Acetaminophen-sensitive prostaglandin production in rat cerebral endothelial cells.
Acetaminophen is a widely used antipyretic and analgesic drug whose mechanism of action has recently been suggested to involve inhibitory effects on prostaglandin synthesis via a newly discovered cyclooxygenase variant (COX-3). Because COX-3 expression is high in cerebral endothelium, we investigated the effect of acetaminophen on the prostaglandin production of cultured rat cerebral endothelial cells (CECs). Acetaminophen dose-dependently inhibited both basal and LPS-induced PGE(2) production in CECs with IC(50) values of 15.5 and 6.9 microM, respectively. Acetaminophen also similarly inhibited the synthesis of 6-keto-PGF(1alpha) and thromboxane B(2). LPS stimulation increased the expression of COX-2 but not COX-1 or COX-3. In addition, the selective COX-2 inhibitor NS398 (1 microM) was equally as effective as acetaminophen in blocking LPS-induced PGE(2) production. Acetaminophen did not influence the expression of the three COX isoforms and the inducible nitric oxide synthase. In LPS-stimulated isolated cerebral microvessels, acetaminophen also significantly inhibited PGE(2) production. Our results show that prostaglandin production in CECs during basal and stimulated conditions is very sensitive to inhibition by acetaminophen and suggest that acetaminophen acts against COX-2 and not COX-1 or COX-3. Furthermore, our findings support a critical role for cerebral endothelium in the therapeutic actions of acetaminophen in the central nervous system.
Kis
Bela
B
Dept. of Physiology and Pharmacology, Wake Forest Univ. Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157, USA. bkis@wfubmc.edu.
Snipes
James A
JA
Simandle
Steve A
SA
Busija
David W
DW
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000502:physiology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology
D018712:Analgesics, Non-Narcotic; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011453:Prostaglandins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D000082:Acetaminophen; D015121:6-Ketoprostaglandin F1 alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone