title: Inhibition of prostaglandin E2 and superoxide anion production in rat peritoneal macrophages by the calcium antagonists nifedipine and nisoldipine.
abstract: In order to clarify the possibility of an antiatherogenic action of the calcium antagonists nifedipine (CAS 21829-25-4) and nisoldipine (CAS 63675-72-9) the effect of nifedipine and nisoldipine on phorbol myristate acetate (PMA)- and calcium ionophore A23187-stimulated O2- and PGE2 production from macrophages was investigated. Nifedipine and nisoldipine inhibited dose-dependently PMA-stimulated O2- and PGE2 production, but not A23187-stimulated PGE2 production. The 50% inhibitory concentration (IC50) of nifedipine and nisoldipine for PMA-stimulated O2- production were 60 and 8 mumol/l, respectively, whereas those for A23187-stimulated O2- were 9.3 and 2.0 mumol/l. IC50 of nifedipine and nisoldipine for PMA-stimulated PGE2 production were 3.0 and 2.8 mumol/l, respectively. The release of [1-14C]-arachidonic acid from labeled macrophages stimulated with PMA was inhibited approximately by 39 to 43% in the presence of 20 mumol/l nifedipine and nisoldipine. The increase of (Ca2+)i in macrophages induced by A23187 could not be attenuated by nifedipine and nisoldipine, and (Ca2+)i level did not alter when stimulated with PMA. These results suggest that the inhibitory mechanism of nifedipine and nisoldipine for O2- production from the macrophages appears to directly inhibit the enzyme system of the NADPH-oxidase complex through the activation of protein kinase C, and that the inhibition of PMA-stimulated PGE2 production may be due to a decrease of phospholipase A2 through protein kinase C. On the basis of the inhibitory action on O2- and PGE2 production from the macrophages, a possible mechanism of antiatherogenic effect of calcium antagonists was discussed.
authors.affiliation: Department of Biochemistry, School of Dentistry, Hokkaido University, Sapporo, Japan.
authors.forename: W
authors.initials: W
authors.lastname: Sakamoto
authors.forename: K
authors.initials: K
authors.lastname: Fujie
authors.forename: H
authors.initials: H
authors.lastname: Handa
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis*; D016257:Fura-2; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009543:Nifedipine / Q000494:pharmacology*; D015737:Nisoldipine / Q000494:pharmacology*; D010529:Peritoneal Cavity / Q000166:cytology; D051381:Rats; D011919:Rats, Inbred Strains; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D013481:Superoxides; D016718:Arachidonic Acid; D000001:Calcimycin; D015737:Nisoldipine; D009543:Nifedipine; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D016257:Fura-2