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Effects of selective and unselective cyclooxygenase inhibitors on prostanoid release from various rat organs
I Tegeder1, W Neupert, H Gühring
1Center of Pharmacology, Johann Wolfgang Goethe-University of Frankfurt, Frankfurt am Main, Germany.
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 degrees 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)(1alpha) 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(1alpha) 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(1alpha) is the stable breakdown product of PGI(2), these results suggest that COX-2 contributes to PGI(2) synthesis in the rat stomach.
Insights
Cyclooxygenase-2 (COX-2) selective inhibitors impact eicosanoid release differently across rat organs. COX-2 inhibition contributes to prostacyclin (PGI2) synthesis in the stomach, challenging its sole role in inflammation.
Area of Science:
- Pharmacology
- Biochemistry
- Toxicology
Background:
- Cyclooxygenase-2 (COX-2) has been traditionally linked to inflammation.
- Recent findings challenge this view, showing COX-2 selective agents can delay ulcer healing and worsen inflammation in rats.
- Organ-specific toxic effects of COX inhibitors require further investigation.
Purpose of the Study:
- To investigate the organ-specific effects of selective and nonselective COX inhibitors on eicosanoid release in rats.
- To characterize the impact of COX inhibition on prostanoid and leukotriene release from various tissues.
- To assess the contribution of COX-2 to prostacyclin (PGI2) synthesis in the rat stomach.
Main Methods:
- Oral administration of COX inhibitors (NS-398, diclofenac, meloxicam, ketorolac) to rats.
- Ex vivo assessment of prostanoid and leukotriene release from stomach, kidney, lung, and brain tissue fragments.
- Incubation of tissue fragments in Tyrode's solution at 37°C for 10 minutes.
Main Results:
- Ketorolac potently inhibited prostanoid release from all organs and increased lung leukotriene release.
- Diclofenac and meloxicam showed similar effects across organs, significantly reducing gastric PGI2 and kidney PGE2 release.
- NS-398, a COX-2 selective inhibitor, reduced gastric PGI2 release, suggesting COX-2 involvement in PGI2 synthesis in the stomach, while having minimal effect on lung prostanoid release.
Conclusions:
- COX-2 selective inhibition affects eicosanoid release differently depending on the organ.
- COX-2 plays a role in prostacyclin (PGI2) synthesis in the rat stomach.
- These findings highlight the complex, organ-specific toxicological profiles of COX inhibitors.