter's syndrome: A disorder characterized by high urinary prostaglandins and a dependence of hyperreninemia on prostaglandin synthesis

Urinary prostaglandins E 2 and F 2∝ were measured by gas chromatography-mass spectrometry in three adult women and an adolescent girl with Bartter's syndrome. On a constant metabolic diet prostaglandin E 2 ranged from 293 to 1,221 ng/day (mean, 640 ng/day) and exceeded the normal range for adults of 76 to 281 ng/day in all patients. Prostaglandins F 2∝ ranged from 291 to 1,061 ng/day (mean, 747 ng/day) in the adult women. Only in a young girl did prostaglandins F 2∝ (1,677 ng/day) clearly exceed the normal range for adults of 422 to 871 ng/day. Treatment with indomethacin, which decreased urinary prostaglandin E-like material by 69 per cent or more, did not affect blood pressure. Plasma renin activity, which ranged from 5.2 to 22.2 ng/ml/hour (patients supine) and from 23.3 to 30.4 ng/ml/hour (patients upright), and urinary aldosterone, which ranged from 14.0 to 45.6 ng/day, decreased by 79, 65 and 52 per cent, respectively. The clearance of creatinine was lower for the eight or nine days of treatment, the balances of sodium and potassium were positive, and serum potassium was higher than in control. Ibuprofen, an inhibitor of prostaglandin synthetase which differs in structure from indomethacin, produced metabolic effects which were qualitatively similar to those of indomethacin. The results indicate that the renal synthesis of prostaglandins is increased in Bartter's syndrome and that prostaglandins mediate the hyperreninemia and hyperaldosteronism which characterize the disorder. The overproduction of prostaglandins by the kidney could be a proximal cause of the syndrome, or secondary to intrarenal changes of an unknown nature. This study provides additional evidence for an important role for prostaglandins in the release of renin.

The effect of indomethacin on proteinuria and kidney function in the nephrotic syndrome.

In 19 nephrotic patients on a dietary intake of 20 mEq sodium/24 hours, indomethacin caused an immediate decrease in glomerular filtration rate (GFR) and urinary protein excretion, an effect completely reversible upon withdrawal of the drug. As a consequence of lower protein excretion, there was eventually a rise in GFR. It is proposed that the therapeutic effect of indomethacin in nephrotic syndrome is caused by its inhibiting action on renal prostaglandin synthesis, thereby potentiating the effect of the renin-angiotensin system on the kidney. The difference between the decrease in GFR (mean 35%) and proteinuria (mean 55%) and the more selective proteinuria during indomethacin administration may be explained by quantitative and qualitative differences in protein leakage between outer cortical and inner cortical nephron populations.

Renal prostaglandin synthesis in hypertension induced by deoxycorticosterone and sodium chloride in the rat.

1. The role of renal medullary prostaglandin E has been examined in rats with hypertension induced by sodium chloride and deoxycorticosterone (salt-DOC). 2. Synthesis of prostaglandin E was normal in early salt-DOC hypertension. Indomethacin exacerbated the hypertension, and depressed synthesis of prostaglandin E equally in hypertensive and control rats. 3. Synthesis of prostaglandin E was depressed in rats with late salt-DOC hypertension. 4. The results lend support to the concept that prostaglandin E is involved in the regulation of arterial pressure.

Mechanisms regulating renin release.

Mechanisms regulating renin release.

Renal prostaglandin synthesis in the Goldblatt hypertensive rat.

The role of prostaglandins in blood pressure regulation was studied in normal rats and in animals with renal artery constriction. The effects of chronic inhibition of prostaglandin (PG) synthesis on arterial pressure were observed, and renal medullary PG synthesis was measured in vitro. The prostaglandin synthetase inhibitor indomethacin was given in a dose of 2 mg/kg/day by mouth to one of two groups of male Wistar rats with a unilateral renal artery constriction and the other kidney untouched, and to one of two sham-clipped groups. Systolic blood pressures were higher in indomethacin-treated clipped rats than in non-indomethacin-treated clipped animals, and at 18 days averaged 188 mm Hg (plus or minus SEM 5.9, n = 36) and 162 mm Hg (plus or minus SEM 7.6, n = 34), respectively (P less than 0.005 for data pooled from two experiments). Indomethacin did not affect pressures of sham-clipped animals treated for 40 days. Analysis of PG synthesis by gas-liquid chromatography in renal medullary slices incubated for 30 minutes in Krebs-Henseleit buffer showed: (1) 40% suppression of PGE synthesis in hypertensive animals (P less than 0.001): (2) no differences between clipped and untouched kidneys; (3) chronic indomethacin treatment did not affect PGE synthesis in the in vitro buffer system; and (4) no PGA synthesis was detected. In a further experiment in which medullary slices were incubated in plasma of rats treated with equivalent doses of indomethacin, PGE synthesis was suppressed by 35%. The experiments support the concept that prostaglandins modulate pressor mechanisms which come into play when renal blood flow is drastically reduced. The effects could be mediated by PG synthesis in the kidney and/or in other systemic vascular beds.

