Superoxide generation by either 1‐oleoyl‐2‐acetylglycerol or A23187 in human neutrophils is enhanced by indomethacin

Abstract

Indomethacin at a concentration ( 1O-4 M) which depressed the effect on O,-generation by fMet-Leu-Phe, markedly enhanced 0; generation by both I-oleoyl-2-acetylglycerol and the calcium ionophore. A23187. These results are explicable in terms of the hypothesis that synergism between cytosolic calcium and protein kinase C is involved in signal transduction for the respiratory burst in the human neutrophil. NeutrophilSuperoxide Phorbol ester Indomethacin Calcium

Comparison of the effects of indomethacin, RHC80267 and R59022 on superoxide production by 1,oleoyl‐2,acetyl glycerol and A23187 in human neutrophils

“…Thus the significance of both pathways in the transduction of the respiratory burst has been well established. In addition it has been found that indomethacin exacerbates O2 generation by both OAG and A23187, shifting the concentration-response curve to the left for each substance, and frequently increasing the maximum response as well (Dale & Penfield, 1985). On the basis of these results we proposed that indomethacin, in addition to inhibiting cyclo-oxygenase, also had an effect on DAG metabolism, inhibiting either DAG kinase or DAG lipase or both (Dale & Penfield, 1985).…”

“…This is strong evidence that the protein kinase C pathway is in fact involved in signal transduction for°2 generation. We had originally put forward a hypothesis, based on Nishizuka's 1984 model of signal transduction, to explain the increase by indomethacin, of 0°release (Dale & Penfield, 1985). We suggested that indomethacin had an inhibitory effect on DAG kinase of DAG lipase or both.…”

“…In the present study we have sought to throw light on the mechanism of indomethacin's effect on O°generation by comparing it with RHC80267, a specific DAG lipase inhibitor (Sutherland & Amin, 1982), and with R59022, a specific DAG kinase inhibitor (de Chaffoy de Courcelies et al, 1985). The effect of indomethacin had been found to be dose-related over the concentration range 10-6 10-4 M (Penfield & Dale, 1985) but in the present study only 10-4 M (which is not in fact the maximally effective concentration) was used, since in order to compare the effect of indomethacin with other agents it was important to ensure that as pronounced an indomethacin response as possible was obtained.…”

“…In addition it has been found that indomethacin exacerbates O2 generation by both OAG and A23187, shifting the concentration-response curve to the left for each substance, and frequently increasing the maximum response as well (Dale & Penfield, 1985). On the basis of these results we proposed that indomethacin, in addition to inhibiting cyclo-oxygenase, also had an effect on DAG metabolism, inhibiting either DAG kinase or DAG lipase or both (Dale & Penfield, 1985). Rittenhouse-Simmons (1980) had provided evidence that indomethacin was, in fact, an effective inhibitor ofhuman platelet DAG metabolism over the range of concentrations which we had found to exacerbate°2 generation.…”

Communications

“…The non-steroidal anti-inflammatory drugs (NSAIDs) are thought to mediate their anti-inflammatory effects by inhibition of cyclooxygenase, but a number of anomalous results suggest that there may be additional effects which could increase inflammatory mechanisms. We have shown that the NSAID, indomethacin, increases superoxide production from neutrophils activated with post-receptor stimuli (Dale & Penfleld, 1985). Here we present another example, sodium meclofenamate, which increases both post-receptor and receptor-mediated superoxide generation.…”