Indomethacin reduces glomerular and tubular damage markers but not renal inflammation in chronic kidney disease patients: a post-hoc analysis

Under specific conditions non-steroidal anti-inflammatory drugs (NSAIDs) may be used to lower therapy-resistant proteinuria. The potentially beneficial anti-proteinuric, tubulo-protective, and anti-inflammatory effects of NSAIDs may be offset by an increased risk of (renal) side effects. We investigated the effect of indomethacin on urinary markers of glomerular and tubular damage and renal inflammation. We performed a post-hoc analysis of a prospective open-label crossover study in chronic kidney disease patients (n?=?12) with mild renal function impairment and stable residual proteinuria of 4.7±4.1 g/d. After a wash-out period of six wks without any RAAS blocking agents or other therapy to lower proteinuria (untreated proteinuria (UP)), patients subsequently received indomethacin 75 mg BID for 4 wks (NSAID). Healthy subjects (n?=?10) screened for kidney donation served as controls. Urine and plasma levels of total IgG, IgG4, KIM-1, beta-2-microglobulin, H-FABP, MCP-1 and NGAL were determined using ELISA. Following NSAID treatment, 24 h -urinary excretion of glomerular and proximal tubular damage markers was reduced in comparison with the period without anti-proteinuric treatment (total IgG: UP 131[38-513] vs NSAID 38[17-218] mg/24 h, p<0.01; IgG4: 50[16-68] vs 10[1-38] mg/24 h, p<0.001; beta-2-microglobulin: 200[55-404] vs 50[28-110] ug/24 h, p?=?0.03; KIM-1: 9[5]-[14] vs 5[2]-[9] ug/24 h, p?=?0.01). Fractional excretions of these damage markers were also reduced by NSAID. The distal tubular marker H-FABP showed a trend to reduction following NSAID treatment. Surprisingly, NSAID treatment did not reduce urinary excretion of the inflammation markers MCP-1 and NGAL, but did reduce plasma MCP-1 levels, resulting in an increased fractional MCP-1 excretion. In conclusion, the anti-proteinuric effect of indomethacin is associated with reduced urinary excretion of glomerular and tubular damage markers, but not with reduced excretion of renal inflammation markers. Future studies should address whether the short term glomerulo- and tubulo-protective effects as observed outweigh the possible side-effects of NSAID treatment on the long term.     

The urinary excretion of prostaglandins and thromboxane B2 in healthy volunteers: a study in males and females, and on the influence of seminal fluid contamination

Radioimmunoassay measurements of prostaglandins (PGs) E2, F2 alpha, 6-keto-PGF1 alpha and thromboxane (Tx) B2 in 24 h urine specimens from a male and a female healthy volunteer on several consecutive days revealed a dramatic increase of PGE2, PGF2 alpha, 6-keto-PGF1 alpha on days, upon which they had sexual intercourse; only TxB2 remained stable. Furthermore, the PGE2/PGF2 alpha ratio rose to values greater than 0.5 on days with sexual intercourse. This was found to be due to contamination of the urine samples by seminal fluid. Two 24 h urine samples from each of 26 healthy male and female volunteers (HV) revealed higher (p less than 0.01) mean PGE2 and PGF2 alpha values in males than in females. The results show that the interpretation of the urinary PG excretion as a measure of renal PG synthesis should be considered carefully, and that a PGE2/PGF2 alpha ratio greater than 0.5 indicates probable seminal contamination of urine.     

Basal prostaglandin synthesis by the isolated perfused rat kidney

In order to assess the main characteristics of the prostaglandin (PG) biosynthesis by the isolated perfused rat kidney, the urinary and venous outputs of PGE2, PGF2alpha, 6-keto-PGF1alpha and of thromboxane (Tx)B2 were followed during 120 min after an equilibration period of 30 min. Single pass kidneys were perfused with a Krebs-Henseleit solution added with Polygeline at a constant flow rate providing a perfusion pressure about 90 mm Hg. From the beginning of the study, major differences could be observed in the renal biosynthetic rate of the 4 PG studied which were mainly excreted into the venous effluent. During the perfusion, urinary and venous outputs of PGE2, PGF2alpha and of TxB2 remained stable whereas those of 6-keto-PGF1alpha sharply increased and were found inversely related to the glomerular filtration rate (r = -0.95; p n 0.001). Finally, the urinary and venous outputs of each of the four PGs studied were found positively related. It is concluded that the isolated perfused rat kidney is a valuable preparation for studying the biosynthesis of PGs and that, at least in thi model, the urinary excretion of PGs is a good index of their renal synthesis.     

