Long-term effects of aldosterone on kallikrein, prostaglandin E2 and sodium in rats

To assess the long-term effects of mineralocorticoids on the regulation of the synthesis or release of kallikrein and prostaglandin E2 in the renal kallikrein-kinin-prostaglandin E system, we studied the effects of chronic infusion of aldosterone (50 micrograms/kg/day) on urinary excretion of total and active kallikrein, and prostaglandin E2 for 10 days in conscious rats on regular intakes of sodium and on sodium loading with 1% NaCl as a drinking water. Chronic infusion of aldosterone induced a prompt and transient decrease in the ratio of sodium to potassium and a sustained increase in urinary prostaglandin E2 excretion in rats on regular diets, whereas urinary total and active kallikrein excretion did not increase significantly until the 4th day of aldosterone infusion. In rats loaded with sodium, aldosterone did not induce any changes in urinary total and active kallikrein excretion, whereas it induced similar changes in the ratio of sodium to potassium and urinary prostaglandin E2 excretion to those in rats on regular diets. Thus, the present results suggest that aldosterone might stimulate the synthesis or release of renal prostaglandin E2 independent of sodium balance. Furthermore, it is also suggested that aldosterone might stimulate the synthesis or release of kallikrein, at least partly, via the same pathway as sodium loading does.     

The contribution of PGI2 to the effects of captopril in conscious dogs in differing states of sodium balance

There is some evidence that increased prostaglandin synthesis may mediate some of the effects of the angiotensin converting enzyme inhibitor captopril. The potential role of prostaglandin (PG)I2 in this process was assessed by measurement of changes in urinary 6-keto-PGF1 alpha excretion after captopril in eight sodium replete and depleted conscious dogs. In sodium replete animals captopril induced a small decrease in blood pressure, transient increases in effective renal plasma flow and urinary 6-keto-PGF1 alpha excretion, and progressive increases in plasma renin activity (PRA) and urinary sodium excretion. By contrast, during sodium depletion captopril induced a large decrease in blood pressure, a transient increase in effective renal plasma flow and urinary 6-keto-PGF1 alpha excretion, an early large but transient increase in PRA and small progressive increase in sodium excretion. The time course of changes after captopril suggested that increased PGI2 synthesis may contribute to the transient decrease in renal vascular resistance. The increase in PRA during sodium depletion was not associated with any change in urinary 6-keto-PGF1 alpha excretion.     

The kidney and cardiovascular system in obstructive jaundice: functional and metabolic studies in conscious rats

1. The effects of jaundice on renal and circulatory function were investigated in chronic bile duct ligated (CBDL) rats 6 days after surgery. Sham operated (SO) animals served as controls. 2. Body weight was significantly reduced, whereas blood pressure remained unaltered, 6 days after bile duct ligation when serum bilirubin had risen to 169 +/- 18 (SEM) as compared with 2.8 +/- 0.3 mumol/l in SO rats. When compared with control values before surgery, urinary volume had significantly increased and absolute excretion of sodium, potassium, chloride and phosphate had decreased on day 6 after CBDL. Endogenous creatinine clearance was markedly depressed when compared with SO rats. Whereas fractional excretion of potassium remained unaltered, fractional excretion of sodium and of phosphate was significantly increased. 3. Except for a significant increase in urinary thromboxane B2 (TXB2) excretion in CBDL rats, no significant changes were observed in urinary excretion of prostaglandin (PG) E2, in the synthesis of PGE2, 6-keto-PGF1 alpha and TXB2 by isolated aortic tissue in vitro, nor in renal and cardiac adenosine triphosphatase activities or renal cortical mitochondrial function. 4. The adenosine triphosphate content of kidney cortex and cardiac mitochondrial function were significantly depressed in CBDL rats. 5. The results demonstrate that jaundice in CBDL rats is associated with functional and metabolic disturbances of the kidney and cardiac muscle, which may contribute to the renal and haemodynamic characteristics observed in jaundiced animals and humans.     

