Article date: April 1980
By: J.R.S. HOULT, P.K. MOORE in Volume 68, Issue 4, pages 719-730
We have investigated the effects of sulphasalazine and of its principal colonic metabolites (5‐aminosalicylic acid and sulphapyridine) on prostaglandin inactivation, synthesis and actions on gastrointestinal smooth muscle.
Sulphasalazine inhibits prostaglandin F2α breakdown in 100,000 g supernatants in all organs so far tested from 7 species with an ID50 of approx. 50 μm; it has a selective action on prostaglandin 15‐hydroxydehydrogenase and does not inhibit prostaglandin Δ‐13 reductase, prostaglandin 9‐hydroxydehydrogenase or ‘enzyme X’ at millimolar concentrations. Enzyme activities were measured radiochemically or by bioassay.
Sulphapyridine and 5‐aminosalicylic acid do not inhibit prostaglandin inactivation in vitro (4 species tested). A methyl analogue of sulphasalazine is a more potent inhibitor than the parent compound. Rabbit colon prostaglandin F2α metabolism in vitro was inhibited by the following drugs with ID50 values (μm) of: diphloretin phosphate 20, sulphasalazine 50, indomethacin 220, frusemide 1000 and aspirin 10,000. A similar rank order of potencies was obtained with rabbit kidney.
Sulphasalazine at 50 to 100 μm inhibited inactivation of prostaglandin E2 in the perfused rat and guinea‐pig lung by 3 to 40% (rat) and 32 to 100% (guinea‐pig) when measured by superfusion cascade bioassay and of prostaglandin F2α by 43.6 ± 6.5% in rat lung perfused with 50 μm sulphasalazine and assayed radiochemically.
Prostaglandins E1 and E2 were 97.0 ± 8.2% and 92.3 ± 6.8% inactivated in the lungs after intravenous injection in the anaesthetized rat as measured by reference to their vasodepressor potencies when injected intra‐arterially. Prostaglandin A2 was not similarly inactivated. Pulmonary inactivation was prevented in the presence of an intravenous infusion of 16.3 μg kg−1 min−1 sulphasalazine and partially inhibited at a lower infusion rate.
Prostaglandin biosynthesis from arachidonic acid was measured in microsomal preparations from four sources by bioassay and radiochemical methods. Indomethacin was a potent inhibitor (ID50 0.8 to 4.1 μm) but sulphasalazine and its methyl analogue were very weak inhibitors (ID50 1500 to > 5000 μm), 5‐aminosalicylic acid was weaker still and sulphapyridine inactive.
Sulphasalazine at 50 μm did not affect the actions of prostaglandins on five smooth muscle preparations; at 500 μm there was a rapidly reversible and probably non‐specific antagonism of responses to low doses of prostaglandins.
The specificity and selectivity of the interaction of sulphasalazine and its metabolites with the formation, breakdown and actions of prostaglandins are discussed.
We have investigated the effects of sulphasalazine and of its principal colonic metabolites (5‐aminosalicylic acid and sulphapyridine) on prostaglandin inactivation, synthesis and actions on gastrointestinal smooth muscle.
Sulphasalazine inhibits prostaglandin F2α breakdown in 100,000 g supernatants in all organs so far tested from 7 species with an ID50 of approx. 50 μm; it has a selective action on prostaglandin 15‐hydroxydehydrogenase and does not inhibit prostaglandin Δ‐13 reductase, prostaglandin 9‐hydroxydehydrogenase or ‘enzyme X’ at millimolar concentrations. Enzyme activities were measured radiochemically or by bioassay.
Sulphapyridine and 5‐aminosalicylic acid do not inhibit prostaglandin inactivation in vitro (4 species tested). A methyl analogue of sulphasalazine is a more potent inhibitor than the parent compound. Rabbit colon prostaglandin F2α metabolism in vitro was inhibited by the following drugs with ID50 values (μm) of: diphloretin phosphate 20, sulphasalazine 50, indomethacin 220, frusemide 1000 and aspirin 10,000. A similar rank order of potencies was obtained with rabbit kidney.
Sulphasalazine at 50 to 100 μm inhibited inactivation of prostaglandin E2 in the perfused rat and guinea‐pig lung by 3 to 40% (rat) and 32 to 100% (guinea‐pig) when measured by superfusion cascade bioassay and of prostaglandin F2α by 43.6 ± 6.5% in rat lung perfused with 50 μm sulphasalazine and assayed radiochemically.
Prostaglandins E1 and E2 were 97.0 ± 8.2% and 92.3 ± 6.8% inactivated in the lungs after intravenous injection in the anaesthetized rat as measured by reference to their vasodepressor potencies when injected intra‐arterially. Prostaglandin A2 was not similarly inactivated. Pulmonary inactivation was prevented in the presence of an intravenous infusion of 16.3 μg kg−1 min−1 sulphasalazine and partially inhibited at a lower infusion rate.
Prostaglandin biosynthesis from arachidonic acid was measured in microsomal preparations from four sources by bioassay and radiochemical methods. Indomethacin was a potent inhibitor (ID50 0.8 to 4.1 μm) but sulphasalazine and its methyl analogue were very weak inhibitors (ID50 1500 to > 5000 μm), 5‐aminosalicylic acid was weaker still and sulphapyridine inactive.
Sulphasalazine at 50 μm did not affect the actions of prostaglandins on five smooth muscle preparations; at 500 μm there was a rapidly reversible and probably non‐specific antagonism of responses to low doses of prostaglandins.
The specificity and selectivity of the interaction of sulphasalazine and its metabolites with the formation, breakdown and actions of prostaglandins are discussed.
DOI: 10.1111/j.1476-5381.1980.tb10865.x
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