Urinary prostaglandins. Identification and origin.

Human urine was analyzed by mass spectrometry for the presence of prostaglandins. Prostaglandin E2 and F2alpha were detected in urine from females by selected ion monitoring of the prostaglandin E2-methylester-methoxime bis-acetate and the prostaglandin F2alpha-methyl ester-Tris-trimethylsilylether derivative. Additional evidence for the presence of prostaglandin F2alpha was obtained by isolating from female urine an amount of this prostaglandin sufficient to yield a complete mass spectrum. The methods utilized permitted quantitative analysis. The origin of urinary prostaglandin was determined by stimulating renal prostaglandin synthesis by arachidonic acid or angiotensin infusion. Arachidonic acid, the precursor of prostaglandin E2, when infused into one renal artery of a dog led to a significant increase in the excretion rate of this prostaglandin. Similarly, infusion of angiotensin II amide led to a significantly increased ipsilateral excretion rate of prostaglandin E2 and F2a in spite of a simultaneous decrease in the creatinine clearance. In man, i.v. infusion of angiotensin also led to an increased urinary eliminiation of prostaglandin E. These results show that urinary prostaglandins may originate from the kidney, indicating that renally synthesized prostaglandins diffuse or are excreted into the tubule. Thus, urinary prostaglandins are a reflection of renal prostaglandin synthesis and have potential as a tool to delineate renal prostaglandin physiology and pathology.

Indomethacin enhancement of glycerol-induced acute renal failure in rabbits

Seventy-three rabbits (2 to 3 kg in weight) were studied during a control period and after receiving 50% glycerol (G) or mercuric chloride (M) with or without indomethacin (I) (controls received the diluent used for I). Plasma creatinine, plasma renin activity, blood pressure, sodium and potassium concentrations, hematocrit value, urinary output, body wt and histologic appearance of the kidney were determined. I enhanced the incidence and severity of the acute renal failure produced by G but failed to aggravate that produced by M. Because the dose of I used in this study blocked the synthesis of renal prostaglandins in the rabbit, we suggest that renal prostaglandins protect against the development of G-induced acute renal failure (a circulatory type of renal failure) in this animal model. Furthermore, the failure of I to aggravate M-induced acute renal failure indicates that it is unlikely that I aggravates G-induced acute renal failure by a direct nephrotoxic effect. No evidence was found for other possible side actions of I being responsible for the observed aggravation.

Enhanced renal prostaglandin production in the dog. I. Effects on renal function.

The changes in renal function produced by endogenous synthesis of prostaglandins by the kidney were evaluated by infusing sodium arachidonate, the prescursor of the prostaglandins, into one renal artery of the dog. These changes were compared with those produced by similar infusions on performed prostaglandin (PG) E2 and F2alpha.PGE2given at 0.01-0.3 mug/kg min--1 produced dose-related increases in urine flow, sodium and potassium excretion, free water clearance, and renal blood flow. The glomerular filtration rage increased only at the lowest dose and the calculated filtration fraction fell. Arachidonic acid at 1.0-30.0 mug/kg min--1 similarly produced dose-related increases in electrolyte excretion, but the increase in renal blood flow was much less than that produced by PGE2 and there were no changes in glomerular filtration rate, filtration fraction, or free water clearances. PGF2alpha had essentially no effects at infusion rates of 0.03-1.0 mug/kg min--1. All renal effects of arachidonic acid were inhibited by simultaneous infusions of an inhibitor of prostaglandin synthetase, 5, 8, 11,14-eicosatetraynoic acid (20:4). None of the effects produced by PGE2 were inhibited by 20:4. These results indicate that enhanced endogenous renal prostaglandin synthesis, which can be produced by arachidonate infusion, results in significant alterations of renal function. This finding strengthens the hypothesis that renal prostaglandins formed in vivo have physiological importance as regulators of renal function.

Specific stimulation and inhibition of renal prostaglandin release by angiotensin analogs.

Specific stimulation and inhibition of renal prostaglandin release by angiotensin analogs.

Release of prostaglandin-like material from dog kidney during nerve stimulation

Canine kidneys were autoperfused in situ at constant flow in 28 experiments. Renal venous effluent was examined for (PLM) prostaglandin-like material following acidic lipid extraction and thin layer chromatography or by continuous bioassay utilizing the bloodbathed organ technique. There was a low basal efflux of PLM from the kidney which was markedly enhanced during the renal vascular constriction elicited by renal nerve stimulation at 2-10 cycles/second or by infusion of norepinephrine. The PLM was tentatively identified as an E-type prostaglandin based on chromatographic behavior and bioassay. The present study indicates that PLM is released from the dog kidney during an increase in renal vascular resistance. Release is not necessarily dependent upon changes in total renal blood flow although alterations in the distribution of intrarenal blood flow might be involved. (authors)