Inhibition of prostaglandin synthesis by indomethacin interacts with the antihypertensive effect of atenolol

The interaction of inhibition of prostaglandin (PG) synthesis by indomethacin (75 mg/day) with the antihypertensive effect of atenolol (50 mg b.i.d.) was studied in 11 untreated otherwise healthy men 35 to 45 years old with essential hypertension. Atenolol for 3 weeks decreased supine blood pressure (BP) from 157/109 mm Hg during placebo to 148/97 mm Hg. Indomethacin alone for 1 week slightly increased BP and antagonized the antihypertensive action of atenolol. Atenolol reduced plasma renin activity (PRA) to 40% but did not modify either the urinary excretion of vasodilatory PGs (PGE2 and prostacyclin measured as 6-keto-PGF1 alpha) or plasma kininogen and urine kallikrein. Indomethacin suppressed PRA to 27% and PG excretion to approximately 70% but did not markedly change plasma kininogen and urine kallikrein excretion. The decreased excretion of 6-keto-PGF1 alpha, the metabolite of the main vasodilatory prostanoid prostacyclin, correlated with the increased BP measured in standing subjects. The effects of indomethacin were practically the same when given with atenolol as when given alone. We conclude that the slight increase in BP by indomethacin in essential hypertension is associated with the reduced production of vasodilatory PGs but not with alterations in activities of the renin-angiotensin or kallikrein-kinin systems.     

Effect of a kinin antagonist on renal function and haemodynamics during alterations in sodium balance in conscious normotensive rats

1. To evaluate whether sodium intake can modulate the action of endogenous kinins on renal function and haemodynamics, a receptor antagonist of bradykinin was infused in conscious normotensive rats maintained on either a normal or a low sodium diet. 2. The antagonist inhibited the hypotensive effect of exogenously administered bradykinin. It did not change the vasodepressor effect of acetylcholine, dopamine or prostaglandin E2. 3. The antagonist did not affect mean blood pressure, glomerular filtration rate, renal blood flow or urinary sodium excretion, in rats on sodium restriction. It did not change mean blood pressure, glomerular filtration rate or urinary sodium excretion, but decreased renal blood flow, in rats on a normal sodium intake. 4. The kallikrein-kinin system has a role in the regulation of renal blood flow in rats on a normal sodium diet.     

Renal tubular action of prostaglandin E2 on water and electrolyte excretion in the nonanesthetized chicken

The tubular effects of prostaglandin (PG) E2 on electrolyte and water excretion were investigated in vitro in the nonanesthetized chicken by the Sperber technique. This technique allowed the administration of PGE2 directly into the peritubular space of one kidney by way of the venous portal circulation. When compared to the contralateral, noninfused kidney, PGE2 in the infused kidney (0.6-4.5 X 10(-10) mol/kg X min) induced a dose-dependent increase in urinary flow rate, a mild natriuresis and kaliuresis, with a concomitant decrease in urinary osmolality and an increase in free-water clearance. These effects occurred without changes in renal plasma flow or glomerular filtration rate. PGA2 (1.7-7.8 X 10(-10) mol/kg X min), another vasodepressor PG, did not modify electrolyte excretion. The tubular handling of PGE2 was observed by following the administration of [3H]PGE2. [3H] PGE2 was metabolized extensively during its renal tubular excretion. The 3H label was secreted actively into the urine by the organic anion transport system which was inhibited by novobiocin. Inhibition of the organic anion transport system did not modify the renal tubular effects of PGE2 on electrolyte and water excretion. These results indicate that PGE2 exerts a tubular inhibitory effect on sodium and water excretion, this action being located on the peritubular side.     

Altered prostaglandin synthesis and impaired sodium conservation in the kidneys of old rats.

1. The aim of this investigation was to study the role of prostaglandins in the impaired Na+ conservation of the ageing kidney. 2. We measured the urinary excretion of thromboxane B2, 6-keto-prostaglandin F1 alpha and prostaglandin E2 in young (3-4 months) and old (20-21 months) rats after 12, 24 and 36 h of Na+ deprivation. In a separate protocol, we measured prostanoid synthesis by isolated glomeruli, cortical homogenates, medullary slices and papillary slices from young and old rats in basal conditions and after 15 days of dietary Na+ deprivation. 3. In the acute study, urinary excretion of 6-keto-prostaglandin F1 alpha and prostaglandin E2 decreased in young but not in old rats. Urinary excretion of prostaglandin E2 was lower in old rats, but did not vary significantly with Na+ deprivation. 4. In old rats, thromboxane B2 synthesis was increased in all the portions of the kidney except the medulla. Production of 6-keto-prostaglandin F1 alpha was elevated in glomeruli and tended to increase in the cortex. Prostaglandin E2 synthesis was also elevated in the cortex. Thromboxane B2 synthesis tended to increase in the medulla and was enhanced in the papilla. After Na+ deprivation, only glomerular prostaglandin E2 synthesis increased in young rats. In old rats, cortical and papillary synthesis of 6-keto-prostaglandin F1 alpha increased, whereas prostaglandin E2 synthesis did not change. 5. The results suggest increased thromboxane synthesis in the ageing kidney. Increased prostacyclin and prostaglandin E2 synthesis may be an attempt to counteract enhanced thromboxane production.(ABSTRACT TRUNCATED AT 250 WORDS)     

