Indomethacin decreases optic nerve oxygen tension by a mechanism other than cyclo-oxygenase inhibition

Abstract

Aims: We investigated the effect of several Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), on the preoptic nerve oxygen tension (ONPO 2 ), as indomethacin previously has demonstrated a strong decreasing effect on ONPO 2 . We tested whether these NSAIDs, like indomethacin, also reduce the increasing effect of dorzolamide on ONPO 2 . Methods: ONPO 2 was measured 0.5 mm above the optic disc in 23 domestic pigs (26-36 kg) with a polarographic oxygen-sensitive electrode. One of the following NSAIDs was administered intravenously as increasing doses or as one large dose: indomethacin, ibuprofen, diclofenac, ketoprofen, parecyclo-oxygenase-2 inhibitor and lornoxicam. Indomethacin was both tested alone and after preceding administration of the other NSAIDs. Dorzolamide was also tested after preceding administration of NSAIDs different from indomethacin. Results: Indomethacin decreased ONPO 2 significantly in a dose-dependent manner. None of the other NSAIDs produced any effect on the ONPO 2 (p..0.05; n = 17). No difference was found between the effect of indomethacin injected alone, and after preceding administration of the other NSAIDs. Intravenous dorzolamide (500 mg) increased ONPO 2 by 32 (7)% (n = 7; p,0.001) after preceding administration of several NSAIDs different from indomethacin. Conclusions: Indomethacin decreased ONPO 2 , while the other NSAIDs showed no effect on ONPO 2 , and they did not affect the effect of indomethacin. The hypoxic effect of indomethacin must be due to another mechanism than cyclo-oxygenase inhibition. The effect of dorzolamide on ONPO 2 is not related to prostaglandin production.Optic nerve head hypoxia and retinal ischaemia are believed to play an important role in the pathogenesis of glaucoma, 1 2 and diabetic retinopathy. 3 We have previously reported that a large dose of indomethacin decreases preoptic nerve oxygen tension, ONPO 2 , by 41% and almost abolishes the augmenting effect of dorzolamide, a carbonic anhydrase inhibitor, and hypercapnia on the porcine ONPO 2 .4 It is not known whether these effects of indomethacin persist with smaller, more clinically relevant, doses of the drug.Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) which, along with all other drugs of this class, inhibits the cyclo-oxygenase, or COX, enzyme.5 However, it is clear from previous studies that indomethacin possesses additional effects that are not dependent on the COX enzyme when compared with other NSAIDs. 6-10It is not known whether the decreasing effect of indomethacin on ONPO 2 is dependent on the COX enzyme, or whether it is caused by another mechanism.In the present study, we investigated the doseresponse curve for the effects of indomethacin on the porcine ONPO 2 . We also tested whether other NSAIDs than indomethacin might have a similar decreasing effect on the ONPO 2 . We further tested whether the effect of indomethacin on ONPO 2 could be inhibited with preceding COX inhibition by other NSAIDs. Finally, we investigated the mechanism of dorzolamide on the ONPO 2 , b...