Effects of Selective and Unselective Cyclooxygenase Inhibitors on Prostanoid Release from Various Rat Organs 1 IRMGARD TEGEDER, WERNER NEUPERT, 2 HANS G ¨ UHRING, 3 and GERD GEISSLINGER Center of Pharmacology, Johann Wolfgang Goethe-University of Frankfurt, Frankfurt am Main, Germany Accepted for publication November 17, 1999 This paper is available online at http://www.jpet.org ABSTRACT It has been assumed that cyclooxygenase-2 (COX-2) is solely responsible for inflammatory processes. Recently, this view has been challenged because COX-2-selective agents caused a delay of gastric ulcer healing and exacerbation of inflammation in rats. To further characterize organ-specific toxic effects of selective and nonselective COX inhibitors, we assessed the eicosanoid release from different rat organs ex vivo after oral administration of the COX-2-selective inhibitor NS-398 and the unselective COX inhibitors diclofenac, meloxicam, and ketorolac. Prostanoid and leukotriene release from tissue fragments of the stomach, kidney, lung, and brain were determined after ex vivo incubation of tissue fragments in Tyrode’s solution for 10 min at 37°C. Ketorolac (0.1, 0.3, and 0.9 mg/kg) inhibited prostanoid release from all organs most potently and led to a significant increase of leukotriene release from the lung. Effects of diclofenac and meloxicam (1, 3, and 9 mg/kg each) were similar for all organs tested. At 9 mg/kg, 6keto-prostaglandin F (PGF) 1 release from gastric mucosa was reduced by 79.1  11.4 and 87.6  7.7% and PGE 2 release from rat kidney was inhibited by 60.4  6.8 and 78.6  16.6% by diclofenac and meloxicam, respectively. NS-398 did not reduce prostanoid release from the lung. Consistent with the reported constitutive expression of COX-2, prostanoid release from kidney and brain was reduced by 20 to 30%. The release of 6keto-PGF 1 from gastric mucosa was reduced by 34.7  22.2% at 3 mg/kg and by 86.9  12.7% at 9 mg/kg. At these doses, NS-398 has been previously shown to be COX-2 selective. Because PGF 1 is the stable breakdown product of PGI 2 , these results suggest that COX-2 contributes to PGI 2 synthesis in the rat stomach. The chronic use of classical nonsteroidal anti-inflamma- tory drugs (NSAIDs) for treatment of pain and inflammation is limited by their gastrointestinal and renal toxicity. Since the discovery of the “inducible” cyclooxygenase-2 (COX-2), great resources have been invested in developing selective inhibitors of this isoenzyme as gastrointestinal and kidney sparing anti-inflammatory and analgesic drugs. This is based on the premises that 1) COX-2 is solely responsible for pros- taglandin synthesis at sites of inflammation, and 2) COX-1 solely produces prostaglandins required for physiological or- gan functions such as cytoprotection of the gastric mucosa or regulation of renal blood flow. A number of recent studies, however, have raised questions about this “COX-2-selective” theory. A recent study comparing the anti-inflammatory activity of four different COX-2-selective compounds found that signif- icant anti-inflammatory effects occurred only at doses that also inhibited COX-1. At these doses, gastric prostaglandin synthesis also was significantly suppressed and gastric mu- cosal erosions occurred (Wallace et al., 1998). In the rat formalin-induced nociceptive test, the selective COX-2 inhib- itor NS-398 reduced the nociceptive response only at high doses (27 mg/kg) that most probably inhibit both isoenzymes (Euchenhofer et al., 1998). Mice lacking the gene for COX-2 exhibited inflammatory responses similar to those observed in wild-type mice (Morham et al., 1995), whereas mice devoid of the COX-1 gene showed diminished inflammatory re- sponses (Langenbach et al., 1995). Thus, COX-1 may make important contributions to inflammatory responses. In contrast, COX-2 appears to contribute to healing pro- cesses and physiological functions. During inflammation or ulceration in the gastrointestinal tract, COX-2 was shown to produce prostaglandins that are essential for repair (Mizuno et al., 1997; Schmassmann et al., 1998). In these circum- stances, inhibition of COX-2 caused a delay of ulcer healing and exacerbation of inflammation (Mizuno et al., 1997; Schmassmann et al., 1998). Importantly, the inhibition of ulcer healing was observed at doses of the selective COX-2 inhibitor L745,337 previously shown to be COX-2-selective (Chan et al., 1995). Prostaglandins produced by the colonic mucosa in a rat model of colitis were largely derived from Received for publication September 23, 1999. 1 This study was supported by Sonderforschungsbereich (SFB 353 and 553). 2 Current address: Medical Clinic IV, Friedrich Alexander University Er- langen/Nu ¨ rnberg, 91054 Erlangen, Germany. 3 Current address: Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen/Nu ¨ rnberg, 91054 Erlangen, Germany. ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; COX-2, cycclooxygenase-2; PGF, prostaglandin F; LT, leukotriene; TX, throm- boxane. 0022-3565/00/2923-1161$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 292, No. 3 Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 292:1161–1168, 2000 1161 at ASPET Journals on September 27, 2016 jpet.aspetjournals.org Downloaded from