Attenuation of hypotensive effect of propranolol and thiazide diuretics by indomethacin.

The effects of 100 mg indomethacin daily for three weeks on blood pressure and urinary excretion of prostaglandin F2 alpha were studied in a double-blind, placebo-controlled comparison of two groups of patients with essential hypertension, eight receiving propranolol and seven thiazide diuretics. Compared with placebo, adding indomethacin to the patients'' established antihypertensive treatment increased blood pressure by 14/5 Hg supine and 16/9 mm Hg erect in the patients receiving propranolol, and by 13/9 mm Hg supine and 16/9 mm Hg erect in the patients receiving thiazide diuretics (all p less than or equal to 0.05). The excretion of the major urinary metabolite of prostaglandin F2 alpha was reduced by 67% in the propranolol-treated patients and by 57% in those receiving a thiazide diuretic. Body weight increased by 0 . 8 kg (propranolol) and 1 . 1 kg (thiazide diuretic) when indomethacin was given, but there were no significant changes in creatinine clearance, urinary sodium excretion, or packed cell volume in either treatment group. These results suggest that products formed by the arachidonic acid cyclo-oxygenase contribute to the regulation of blood pressure during treatment with both propranolol and thiazide diuretics. Inhibition of the cyclo-oxygenase with indomethacin partially antagonises the hypotensive effect of these drugs.     

Acute prostaglandin reduction with indomethacin and chronic prostaglandin reduction with an essential fatty acid deficient diet both decrease plasma flow to the renal papilla in the rat

Renal distribution of prostaglandin synthetase is mainly medullary, whereas the major degrading enzyme, prostaglandin dehydrogenase is primarily cortical. This suggests that prostaglandins (PG) released from the renal medulla could affect the medullary blood vessels. In two different experiments we studied the role of PG in the regulation of renal papillary plasma flow in the rat. First study: PG synthesis were stimulated in 34 adult Sprague-Dawley rats by bleeding from the femoral artery 1% of the body weight over a period of 10 minutes. Following this, indomethacin (a PG inhibitor, 10 mg/kg i.v.) was given slowly and then renal papillary plasma flow was measured 25 minutes after the end of infusion. In 17 indomethacin rats the renal papillary plasma flow averaged 18.8 ml/100 g/minute, whereas it averaged 23.0 in 17 non-indomethacin rats given diluent, an 18% reduction (p less than .025). Second study: Male Sprague-Dawley rats were made prostaglandin deficient by fasting rats for one week, followed by 10% dextrose fluid for one week and subsequent institution of an essential fatty acid (EFA) deficient diet for two weeks. With urinary PG excretion in prostaglandin deficient rats 28 ng/24 hours compared to 149 ng in control rats, they could be considered as prostaglandin deficient. When renal papillary plasma flow was measured, the 16 prostaglandin deficient rats had a 16% lower papillary plasma flow than 16 control rats, 21.6 vs 25.6 (p less than .005). These results clearly demonstrate that PG inhibition in rats decreases plasma flow to the papilla, strongly suggesting that PG are vasodilators for the vessels supplying the renal papilla.     

Synergic effects of kallikrein-kinin and prostaglandins on renin release on infusion of isolated hog kidney with aldosterone

The effects of infusion of a large amount of aldosterone into the renal artery of isolated perfused hog kidney on the release of renin, prostaglandins (PG) and kinin and the excretion of urinary kallikrein were investigated. Infusion of aldosterone at a rate of 100 ng/min (100 to 800 ng/ml of perfusate) resulted in significant releases of renin, PG (PGE₂, 6-0-PGF_1α), and kinin and increase in urinary kallikrein. Infusion of aldosterone and an inhibitor of kallikrein, aprotinin, decreased the releases of renin, PG and kinin and infusion of aldosterone with indomethacin decreased the release of PG but increased that of kinin and urinary kallikrein without significant change in renin releases. These findings suggest that the release of renin by aldosterone may result from synergic effects of renal PG and the kallkrein-kinin system.     

Reversal of indomethacin-induced decreases in renal function by an isosterically-modified prostaglandin analog

A recently discovered isosterically-modified prostaglandin analog, 4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl ] propyl) benzoic acid, was studied in conscious Na-deficient dogs to determine if this compound could reverse the deleterious renal effects induced by inhibition of renal cyclooxygenase. Indomethacin (2 mg/kg i.v.) reduced renal function significantly in all dogs studied: GFR decreased from 38 +/- 3 to 26 +/- 1 ml/min (P less than 0.01) and ERPF from 124 +/- 15 to 79 +/- 8 ml/min (P less than 0.01). On separate occasions, the six dogs used in this study were treated with a saline placebo intravenously or with the PG analog (0.1 mg/kg i.v.) 60 min after receiving indomethacin. After placebo treatments renal function remained suppressed for the duration of observation (2 hours). After treatment with PG analog, GFR was restored to pre-indomethacin levels within 1 hour (36 +/- 3 ml/min) and remained at this level or higher for the duration of the experiment. ERPF was restored to pre-indomethacin levels within 30 min of PG analog injection (140 +/- 7 ml/min) and subsequently rose ml/min) for the duration of the experiment. Urinary electrolyte excretion was suppressed by indomethacin and despite the large increase in ERPF, Na excretion was not augmented by PG analog. This study demonstrates that a synthetic, isosterically-modified prostaglandin analog can effectively reverse the hemodynamic effects of non-steroidal antiinflammatory drug treatment on renal function while not affecting renal Na excretion.     

The effect of suppression of prostaglandin synthesis on renal function in rats with intact and reduced renal mass

The present study was undertaken to assess the role of prostaglandin system in the compensatory response to reduced nephron population, respective to renal function and electrolyte excretion. Intact and nephrectomized rats were divided in 4 groups: 1) rats pretreated with indomethacin, 2) rats pretreated with the vehicle of indomethacin, 3) rats pretreated with sulindac, and 4) rats pretreated with the vehicle of sulindac.In normal rats, indomethacin administration resulted in a mild decrease in creatinine clearance and a significant reduction of the urinary Na excretion. In the rats with reduced renal mass treated with indomethacin, the creatinine clearance did not differ from that in the control group. The 24 h urinary sodium excretion and the fractional excretion of sodium, however, were significantly lower in the indomethacin treated animals than in the control rats. No change in the creatinine clearance or in the sodium excretion was observed in all groups pretreated with sulindac.The urinary PGE₂ and thromboxane excretion was significantly lower in the indomethacin treated intact rats and the rats with reduced renal mass. Sulindac induced a slight decrease in urinary excretion of PGE₂ in intact rats. No significant change in urinary excretion of PGE₂ or thromboxane was seen after sulindac in the rats with reduced renal mass.The antinatriuretic effect of indomethacin was dissociated from changes in urine flow in all groups of animals, suggesting that the increase in Na reabsorption tool place in a water impermeable segment of nephron.These results suggest that the compensatory increase in urinary Na excretion per nephron in rats with reduced nephron population at least partly depends on an intact prostaglandin synthesis.     

Volume-induced natriuresis in healthy women: renal metabolism of prostacyclin and thromboxane, and physiological role of prostanoids

