Inhibition of prostaglandin E2 and superoxide anion production in rat peritoneal macrophages by the calcium antagonists nifedipine and nisoldipine.
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.
Sakamoto
W
W
Department of Biochemistry, School of Dentistry, Hokkaido University, Sapporo, Japan.
Fujie
K
K
Handa
H
H
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
D013481:Superoxides; D016718:Arachidonic Acid; D000001:Calcimycin; D015737:Nisoldipine; D009543:Nifedipine; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D016257:Fura-2