Inhibition of phospholipase A2 (PLA2) activity by nifedipine and nisoldipine is independent of their calcium-channel-blocking activity.
The effects of several calcium antagonists on phospholipase A2 (PLA2) activity were examined. Nifedipine and nisoldipine inhibited a cell-free preparation of PLA2 in a dose-dependent manner with maximal inhibition of 71-77% observed at 100 microM. More potent or equipotent dihydropyridine calcium antagonists such as nitrendipine and felodipine did not inhibit PLA2 activity. In addition, nondihydropyridine calcium antagonists such as diltiazem, verapamil, and cinnarazine failed to reduce PLA2 activity markedly. Nifedipine and nisoldipine also reduced PLA2 activity in intact mouse peritoneal macrophages where PLA2 activity was monitored by free [14C]arachidonic acid release from [14C]arachidonic acid-prelabeled cells. When levels of PGE2 and LTC4 were measured by radioimmunoassay, it was found that the synthesis of these two metabolites was concomitantly inhibited by nifedipine and nisoldipine. In vivo, nifedipine and nisoldipine inhibited tetradecanoylphorbol acetate (TPA) induced ear edema. UV irradiation of nifedipine and nisoldipine (which destroys the slow calcium-channel-blocking activity of these compounds) did not result in a loss of PLA2 inhibitory activity. In fact, in both instances the UV-irradiated forms of nifedipine and nisoldipine were slightly more potent PLA2 inhibitors than the parent compound alone. We therefore conclude that the ability of nifedipine and nisoldipine to inhibit PLA2 was direct and unrelated to their actions on slow calcium channels.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000528:radiation effects; D015737:Nisoldipine; D010529:Peritoneal Cavity / Q000166:cytology; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054467:Phospholipases A2; D013189:SRS-A / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects; D014466:Ultraviolet Rays
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D002250:Carbon Radioisotopes; D013189:SRS-A; D016718:Arachidonic Acid; D015737:Nisoldipine; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2; D009543:Nifedipine; D013755:Tetradecanoylphorbol Acetate