The antihypertensive and renal activities of potassium canrenoate are associated with increased renal prostaglandin excretion

1. In a double-blind, randomized, cross-over study the effects of potassium canrenoate administration (100 mg twice daily for 10 days orally) on renal prostaglandin synthesis (prostaglandin E2 and prostaglandin F2 alpha) were evaluated in 10 normotensive females and in 10 females with essential hypertension. 2. When compared with normotensive subjects, hypertensive patients in baseline conditions showed a reduced excretion of urinary prostaglandin E2 associated with an excessive prostaglandin F2 alpha production. 3. Potassium canrenoate significantly reduced mean blood pressure in hypertensive patients [from 118.9 +/- 8.7 mmHg (1.62 +/- 0.12 kPa) to a peak minimum value of 104.7 +/- 9.8 mmHg (1.42 +/- 0.13 kPa) on the seventh day of treatment; P less than 0.01 for the whole period] but not in control subjects [from 88 +/- 9.4 mmHg (1.20 +/- 0.13 kPa) to 84.3 +/- 8.3 mmHg (1.15 +/- 0.11 kPa) on the eighth day, NS] even though potassium canrenoate significantly increased sodium excretion in both groups. Renal prostaglandin excretion was affected differently in the two groups: in control subjects excretion of both prostaglandin E2 and prostaglandin F2 alpha was increased after drug administration, whereas in hypertensive patients only prostaglandin E2 excretion was enhanced.     

Effect of Sar1-Ileu8-angiotensin on renal prostaglandin E2 biosynthesis and excretion

To test the hypothesis that renal prostaglandin (PG) biosynthesis is regulated by angiotensin (AII), rabbits were given prolonged treatment with the AII analogue, Sar1-Ileu8AII (200 micrograms/kg/4 hr, subcutaneously), for 2 days during a low, normal, and high sodium intake. Sodium restriction augmented plasma renin activity (PRA), which was associated with a rise in basal renal PGE2 synthesis and urinary excretion, whereas sodium supplementation attenuated PRA with a decrease in renal PGE2 synthesis and urinary excretion. Sar1-Ileu8AII administration, with either a low, normal, or high salt intake, suppressed PRA. Sar1-Ileu8AII injection with a low sodium intake also suppressed renal PGE2 synthesis and excretion that was associated with a fall in blood pressure, suggesting an antagonistic action of this agent on vascular beds and renal PGE2 synthesis. On the other hand, with a high sodium intake Sar1-Ileu8-AII increased renal PGE2 synthesis and excretion as well as blood pressure, revealing an agonistic action of this compound under these conditions. The results suggest that exogenous AII analogue may act as an antagonist or agonist depending on sodium intake and endogenous AII levels, renal PGE2 synthesis is dependent on AII levels, either endogenously produced or exogenously administered (as an AII agonist), and the action of AII analogue on vascular beds and renal PGE2 synthesis does not appear to parallel its action on renin-AII feedback regulation at the juxtaglomerular cell especially under conditions of high sodium intake.     

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.     