In healthy women submitted to a short-term expansion in extracellular fluid volume we have evaluated the urinary excretory profile of the stable metabolites of prostaglandin(PG) I2 and thromboxane(TX) A2, 6-keto-PGF1 alpha(6KPGF) and TXB2 respectively, and assessed the physiological role played by the prostanoids in this experimental condition. Salt retention (SR group, n=9) was induced by repeated i.v. infusion of saline solution (0.9% NaCl). At the end of the treatment the body weight had increased by 0.7+/-0.2 kg (mean+/-SEM) (P<0.05). Renal functional exploration [clearance (cl.) method] was performed during hypotonic polyuria (induced by oral water load) and subsequent moderate antidiuresis (induced by low-dose infusion of an antidiuretic hormone analogue). Urinary 6KPGF and TXB2 concentrations were estimated by RIA method during polyuria (P cl. period), early and late antidiuresis (A1 and A2 cl. periods). Paired functional explorations were performed in absence (control study) and presence of indomethacin. Basal values of plasma sodium and potassium concentrations, plasma renin activity (PRA) and urinary aldosterone excretion were determined just before the control study. The results in salt retention were compared to those previously obtained in healthy women submitted to a moderate salt depletion (SD2 group, n=6), in absence and presence of the drug. Women in salt retention received 100 mg i.m. of the drug, whereas salt-depleted women received only a halved dose as in previous studies in salt depletion the full dose produced prolonged anuria. (I) Salt retention vs salt depletion. The basal values of PRA and urinary aldosterone excretion were significantly lower. During polyuria, urinary excretion of 6KPGF, 6KPGF/TXB2 ratio, urinary flow rate, creatinine cl. and absolute and fractional excretions of sodium and chloride were significantly higher. In salt retention during polyuria, significant positive correlations were found between 6KPGF excretion and functional excretory parameters. (II) Indomethacin in salt retention. The following effects were significant: (a) a reduction in prostanoid excretions in P and A1 cl. periods only; (b) during polyuria, an increase in arterial pressure, a reduction in urinary flow rate and creatinine cl. (saluresis showed not significant reduction). During polyuria significant positive correlations occurred between the absolute effects of indomethacin on 6KPGF excretion and those on functional excretory parameters. (III) Comparative effects of indomethacin in salt retention and salt depletion. Despite the double dosage of the drug, the significant reductions in urinary metabolite excretions were not significantly different during P cl. period and significantly lower in A1 cl. period compared to the corresponding significant reductions in salt depletion. During polyuria, the significant increase in arterial pressure was significantly different from the not significant effect in salt depletion; the not significant effect on saluresis was significantly different from the significant reduction in salt depletion. The results suggest the following conclusions: (1) The present model showed the functional pattern of the volume-natriuresis; (2) In salt retention, in contrast with salt depletion, indomethacin induced an increase in arterial pressure consistent with the inhibition of a PG-dependent vasodilator mechanism active at the systemic level; (3) In salt retention, in contrast with salt depletion, indomethacin failed to induce a significant reduction in saluresis. This failure can be attributed to the drug's blunted effectiveness in inhibiting the renal synthesis of saluretic PGs, and probably to the interference of the concurrent increase in arterial pressure in the renal treatment of sodium and chloride.     

The effect of dietary protein on the excretion of alpha2u, the sex-dependent protein of the adult male rat.

Adult male rats were maintained on normal (20% casein), protein-free (0% casein), high protein (50% casein), decicient protein (20% zein), and a supplemented, deficient protein (20% zein plus L-lysine and L-tryptophan) diets. Rats on a protein-free diet excreted approximately 1 mg alpha2u/24 h compared with a normal of 10-15 mg/24 h. Depleted rats placed on a 20% casein diet showed a rapid restoration of the normal alpha2u excretion as well as total urinary proteins. Accumulation of alpha2u in the blood serum was measured in nep-rectomized rats. Rats on a 0% casein diet accumulated only 30% of the alpha2u compared to normals. On a 50% casein diet, rats excreted 30-50 mg alpha2u/24 h. However, the accumulation was normal in the serum of nephrectomized rats. A high protein diet did not stimulate alpha2u synthesis but probably increased the renal loss of all urinary proteins. The excretion of alpha2u on a zein diet was reduced to the same degree as with the protein-free diet. Supplementation with lysine and tryptophan restored the capacity to eliminate alpha21 to near normal levels. Accumulation of alpha2u in the serum of nephrectomized rats kept on the zein diets showed that the effect to suppress the synthesis of the ahpha2u. Supplementation restored the biosynthesis of alpha2u. We conclude that the effect of dietary protein on the excretion of urinary proteins in the adult male rat is caused in large part by an influence on the hepatic biosynthesis of alphay2u. The biosynthesis of this protein, which represents approximately 30% of the total urinary proteins, is dependent on an adequate supply of dietary protein.     

Renal excretion of fluoride in renal failure and after renal transplantation.

We have compared the renal excretion of fluoride in a variety of patients with chronic renal failure maintained with and without protein restriction before and during regular dialysis treatment and after transplantation. The patients tended to continue to excrete normal dietary loads of fluoride quite well until renal function was seriously reduced. From a regression of function on excretion the mean level of creatinine clearance when a normal dietary load of fluoride 0.0526 plus or minus 0.019 mmol/2 h (1.0 plus or minus 0.36 mg/24h) has a 90% chance of being excreted lies around 16 ml/min, a level when most patients with renal failure will be symptomatic. Acute loading of such patients with additional fluoride in the form of sodium fluoride from 40 mg to 60 mg/day showed a twofold to threefold increase of serum fluoride concentrations, slight increases in urinary fluoride excretion, and heavy tissue absorption, suggesting that prior fluoride loading of the skeleton had not taken place. These effects contrasted with those in one patient with normal renal function and with those in one patient with skeletal saturation due to prolonged loading. After renal transplantation fluoride excretion increased but reached normal levels within three months of satisfactory function, suggesting that fluoride loading in renal failure and during regular dialysis therapy had not been excessive.     

Abnormal response of urinary eicosanoid system to norepinephrine infusion in patients with essential hypertension.

To define the role of the renal eicosanoid system in sustaining renal homeostasis in hypertension, we investigated the alterations in urinary excretions of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), a stable metabolite of vasodepressor prostacyclin, and thromboxane B2 (TXB2), a stable metabolite of vasoconstrictor TXA2, when norepinephrine was continuously infused for 90 min in hypertensive (n = 13) and normotensive subjects (n = 14). There was no difference in plasma norepinephrine concentration after the infusion between the hypertensive and the normotensive subjects. Moreover, the percent changes in renal vascular resistance elicited by norepinephrine in the hypertensives were equal to those of the normotensive subjects. In the normotensive subjects, the norepinephrine infusion significantly increased urinary 6-keto-PGF1 alpha excretion and decreased urinary excretion of TX, both of which are beneficial for sustaining renal function. In fact, the greater the production of renal 6-keto-PGF1 alpha was, the less the reduction of renal blood flow and urinary sodium excretion was. In the hypertensive subjects, however, these normal responses of the renal eicosanoid system, seen in the normotensives, were abolished; urinary 6-keto-PGF1 alpha was unaltered and thromboxane generation was rather increased. Thus, the renal eicosanoid system dysfunctions in hypertensive subjects when the renal circulation is challenged by norepinephrine. These abnormal responses are likely to cause sodium retention and could contribute, in part, to the hypertensive mechanism in patients with essential hypertension.     

Further research on the role of prostanoids in controlling renal function in humans in normal potassium balance and acute experimental potassium depletion. I: Studies of normal potassium balance. Effects of indomethacin

The renal function was studied by clearance (cl.) method during hypotonic polyuria (oral water load followed by 5% dextrose solution infusion) and successive relative antidiuresis induced by lysine-8-vasopressin (LVP) administration (5 microU in bolo followed by continuous infusion at a rate of 0.04 microU/min). Four 15 min and two 60 min clearance (cl.) periods were performed during hypotonic polyuria and antidiuresis, respectively. Glomerular filtration rate was estimated by creatinine cl.; the osmotic cl. (Cosm, CH2O), the absolute and fractional excretions of water, sodium, potassium and chloride were determined by usual methods. The urinary PGE2, 6-keto-PGF1 alpha and TxB2 concentrations were determined by RIA method. Fourteen healthy women submitted to a normal sodium and potassium daily intake were studied; in 6 of them paired studies in absence and in presence of indomethacin (100 mg, i.m.), respectively, were performed. LVP induced a significant reduction of creatinine cl., urinary flow rate and of prostanoid excretion. In hypotonic polyuria, indomethacin significantly reduced the creatinine cl. and the diuretic response to the water load; moreover the urinary PGE2 and 6-keto-PGF1 alpha excretions were significantly lower (85.6 +/- 1.9% and 37.7 +/- 3.2%) while the reduction of urinary TxB2 excretion was not significant (34.4 +/- 13%). Indomethacin did not affect significantly the LVP renal effects in normal potassium balance.     

