The anti-inflammatory mechanism of MK-447 in rat carrageenin-induced pleurisy.
Intrapleural injection of 2% lambda-carrageenin caused the accumulation of exudate up to 19 hr. The rate of plasma exudation, measured by the exuded dye amounts for 20 min in the pleural cavity after intravenous injection of pontamine sky blue, showed a peak at 5 hr. Aspirin (100 mg/kg, i. p.) suppressed the dye exudation up to 5 hr, but did not at 7 hr. This inhibition coincided with the decrease of the PG and TXB2 levels, which were measured by gas chromatography-mass spectrometry, in the pleural exudate. In in vitro experiments, MK-447, a phenolic compound, stimulates PG endoperoxide biosynthesis at lower doses and inhibits it at higher doses, acting as a tryptophan-like cofactor required by PG endoperoxide synthetase. This drug (0.3, 1.0 and 3.0 mg/kg, i. p.) suppressed the dye exudation dose-dependently up to 5 hr, but did not at 7 hr even at a higher dose, in combination with the dose-dependent decrease of the pleural level of PGE2, which was reported to be a major PG among PGs and TXB2 in the exudate in inducing the plasma exudation (Harada et al; Prostaglandins, 23: 881, 1982). Thus, the anti-inflammatory action of MK-447 can be explained by inhibition of PGE2 generation, giving no consideration to the role of oxygen-derived free radicals as a prime mediator in inflammation.
D000818:Animals; D000893:Anti-Inflammatory Agents; D001241:Aspirin / Q000627:therapeutic use; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002351:Carrageenan; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000893:Anti-Inflammatory Agents; D011453:Prostaglandins; D002084:Butylated Hydroxytoluene; C013753:2-aminomethyl-4-t-butyl-6-iodophenol; D002351:Carrageenan; D001241:Aspirin