Inhibition of the Prostaglandin Synthetase Systems in Ocular Tissues by Indomethacin

Abstract

We have compared the sensitivity of the prostaglandin synthetase systems derived from microsomal fractions of rabbit ocular tissues (anterior uvea, conjunctiva and retina) with other rabbit tissues such as the kidney medulla and spleen, to inhibition by indomethacin. Generation of prostaglandin‐like activity by the microsomal fractions from added arachidonic acid varied with the tissue used. Highest activity was found in the kidney medulla, then in descending order, the conjunctiva, anterior uvea, spleen, retina and cornea. Indomethacin was most potent in the spleen (ID50 0.045 μg/ml) then in decreasing order in the kidney medulla, conjunctiva, anterior uvea and weakest in the retina, where the ID50 for indomethacin was 50 μg/ml. The differential sensitivity to inhibition of the prostaglandin synthetase systems from different tissues is an important consideration in the development of new ocular anti‐inflammatory agents.

Inhibition of Peristalsis in Guinea‐pig Isolated Ileum and Colon by Drugs That Block Prostaglandin Synthesis

“…Poor penetration might explain the tendency for the synthetase inhibitors to be less active intraluminally and might account for the 30-90 min contact time required for maximal effects in isolated strips (Bennett et al, 1975a). The sensitivities of prostaglandin synthesizing enzymes to indomethacin in different rabbit tissues differ over a range of 1100-fold (Bhattacherjee & Eakins, 1974). If enzymes in the gut show a spectrum of sensitivities, drugs might not inhibit prostaglandin synthesis at all sites.…”

Ocular Anti-Inflammatory and Systemic Immunosuppressive Effects of Topically Applied Fluorometholone

“…The nonsteroidal anti-inflammatory agent indomethacin showed no significant effect on the uveitis or circulating antibody and such may be related to the fact that prostaglandin synthetase systems from microsomal fractions of rabbit ocular tissues are much less sensitive to inhibition by indomethacin than are microsomal fractions of other tissues (23).…”

Inhibition of Trauma-Induced Miosis by Indoxole

“…Evidence has accumulated that these events are mediated by the action of a synthetase complex on arachidonic acid, the essential fatty acid parent compound of those prostaglandins with a site of unsat uration in each of the two side chains [Bhattacherjee and Eakins, 1974a]. These have particular importance in anterior ocular segment inflamma tion.…”

“…Topically administered indoxole may be a significantly more potent inhibitor of this reaction in the anterior ocular segment than the more widely investigated indomethacin [Glenn et al, 1966;Podos and Becker, 1976;Bhattacherjee and Eakins, 1974b], but some uncertainty remains because of variation of relative effect in differing models [Bhattacherjee and Eakins 1975;Smolin et al, 1979].…”