Mechanism of action of indomethacin in tubular defects.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
D000293:Adolescent; D000450:Aldosterone / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003919:Diabetes Insipidus / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D015232:Dinoprostone; D005199:Fanconi Anemia / Q000150:complications / Q000188:drug therapy; D005500:Follow-Up Studies; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use*; D007223:Infant; D007674:Kidney Diseases / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000503:physiopathology*; D008297:Male; D011458:Prostaglandins E / Q000652:urine
D011458:Prostaglandins E; D000450:Aldosterone; D015232:Dinoprostone; D007213:Indomethacin