Mechanism of Action of Indomethacin in Tubular Defects

PEDIATRICS ◽  
1985 ◽  
Vol 75 (3) ◽  
pp. 501-507
Author(s):  
Mario Usberti ◽  
Carmine Pecoraro ◽  
Stefano Federico ◽  
Bruno Cianciaruso ◽  
Bruna Guida ◽  
...  
Keyword(s):  
Prostaglandin E2 ◽  
Diabetes Insipidus ◽  
Mechanism Of Action ◽  
Nephrogenic Diabetes Insipidus ◽  
Fanconi Syndrome ◽  
Free Water ◽  
Synthesis Inhibitor ◽  
Free Water Clearance ◽  
Water Excretion ◽  
Water Load

Indomethacin, a potent prostaglandin synthesis inhibitor, has been proven to be effective in a number of tubular defects characterized by enhanced prostaglandin (namely, prostaglandin E2 (PGE2) production, but its mechanism of action is poorly understood. To elucidate further the mechanism(s) by which indomethacin reverses the abnormal tubular functions, five children with different tubular defects (nephrogenic diabetes insipidus, three cases; Fanconi syndrome, one case; and pseudohypoaldosteronism, one case) were treated with indomethacin. Indomethacin, 1 mg/kg every eight hours, was given for 1 week to all children and then was given chronically to four of the children who responded to the drug. Its use was suspended in a 10 year-old-boy with nephrogenic diabetes insipidus because it proved ineffective. To assess the site along the nephron where indomethacin affects the solute and water excretion, an acute water load study was performed in three responsive children before and during the treatment. Indomethacin did not significantly alter the glomerular filtration rate but was effective in reducing diuresis and levels of urinary sodium and potassium excretion. In the child with Fanconi syndrome, indomethacin was also effective in controlling the urinary loss of phosphate, urate, glucose, and bicarbonate. Results of the water load studies show that indomethacin decreases the delivery of solute from the proximal tubule, reduces the fractional free water clearance, and increases the urine-plasma osmolar ratio. The rate of urinary excretion of prostaglandin E2 was high in all five children; it decreased below normal values in four of them after 1 week of treatment. In the child with nephrogenic diabetes insipidus who did not respond to indomethacin therapy, prostaglandin E2 excretion decreased but the rate remained higher than normal. These results suggest that indomethacin induces retention of solute and water mainly through an enhanced proximal tubular reabsorption.

Effects of subpicomolar changes in vasopressin on urinary concentration

1988 ◽  
Vol 255 (6) ◽  
pp. R940-R945 ◽  
Author(s):  
M. Baerwolff ◽  
P. Bie
Keyword(s):  
Free Water ◽  
Urine Osmolality ◽  
Urinary Concentration ◽  
Metabolic Clearance ◽  
Free Water Clearance ◽  
Water Excretion ◽  
Control Series ◽  
Water Load ◽  
Small Increments ◽  
Solute Excretion

The possibility that small amounts of vasopressin (AVP) reduce water excretion without affecting solute excretion was investigated in conscious dogs. AVP was infused intravenously for 120 min at rates of 2 and 5 pg.min-1.kg body wt-1 during water diuresis elicited by a sustained water load of 2% body wt. During control experiments urine osmolality was constantly approximately 60 mosmol/kgH2O; during AVP infusions it increased by factors of 1.36 (P less than 0.01) and 2.12 (P less than 0.01), respectively, concomitant with 39 +/- 6 and 61 +/- 7% reductions in urine flow. Osmolar and free water clearances decreased significantly. Sodium excretion did not change; changes in potassium excretion during AVP were similar to those of the control series, i.e., a gradual decline. During AVP, 5 pg.min-1. kg-1, creatinine and urea clearances decreased (25 +/- 2 and 31 +/- 7%, respectively, both P less than 0.01). With the assumption of metabolic clearance rates of AVP of 15-40 ml.min-1.kg body wt-1, the increase in plasma AVP during the infusion of 2 pg.min-1.kg body wt-1 was 5-13 X 10(-14) M. It is concluded that small increments in plasma AVP may reduce glomerular filtration rate and that with increasing levels of AVP in plasma 1) reduction of free water clearance, 2) reduction in urea clearance, and 3) natriuresis-kaliuresis occur in that order. Apparently AVP cannot reduce water excretion without changing the rate of excretion of solutes.

Hyponatraemia in quadriplegic patients

1988 ◽  
Vol 75 (4) ◽  
pp. 441-444 ◽  
Author(s):  
David J. Leehey ◽  
Alicia A. Picache ◽  
Gary L. Robertson
Keyword(s):  
Arginine Vasopressin ◽  
Fluid Intake ◽  
Plasma Osmolality ◽  
Free Water ◽  
Plasma Sodium ◽  
Free Water Clearance ◽  
Water Excretion ◽  
Water Load ◽  
Daily Urine ◽  
Plasma Arginine

1. Studies were performed in five hyponatraemic (plasma sodium 129 ±1.6 mmol/l; plasma osmolality 268 ±3.0 mosmol/kg) quadriplegic patients in order to elucidate its aetiology. Five age- and sex-matched healthy subjects served as controls. 2. Daily urine volumes were high (4454 ± 624 ml) in the quadriplegic patients secondary to habitually increased fluid intake. 3. All quadriplegic patients had suppressed plasma arginine vasopressin levels (< 0.8 pmol/l) and were able to form dilute urine after a water load (20 ml/kg). However, free water clearance and the ability to excrete the water load were frequently impaired, and these defects were associated with reductions in both osmolar clearance and delivery of filtrate to the distal diluting sites of the nephron. 4. During hypertonic saline (5%, w/v, NaCl) infusion, plasma arginine vasopressin rose progressively before plasma osmolality reached the normal range, consistent with a resetting of the osmostat. 5. We conclude that hyponatraemia in quadriplegic patients is related to an intrarenal defect in water excretion and resetting of the osmostat coupled with increased fluid intake.

Cooperative mechanisms of acute antidiuretic response to bendroflumethiazide in rats with lithium-induced nephrogenic diabetes insipidus

2010 ◽  
Vol 88 (12) ◽  
pp. 1191-1201 ◽  
Author(s):  
S. Mostafa Shid Moosavi ◽  
Masoud Haghani
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Urine Volume ◽  
Free Water ◽  
Urine Flow ◽  
Water Reabsorption ◽  
Free Water Clearance ◽  
Urinary Osmolality ◽  
Antidiuretic Effect ◽  
Water Clearance

The exact mechanism underlying thiazides-induced paradoxical antidiuresis in diabetes insipidus is still elusive, but it has been hypothesized that it is exerted either via Na+-depletion activating volume-homeostatic reflexes to decrease distal delivery, or direct stimulation of distal water reabsorption. This study examined how these two proposed mechanisms actually cooperate to induce an acute bendroflumethiazide (BFTZ)-antidiuretic effect in nephrogenic diabetes insipidus (NDI). Anaesthetized rats with lithium (Li)-induced NDI were prepared in order to measure their renal functional parameters, and in some of them, bilateral renal denervation (DNX) was induced. After a 30 min control clearance period, we infused either BFTZ into 2 groups, NDI+BFTZ and NDI/DNX+BFTZ, or its vehicle into a NDI+V group, and six 30 min experimental clearance periods were taken. During BFTZ infusion in the NDI+BFTZ group, transiently elevated Na+ excretion was associated with rapidly increased urinary osmolality and decreased free water clearance, but Li clearance and urine flow declined in the later periods. However, in the NDI/DNX+BFTZ group, there was persistently elevated Na+ excretion with unchanged Li clearance and urine flow during the experimental period, while alterations in free water clearance and urinary osmolality resembled those in the NDI+BFTZ group. In conclusion, BFTZ initially exerted two direct effects of natriuresis–diuresis and stimulating free water reabsorption at the distal nephron in NDI, which together elevated Na+ excretion and urinary osmolality but kept the urine volume unchanged in the first hour. Thereafter, the resultant sodium depletion led to the activation of neural reflexes that reduced distal fluid delivery to compensate for BFTZ-induced natriuresis–diuresis which, in cooperation with the direct distal BFTZ-antidiuretic effect, resulted in excretion of urine with a low volume, high osmolality, and normal sodium.