Effect of indomethacin on blood pressure in the normotensive unanaesthetized rabbit: possible relation to prostaglandin synthesis inhibition

1. To test the hypothesis that endogenous prostaglandins contribute to the regulation of blood pressure, we studied the effect of an inhibitor of prostaglandin synthesis, indomethacin, on mean aortic blood pressure in the normotensive, unanaesthetized rabbit. 2. Daily administration of indomethacin at 42 mumol/kg subcutaneously, but not of vehicle only, for 14 consecutive days, elevated the average mean arterial pressure in seven rabbits from 88 +/- 3 mmHg on the last day of the control period to 105 +/- 3 mmHg (P less than 0.01) and 107 +/- 2 mmHg (P less than 0.01) on days 6 and 14 of indomethacin treatment respectively, and reduced the urinary excretion of prostaglandin-like substance from 1.06 +/- 0.26 to 0.17 +/- 0.05 nmol of prostaglandin E2 equivalents/day (P less than 0.05; n = 5). Neither indomethacin nor the vehicle affected the intake of water, the 24 h urine volume, the cumulative difference between sodium intake and urinary sodium excretion, or the plasma volume. 3. The results of the study are compatible with the hypothesis that one or more prostaglandins contribute to maintain normotension in the rabbit and that reduction in prostaglandin biosynthesis may cuase blood pressure to rise.     

Renal prostaglandins in cirrhosis of the liver

Urinary prostaglandin excretion was studied in 42 patients with liver cirrhosis and in nine control subjects on restricted sodium intake and on bed rest. Creatinine clearance (CCr), sodium excretion (UNaV), plasma renin activity (PRA) and plasma aldosterone were also evaluated. Patients without ascites and ascitic patients without renal failure showed increased urinary excretion of immunoreactive 6-ketoprostaglandin F1 alpha (i6-keto-PGF1 alpha), prostaglandin E2 (iPGE2) and thromboxane B2 (iTXB2) when compared with controls, while immunoreactive PGF2a (iPGF2 alpha) levels did not differ from those in the control group. Patients with functional renal failure (FRF) presented a significant reduction of vasodilator prostaglandins but urinary excretion of iTXB2 was higher than in controls. On the whole, cirrhotic patients with higher urinary excretion of prostaglandins had normal or nearly normal PRA and aldosterone levels. i6-keto-PGF1 alpha and iPGE2 inversely correlated with PRA and aldosterone. The relationship between i6-ketoPGF alpha alpha and CCr was found to be highly significant in cirrhotic patients but not in the control group. On the other hand, iPGE2 significantly correlated with UNaV and with the fractional excretion of sodium (FENa). We concluded that: (a) enhanced renal prostaglandin synthesis in cirrhosis, inversely related to PRA and aldosterone, may be dependent on volume status; and (b) preserved renal function in these patients is associated with the ability to synthesize prostacyclin and PGE2.     

Renal prostaglandins and water balance: studies in normal volunteer subjects and in patients with central diabetes insipidus

1. In six healthy volunteer subjects polydipsic water loading significantly increased urine volume from 1203 +/- 242 (SEM) to 5072 +/- 320 ml/24 h (P less than 0.001) with a significant decrease in urinary osmolality. This increase in urine volume by more than fourfold was associated with a slight increase in urinary excretion of prostaglandin E2 from 466 +/- 66 to 1017 +/- 174 pmol/24 h (P = 0.05). 2. In five patients with central diabetes insipidus mean urine volume of 10 838 +/- 107 ml/24 h was reduced to 1205 +/- 204 ml/24 h (P less than 0.001) by treatment with 1-desamino-8-arginine vasopressin (desamino-[Arg8]vasopressin; 15 microgram/day) with a significant rise in urinary osmolality. Desamino-[Arg8]vasopressin treatment was associated with a significant increase of suppressed urinary excretion of prostaglandin E2 (PGE2) in four of these patients from 246 +/- 66 to 2643 +/- 677 pmol/24 h (P less than 0.01). 3. Concomitant treatment with indomethacin in addition to desamino-[Arg8]vasopressin significantly suppressed urinary excretion of PGE2 and significantly increased urinary osmolality as compared with treatment with desamino-[Arg8]vasopressin alone. 4. Desamino-[Arg8]vasopressin significantly increased urinary excretion of adenosine 3':5'-cyclic monophosphate (cyclic AMP). However, there was no further change in urinary excretion of cyclic AMP during concomitant indomethacin treatment. 5. The results suggest that urine flow itself is not an important determinant of urinary PGE2 excretion. In patients with central diabetes insipidus the urinary concentrating response to desamino-[Arg8]vasopressin is enhanced during inhibition of prostaglandin synthesis without changes in urinary excretion of cyclic AMP.     

