The calcium antagonist nifedipine inhibits the uptake of acetylated LDL into endothelial cells.
The uptake of LDL and modified LDL into macrophages via specific receptors is one of the crucial steps during atherogenesis. Recently, similar receptors for acetylated and oxidized LDL were characterized in endothelial cells. It is known that dihydropyridine calcium antagonists may attenuate the formation of atherosclerotic plaques presumably by an increased nitric oxide (NO) release from endothelial cells. Therefore, we investigated whether the uptake of acetylated LDL into endothelial cells may be altered by the calcium antagonist nifedipine with special emphasis on the NO metabolism. Treatment of porcine endothelial cell cultures with nifedipine induced a significant concentration-dependent inhibition of the uptake of acetylated LDL. This effect could be completely prevented by coincubation with L-nitro-N-arginine, a competitive NO synthase inhibitor. Treatment with the NO donor SNAP resulted in a similar significantly reduced uptake of acetylated LDL. To test whether this effect is due to an NO-mediated cGMP mechanism, we incubated cells with 8-bromo-cGMP and coincubated cells with nifedipine and the soluble guanylyl cyclase inhibitor ODQ. 8-bromo-cGMP partly mimicked the nifedipine effect and ODQ partly reversed the nifedipine effect but not to a significant extent. Therefore, we conclude that the calcium antagonist nifedipine inhibits the uptake of acetylated LDL into endothelial cells via an NO- but presumably not by a cGMP-mediated process, which may possibly contribute to the antiatherogenic action of this drug.
Berkels
R
R
Institut für Pharmakologie, Cologne, Germany. Reinhard.Berkels@medizin.uni-koeln.de
Hass
U
U
Klaus
W
W
D000107:Acetylation; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine; D013552:Swine
D002121:Calcium Channel Blockers; D008078:Cholesterol, LDL; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D017869:Cyclic GMP-Dependent Protein Kinases; D010396:Penicillamine; D006152:Cyclic GMP; D009543:Nifedipine