Effect of Acetylsalicylic Acid and of Indomethacin on Diuresis in Man: The Role of Cyclo-Oxygenase Inhibition

1984 ◽  
Vol 67 (6) ◽  
pp. 579-583 ◽  
Author(s):  
H. Vierhapper ◽  
J. Jörg ◽  
W. Waldhäusl
Keyword(s):  
Prostaglandin E2 ◽  
Acetylsalicylic Acid ◽  
Free Water ◽  
Healthy Male ◽  
Free Water Clearance ◽  
Water Load ◽  
Healthy Male Volunteers ◽  
Male Volunteers ◽  
Water Clearance

1. The effect of acetylsalicylic acid (ASA, 3 g/day for 3 days) and of indomethacin (IND, 150 mg/day for 3 days) on diuresis and on the excretion of prostaglandin E2 (PGE2) was studied in six healthy, male volunteers. After overnight deprivation the subjects received an oral water load (20 ml/kg) and hourly urine volumes were replaced by an equivalent volume of water by mouth for 4 h. 2. Pretreatment with both ASA and IND induced a comparable suppression (P<0.05 to <0.001) in the excretion of PGE2, but only IND also reduced (P<0.05) diuresis, free water clearance and the excretion of sodium. The excretion of creatinine was uninfluenced by both ASA and IND. 3. These data indicate that a mechanism other than cyclo-oxygenase inhibition is involved in the effect of IND and ASA on diuresis in man.

Comparative therapeutic benefit of indomethacin, hydrochlorothiazide, and acetyl-salicylic acid in a patient with nephrogenic diabetes insipidus

1984 ◽  
Vol 106 (3) ◽  
pp. 311-316 ◽  
Author(s):  
H. Vierhapper ◽  
J. Jörg ◽  
L. Favre ◽  
M. B. Vallotton ◽  
W. Waldhäusl
Keyword(s):  
Salicylic Acid ◽  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Free Water ◽  
Therapeutic Benefit ◽  
Prostaglandin Synthesis ◽  
Acetyl Salicylic Acid ◽  
Free Water Clearance ◽  
Endogenous Prostaglandin ◽  
Excretion Rates

Abstract. To define the importance of renal prostaglandins in nephrogenic diabetes insipidus (NDI), diuresis and the urinary excretion of PGE2 and PGF2α were studied in a patient with NDI before and during inhibition of endogenous prostaglandin synthesis with either indomethacin (IND) or acetyl-salicylic acid (ASA). The excretion rates of PGE2 and PGF2α were in the low normal range for the patient's age group, remained unchanged during 6 h of fluid deprivation and were suppressed by IND (150 mg/day), ASA (3 g/day), and by the combination of IND and hydrochlorothiazide (HCT, 50 mg/day). However, whereas IND, HCT, and the combination of IND and HCT reduced diuresis ASA did not. Free water clearance as determined during fluid deprivation remained positive during each phase of therapy. These data fail to demonstrate a direct effect of endogenous ADH on renal prostaglandin synthesis in NDI. The ineffectiveness of ASA to reduce diuresis indicates that indomethacin affects diuresis in NDI by a mechanism other than inhibition of cyclooxygenase.

Effects of terlipressin on the aquaretic system: evidence of antidiuretic effects

2008 ◽  
Vol 295 (5) ◽  
pp. F1295-F1300 ◽  
Author(s):  
Aleksander Krag ◽  
Flemming Bendtsen ◽  
Erling Bjerregaard Pedersen ◽  
Niels-Henrik Holstein-Rathlou ◽  
Søren Møller
Keyword(s):  
Free Water ◽  
Urine Osmolality ◽  
Refractory Ascites ◽  
Plasma Sodium ◽  
Receptor Stimulation ◽  
Free Water Clearance ◽  
Water Excretion ◽  
Water Load ◽  
Before And After ◽  
Placebo Infusion

The vasopressin analog terlipressin is believed to cause vasoconstriction selectively by V1 receptor stimulation. However, a possible antidiuretic effect by V2 receptor stimulation has never been ruled out. Twenty-two patients with ascites, including seven with refractory ascites, were included. The subjects were studied during a 400 ml/h oral water load before and after infusion of 2 mg of terlipressin (18 patients) or placebo infusion (4 patients). Effects on the V2 receptors were assessed by evaluating aquaporin (AQP)2 excretion, free water clearance (C[Formula: see text]), urine osmolality (Uosm), and fractional distal water excretion (DFeH2O). After terlipressin the excretion of AQP2 increased by 89% [144 ng/mmol creatinine, 95% confidence interval (CI) 73–214 ng/mmol creatinine, P = 0.001]. C[Formula: see text] decreased 1.05 ml/min (from 0.17 to −0.89 ml/min, P = 0.001), and DFeH2O decreased 37% (19 vs. 12; 95% CI 2–11, P = 0.01). Uosm increased by 27% (93 mosmol/kgH2O, 95% CI 23–164 mosmol/kgH2O, P = 0.02). Plasma sodium decreased 1.1 mmol/l ( P < 0.01). An increase in AQP2 excretion and a decrease in C[Formula: see text] and distal water excretion after terlipressin despite water loading is a clear indication of activation of the antidiuretic system (V2 receptor effect).