Renal effects of prostaglandin E1 in hypertensive patients.

The effects of prostaglandin E1 on fluid and sodium excretion, creatinine clearance and renin release were examined in 26 hypertensive patients including 9 cases of essential hypertension, 10 of renovascular hypertension and 7 of primary aldosteronism. When prostaglandin was infused intravenously in a total dose of 120 mug in 60 min, urine volume was increased in 70% of cases, and sodium excretion in 61%, but little changes were observed in creatinine clearance. The most prominent diuresis and natriuresis were obtained in primary aldosteronism (mean increase was 319% in urinary volume, and 222% in sodium output). The average increases in urinary volume were 61% in patients with essential hypertension and 97% in renovascular hypertension. And urinary output of sodium was increased by 63% in the former and 56% in the latter. The remarkable renal effects of prostaglandin E1 in primary aldosteronism were completely abolished after the administration of spironolactone. Significant elevation of plasma renin activity resulted from prostaglandin E1 infusion in essential hypertension, while no constant effect was obtained in renovascular hypertension and primary aldosteronism. The present experiments indicate that prostaglandin E1 has different effects on the kidney according to the types of hypertension and the effects correlate closely with patient's status of extracellular fluid volume or sodium balance.     

Renal disposition and effects of naproxen and its l-enantiomer in the isolated perfused rat kidney

Renal handling, metabolism and effects on kidney function of naproxen and its l-enantiomer were examined in the isolated perfused rat kidney (IPK). Urinary excretion rate of naproxen was much lower than the filtration rate, indicating extensive reabsorption. Naproxen is accumulated considerably in the IPK. This accumulation is concentration-dependent and is probably the result of active secretion of naproxen. Considerable amounts of desmethyl-naproxen were formed in the IPK. The kinetic behavior of the l-enantiomer of naproxen did not differ from naproxen. Addition of 37.5 to 3750 micrograms naproxen caused a decrease in urinary flow, glomerular filtration rate and fractional excretion of sodium, chloride, potassium, magnesium and calcium. The presence of prostaglandin E2 in the perfusate fully opposed the effects of naproxen on kidney function. Addition of 375 micrograms l-enantiomer of naproxen did not influence kidney function. Addition of very high doses (1 x 10(5) micrograms) of naproxen and its l-enantiomer to the IPK caused diuresis and increased the fractional excretion of sodium, chloride, potassium, glucose and calcium. We conclude that the pharmacokinetic behavior and the metabolism of naproxen in the IPK is probably not stereoselective; that relatively low doses of naproxen exert a specific, stereoselective effect on kidney function caused by inhibition of the prostaglandin E2 synthesis and that high doses of naproxen exert a nonstereoselective effect on kidney function.     

Dietary fish oil prevents dexamethasone induced hypertension in the rat

This study was designed to examine the effect of dexamethasone treatment on tissue and urinary prostanoids, and to determine whether inhibition of prostaglandin biosynthesis by manipulation of dietary fatty acids accelerates the development of glucocorticoid hypertension. Forty-eight rats were placed on either a 2-series prostaglandin 'inhibitory' diet (cod liver oil/linseed oil) or a control diet of saturated fat for an initial period of 4 weeks. The groups were then divided into two so that half of each received dexamethasone in their drinking water (2.5 mg/l) for 1 week whilst continuing their respective dietary regimens. Rats on the cod liver oil diet incorporated eicosapentaenoic acid into tissue stores with a corresponding decrease in arachidonic acid, and significantly impaired ability to generate serum thromboxane B2 (33%), aortic 6-oxo-prostaglandin F1 alpha (44%), renal homogenate prostaglandin E2 (45%) and 6-oxo-prostaglandin F1 alpha (74%) and urinary prostaglandin E2 (84%) and 6-oxo-prostaglandin F1 alpha (79%). Despite the diminished levels of vasodilator 2-series prostaglandins, the cod liver oil diet prevented the development of glucocorticoid induced hypertension. Relative to their respective dietary controls, dexamethasone treatment resulted in decreased serum thromboxane B2 (20%) but increased aortic 6-oxo-prostaglandin F1 alpha (186%), renal homogenate prostaglandins (127-230%) and urinary excretion of prostaglandin E2 (640-860%) and 6-oxo-prostaglandin F1 alpha (230-365%) in both dietary groups. It therefore seems unlikely that glucocorticoid induced hypertension is a consequence of inhibition of vasodilator prostaglandin synthesis.     

