Suppression of inflammatory responses to 12-O-tetradecanoyl-phorbol-13-acetate and carrageenin by YM-26734, a selective inhibitor of extracellular group II phospholipase A2.
1. YM-26734 [4-(3,5-didodecanoyl-2,4,6-trihydroxyphenyl)-7-hydroxy-2-(4-hydroxyph eny l) chroman] dose-dependently inhibited the activities of extracellular phospholipase A2 (PLA2): rabbit platelet-derived group II and porcine pancreas-derived group I PLA2, with IC50 values of 0.085 (0.056-0.129, n = 5) and 6.8 (5.0-9.6, n = 5) microM, respectively. 2. In contrast, YM-26734 did not reduce the activity of intracellular PLA2 prepared from mouse macrophages, which preferentially hydrolyzed arachidonoyl phospholipids at concentrations up to 50 microM. YM-26734 also showed no effect against either sheep seminal vesicle cyclo-oxygenase or rat leukocyte 5-lipoxygenase. 3. Linewater-Burk analysis showed that YM-26567-1 behaved as a competitive inhibitor of group II PLA2 derived from rabbit platelets, with a Ki value of 48 nM. 4. In mice, YM-26734 inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA, 1 microgram/ear)-induced ear oedema in a dose-dependent manner, with ED50 values of 45 (30-67) micrograms/ear (n = 5) and 11 (4-32) mg kg-1, i.v. (n = 5), but did not decrease arachidonic acid (4 mg/ear)-induced ear oedema at 1 mg/ear and 30 mg kg-1, i.v. 5. In rats, the accumulation of exudate fluids and leukocytes in the pleural cavity in response to carrageenin injection (2 mg) was significantly less in a group treated with YM-26734 (20 mg kg-1, i.v.) than in the control group (0.43 +/- 0.02 vs 0.59 +/- 0.03 g per cavity and 3.8 +/- 0.2 vs 4.9 +/- 0.3 x 10(7) cells per cavity, respectively; n = 5). 6. These results suggest that YM-26734 is a potent and competitive inhibitor of extracellular PLA2 with selectivity for group II PLA2, and that the inhibition of group II enzymes activity may cause the suppression of inflammatory responses to TPA and carrageenin.
Miyake
A
A
Molecular and Cellular Pharmacology, Dept., Yamanouchi Pharmaceutical Co. Ltd., Tokyo, Japan.
Yamamoto
H
H
Kubota
E
E
Hamaguchi
K
K
Kouda
A
A
Honda
K
K
Kawashima
H
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D002351:Carrageenan / Q000037:antagonists & inhibitors*; D002839:Chromans / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004431:Ear, External / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D005110:Extracellular Space / Q000201:enzymology; D005260:Female; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010636:Phenols / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D010998:Pleurisy / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012756:Sheep; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002839:Chromans; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D010636:Phenols; C084181:YM 26734; D016718:Arachidonic Acid; D002351:Carrageenan; D010741:Phospholipases A; D054467:Phospholipases A2; D013755:Tetradecanoylphorbol Acetate