Urinary excretion of 8-iso-PGF(2 alpha) in three patients during sepsis,recovery and state of health

Sepsis is known to be associated with oxidative stress. Novel markers of oxidative stress are now believed to be F2-isoprostanes which are produced in situ in phospholipids and subsequently released into circulation and excreted in the urine. This study, therefore, sought to investigate whether the excretion of the isoprostane, 8-iso-PGF(2 alpha), is elevated during sepsis. The excretion of 8-iso-PGF(2 alpha), in the 24 h urine of three patients was studied in the septic stage, during mobilisation and in the state of health by a radioimmunological method. Extrapolating the urinary excretion of 8-iso-PGF(2 alpha) over time showed an insignificant variation in the excretion values during 24 h. The amount of mean 24 h urinary 8-iso-PGF(2 alpha) was about similar in the septic stage and in the state of health but increased remarkably during mobilisation in two of the patients. We suggest that mobilisation of septic patients can be associated with an increase of oxidative stress which may stem from an increase in oxygen consumption and/or from a depletion of antioxidants leading to the enhanced formation of free radicals.     

The renal haemodynamic and excretory actions of prostacyclin and 6-oxo-PGF1 alpha in anaesthetized dogs.

Intrarenal arterial (i.a.) infusions of prostacyclin (PGI2) at 30-300 ng/min to anaesthetized dogs reduced renal vascular resistance (RVR) and filtration fraction (FF), increased mean renal blood flow (MRBF) but did not alter mean arterial pressure (MAP)or glomerular filtration rate (GFR). The urinary excretion of sodium (UNaV), potassium (UKV) and chloride ions (UC1V) were increased through inhibition of net tubular ion reabsorption. PGI2 (3000 ng/min, i.a.) reduced MAP and increased heart rate. Intravenous (i.v.) infusions of PGI2 (3000 gn/min) reduced MAP, GFR, FF, urine volume and ion excretion, with elevation of heart rate. The measured variables were unaltered by 6-oxo-PGF1 alpha (10,000 ng/min i.a.). Treatment of the dogs with the PG synthetase inhibitor meclofenamic acid (2.5 mg/kg i.v.) did not antagonise the elevation of MRBF to PGI2 (300 ng/min i.a.). Thus the renal effects of PGI2 were due to a direct action rather than through conversion to 6-oxo-PGF1 alpha or through stimulation of endogenous renal PG biosynthesis and release.     

Effect of sodium and chloride depletion on urinary prostaglandin F2α excretion in potassium loaded rats

Previous studies have shown that the urinary excretion of prostaglandin (PG) F2 alpha is stimulated by potassium (K) loading. Because changes of sodium chloride (NaCl) intake also affect renal PG production, in this study we investigated the interaction between the effect of K and that of concomitant reduction of Na and Cl intake. The urinary excretion of PGF2 alpha and PGE2 was measured in 12 groups of female rats on normal, high or low K intake. Na and Cl intake were adjusted so that rats had normal intake (controls, C), were selectively Cl depleted (CD), selectively Na depleted (ND) or Na and Cl depleted (NCD). In rats with normal K intake, urinary PGF2 alpha was not modified by changes of Na or Cl intake, whereas PGE2 was increased in by Cl depletion (in both NCD or CD groups). Potassium chloride loading increased urinary PGF2 alpha and selective Na depletion (ND group) induced a further increase. On the other hand, PGF2 alpha was not stimulated when K load was associated with Cl depletion. Urine PGF2 alpha was directly correlated with plasma aldosterone and urinary kallikrein. Urinary PGE2 did not change with K-loading. The results suggest that PGF2 alpha participates in the renal adaptation to KCl-loading but not when K is accompanied by non-Cl anions.     

Dissociation of beta-adrenergic stimulation of renin secretion and prostacyclin synthesis in the rabbit kidney

The effect of inhibition of prostaglandin (PG) synthesis with indomethacin on basal and isoproterenol-stimulated renin secretion was examined in the isolated perfused rabbit kidney. 6-keto PGF1 alpha' the stable metabolite of prostacyclin, was measured in urine by radioimmunoassay using 125I labelled histamine coupled to 6-keto PGF1 alpha as ligand. The level in urine, prior to isolation and perfusion of the kidney, was 10.7 +/- 5.6 ng/min, and this was reduced to 0.32 +/- 0.25 ng/min (P less than 0.05) in rabbits treated with 2.0 mg/kg of indomethacin. Renin release was markedly stimulated by intrarenal infusion of isoproterenol (0.1 microgram/min) but urinary 6-keto PGF1 alpha did not change. These responses were not affected by indomethacin treatment. Renal perfusion pressure, perfusate flow rate and consequently renal vascular resistance, remained relatively constant during the course of perfusion and were unaltered by indomethacin treatment. These results therefore do not support a role for PGs, and in particular prostacyclin, in the renin response to beta-adrenergic stimulation with isoproterenol.     

