Effect of sulindac on prostaglandin synthesis in human and in cultured rat renal and vascular smooth muscle cells.
To examine the hypothesis that sulindac does not inhibit renal prostaglandin (PG) synthesis, we investigated the effects of sulindac and other nonsteroidal anti-inflammatory drugs on PG synthesis in human and in cultured rat renal and vascular smooth muscle (VSM) cells. In 7 patients with chronic glomerular disease, creatinine clearance and proteinuria were not changed by sulindac but were significantly reduced by diclofenac sodium. However, urinary excretion of PGE2 was decreased by both drugs. In cultured glomerular mesangial (GM), renal papillary collecting tubule (RPCT) and VSM cells from mesenteric artery, indomethacin, tiaprofenic acid, aspirin and ibuprofen inhibited both basal and arachidonic acid (AA)-stimulated PG synthesis dose-dependently. Although sulindac sulfoxide, at the same concentrations, inhibited both basal and AA-stimulated PGE2 synthesis in RPCT cells, it was less potent to inhibit PGI2 synthesis in VSM cells or PGE2 synthesis in GM cells. Active form sulindac sulfide inhibited PG synthesis in all types of cells but its inactive form sulfone did not. We conclude that sulindac inhibits renal PG synthesis but has little effect on renal function. This may be explained by its relatively weak potency on glomerular or vascular PG synthesis inhibition possibly due to the different biotransformation of the sulfoxide to the active sulfide in these cells.
Sato
M
M
Second Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Abe
K
K
Takeuchi
K
K
Yasujima
M
M
Akiu
N
N
Saito
T
T
Yoshinaga
K
K
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000293:Adolescent; D000328:Adult; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D002478:Cells, Cultured; D003404:Creatinine / Q000652:urine; D004008:Diclofenac / Q000494:pharmacology; D015232:Dinoprostone / Q000652:urine; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013467:Sulindac / Q000494:pharmacology*
D001095:Arachidonic Acids; D011453:Prostaglandins; D004008:Diclofenac; D013467:Sulindac; D015121:6-Ketoprostaglandin F1 alpha; D003404:Creatinine; D015232:Dinoprostone; D007052:Ibuprofen