Effect of angiotensin II on urinary dilution in normal man

1964 ◽  
Vol 206 (4) ◽  
pp. 750-754 ◽  
Author(s):  
John R. Gill ◽  
Benjamin H. Barbour ◽  
J. D. H. Slater ◽  
Frederic C. Bartter
Keyword(s):  
Angiotensin Ii ◽  
Diabetes Insipidus ◽  
Renal Plasma Flow ◽  
Free Water ◽  
Normal Subjects ◽  
Diluting Segment ◽  
Free Water Clearance ◽  
Water Excretion ◽  
Urinary Osmolality ◽  
Disease States

Free water clearance (CHH2O) was studied in five normal subjects and in a patient with diabetes insipidus before and during the infusion of angiotensin II (Ciba), .2 µg/min. With angiotensin, CHH2O fell markedly, with only small changes in urinary osmolality both in the normal subjects and in the patient with diabetes insipidus. The fall in CHH2O was accompanied by a fall in UNaV, effective renal plasma flow (ERPF), and glomerular filtration rate (GFR). A physiological dose of Pitressin (25 mU/hr) given after the angiotensin, abolished CHH2O and markedly increased urinary osmolality while UNaV, ERPF, and GFR returned toward normal. The results may be best explained as a direct effect of angiotensin on renal hemodynamics, to decrease filtered sodium and water. Reabsorption of an increased fraction of filtered sodium and water by the proximal tubule would limit the amount reaching the diluting segment of the nephron and excreted in the urine. A possible role for angiotensin in the impaired water excretion of certain disease states, such as Addison's disease and congestive heart failure was suggested.

Nonosmotic release of vasopressin and renal aquaporins in impaired urinary dilution in hypothyroidism

2005 ◽  
Vol 289 (4) ◽  
pp. F672-F678 ◽  
Author(s):  
Yung-Chang Chen ◽  
Melissa A. Cadnapaphornchai ◽  
Jianhui Yang ◽  
Sandra N. Summer ◽  
Sandor Falk ◽  
...  
Keyword(s):  
Protein Expression ◽  
Renal Cortex ◽  
Free Water ◽  
Urine Osmolality ◽  
Protein Abundance ◽  
Oral Gavage ◽  
Water Excretion ◽  
Urinary Osmolality ◽  
Water Load ◽  
Fluid Delivery

The purpose of this study was to examine protein expression of renal aquaporins (AQP) and ion transporters in hypothyroid (HT) rats in response to an oral water load compared with controls (CTL) and HT rats replaced with l-thyroxine (HT+T). Hypothyroidism was induced by aminotriazole administration for 10 wk. Body weight, water intake, urine output, solute and urea excretion, and serum and urine osmolality were comparable among the three groups at the conclusion of the 10-wk treatment period. One hour after oral gavage of water (50 ml/kg body wt), HT rats demonstrated significantly less water excretion, higher minimal urinary osmolality, and decreased serum osmolality compared with CTL and HT+T rats. Despite the hyposmolality, plasma vasopressin concentration was elevated in HT rats. These findings in HT rats were associated with an increase in protein abundance of renal cortex AQP1 and inner medulla AQP2. AQP3, AQP4, and the Na-K-2Cl cotransporter were also increased. Moreover, 1 h following the oral water load, HT rats demonstrated a significant increase in the membrane-to-vesicle fraction of AQP2 by Western blot analysis. The defect in urinary dilution in HT rats was reversed by the V2 vasopressin antagonist OPC-31260. In conclusion, impaired urinary dilution in HT rats is primarily compatible with the nonosmotic release of vasopressin and increased protein expression of renal AQP2. The impairment of maximal solute-free water excretion in HT rats, however, appears also to involve diminished distal fluid delivery.

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