Urinary excretion of 2,3-dinor-thromboxane B2 in man under normal conditions, following drugs and during some pathological conditions

Quantitation of 2,3-dinor-thromboxane B2 (2,3-dinor-TxB2) was performed by gas chromatography-mass spectrometry. Under normal conditions the urinary excretion of 2,3-dinor-TxB2 was relatively constant in the same individual from day to day but during a 24-hour period a somewhat higher excretion rate was found during the first few hours after awakening. A pronounced reduction of the urinary excretion of 2,3-dinor-TxB2 was found after oral administration of 500 mg of aspirin or 50 mg of indomethacin, while 500 mg of paracetamol did not affect the urinary excretion. Increased excretion of 2,3-dinor-TxB2 was found in normal pregnancies and in diseases such as diabetes mellitus and homocysteinuria in comparison to the urinary excretion in normal healthy subjects. We also report one case, where the urinary excretion of 2,3-dinor-TxB2 was increased for a short period following the first symptoms of a myocardial infarction and those data indicate that thromboxane A2 (TxA2) may be of pathophysiological importance in human myocardial infarction. The results strongly indicate that measurements of the urinary excretion of 2,3-dinor-TxB2 should be meaningful as a tool for investigation of the involvement of thromboxane in various pathophysiological processes in vivo in man.     

The effect of sodium intake on renal prostaglandin production

The effect of chronic alterations in dietary sodium intake on renal arachidonic acid (AA) metabolism was studied in male Wistar rats who were maintained for 14 days on a diet consisting of sodium-deficient food and either deionized water (low salt intake, LSI), 1% saline (normal salt intake, NSI), or 2% saline (high salt intake, HSI). 24 h Urinary Sodium (UNaV) and plasma renin activity (PRA) measurements were shown to validate the dietary protocol. Microsomal preparations from the cortices and medullae were incubated with radiolabeled exogenous AA, and endogenous urinary prostaglandin (PG) levels were assayed by RIA to quantify renal PG synthesis. Cortical PGF2 alpha and PGE2 synthesis was found to be the greatest following LSI. In contrast, medullary PGF2 alpha was shown to be the least following LSI and to increase with increased sodium intake. Likewise, urinary PGF2 alpha levels significantly increased with increasing sodium intake. Changes in urinary PGE2 levels showed the same trend as PGF2 alpha but did not achieve statistical significance. These data show that dietary sodium differentially affects renal cortical and medullary PG synthesis and may reflect physiological differences in the regulation of cyclooxygenase in these zones. These data further suggest that the major source of urinary PGs is the renal medulla since the relationship of urinary levels to sodium intake mimics that described for the synthesis of PGs by the medullary tissue.     

Renal prostaglandins in postobstructive diuresis. Comparative study of unilateral and bilateral obstruction in conscious dogs

An experimental model in conscious dogs was developed to investigate the role of prostaglandins (PG) in the obstructed kidney. Renal veins were separately catheterized. Urine flow was shunted to the skin by surgically implanted polyurethane loop ureterostomy so as to allow atraumatic manipulation with maintained continuous flow to the bladder between experiments. One week or more after surgery, renal function parameters as well as renal vein and urinary PGE2 and PGF2 alpha, and renal vein renin were studied during and after unilateral (UUO) and bilateral (BUO) ureteral obstruction. The release of ureteral obstruction produced a constant and marked elevation in urinary PGE2 and PGF2 alpha, two times higher after BUO than after UUO. A close correlation exists between PGE2 and sodium excretion in UUO and BUO. Increasing polyuria was observed only after chronic BUO. In BUO, renal vein renin concentration was augmented after 2 hours but was suppressed after 24 hours of BUO. Renal vein PG concentration was also elevated after chronic UUO and BUO but was in the normal range immediately prior to release of obstruction. The data obtained with the current experimental dog model indicate that the release of ureteral obstruction induces a striking increase in renal PGE2 and PGF2 alpha production which may mediate at least partly the phenomenon of postobstructive diuresis.