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)     

The effect of inhibition of prostaglandin synthesis on urinary sodium excretion in the conscious dog.

Studies were performed to determine the effect of decreased endogenous release of renal prostaglandins on urinary sodium excretion. Two structurally dissimilar inhibitors of prostaglandin synthesis were employed, and studies were performed in conscious dogs allowed to recover from prior surgical instrumentation. Either meclofenamate (2 mg/kg) or the competitive prostaglandin inhibitor RO 20-5720 (1 mg/kg) was given to seven unanesthetized dogs undergoing a water diuresis. The administration of either prostaglandin inhibitor did not alter glomerular filtration rate, renal plasma flow, urinary volume, or potassium excretion. Sodium excretion, however, increased from 32 to 130 mueq/min (P less than 0.02). Essentially, the entire increase in sodium excretion was due to an increase in urinary sodium concentration from 7.7 to 28.3 meq/liter (P less than 0.02). On a different day, the same animals were studied before and after administration of the diluent of the prostaglandin inhibitor. No change was noted in sodium excretion or any other parameter. Thus, these findings suggest that prostaglandin inhibition in the conscious dog is associated with a natriuresis without a change in urinary volume or potassium excretion during water diuresis. This may indicate that the natruiresis was due to diminished sodium reabsorption beyond the distal tubule.     

Effect of triamterene on urinary excretion of immunoreactive prostaglandin E in essential hypertension

The effect of triamterene on urinary excretion of prostaglandin E was studied, and the results were compared with those obtained with spironolactone. Urinary excretion of immunoreactive prostaglandin E was measured radioimmunologically. Triamterene was administered in a dose of 100 mg/day for 8 days to 7 patients with essential hypertension. Following the administration of triamterene, urinary prostaglandin E tended to increase. However, the increment was not significant. The lack of significant increase in urinary prostaglandin E excretion during the administration of triamterene contrasted with our previous finding with spironolactone, in which a significant increase in prostaglandin E excretion was observed on the first day of spironolactone administration. Urinary Na excretion and urinary Na/K ratio were significantly increased and urine volume also tended to increase following the administration of triamterene. Plasma renin activity and plasma aldosterone concentration were increased in all cases. However, there was no significant correlation between these parameters and urinary prostaglandin E. These results suggest that the effect of triamterene on renal prostaglandin E synthesis is different from that of spironolactone and that the change in urinary prostaglandin E after the administration of triamterene is not the reflection of the change in the renin-angiotensin-aldosterone system.     

Acute renal effects of sulindac and indomethacin in chronic renal failure

The effects of 2 days of oral dosing with sulindac (200 mg twice a day) or indomethacin (75 mg twice a day) on glomerular filtration rate, urinary excretion of prostaglandin E2, sodium homeostasis, and other renal function parameters were investigated in eight patients with chronic stable impaired renal function. Indomethacin reduced creatinine clearance (from 41.0 +/- 7.9 to 30.3 +/- 6.3 ml/min) and increased serum levels of creatinine and beta 2-microglobulin. Sulindac had no effect on any of these parameters. Both drugs induced depression of urinary prostaglandin E2 excretion; this depression was greater after indomethacin. Urinary sodium excretion fell from 144.4 +/- 18.7 to 85.5 +/- 9.7 mmol/24 hr after indomethacin and from 131.7 +/- 11.6 to 103.4 +/- 13.3 mmol/24 hr after sulindac. Body weight increased 1.2 kg after indomethacin but was not changed by sulindac. Plasma renin activity was reduced from 2.3 +/- 0.8 to 1.7 +/- 0.6 nmol/L/hr by sulindac and from 2.8 +/- 0.8 to 1.5 +/- 0.5 nmol/L/hr by indomethacin. Urinary N-acetyl-beta-glucosaminidase and kallikrein excretion was not changed by either drug. Our data suggest that sulindac affects renal prostaglandin E2 synthesis and sodium excretion in patients with severe renal failure to a lesser extent than does indomethacin. Sulindac still seems to be the drug of choice in this group of patients, but glomerular filtration rate, body weight, and electrolyte balance should be carefully monitored.