Different antioxidative potencies of dihydropyridine calcium channel modulators in various models.
There is evidence that dihydropyridine calcium antagonists (DHP) play a beneficial role during the development of atherosclerosis. Since antioxidative properties of this substance class may be important, we investigated the antioxidative potency of the DHP prototype calcium channel antagonist nifedipine, the long acting calcium channel antagonist lacidipine, the DHP calcium channel agonist Bay K 8644 and the bulky DHP derivate Bay O 5572 (negligible effects on L-type calcium channels) in three different models. Additionally, we examined the potential correlation between lipophilic and antioxidative properties. In an in vitro model, Bay K 8644 was significantly more effective in scavenging superoxide anions (hypoxanthine/xanthine-oxidase-assay) than lacidipine, Bay O 5572 or nifedipine (micro- to millimolar concentration range). Addition of artificial membrane preparations (dimyristoylphosphatidylcholine) to mimic a physiological environment resulted in an enhanced antioxidative effect, with lacidipine being the most effective DHP to quench radicals (low micromolar concentration range). Thirdly, in a more physiological model of hyperglycemia (30 mmol/l) induced release of reactive oxygen species (ROS) from native endothelial cells of porcine coronary arteries, we showed that nifedipine was a significantly more potent antioxidant (therapeutical nanomolar concentration range) than the other DHP. Calculation of the lipophilicity of the four substances (lacidipine>Bay O 5572>Bay K 8644>nifedipine) showed a positive correlation between the antioxidative potency and the lipophilicity in the model with the artificial membranes but not in the other models. We conclude that it seems necessary to access antioxidative properties of substances in physiological models in which we could demonstrate that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range.
Berkels
Reinhard
R
Department of Pharmacology, University Hospital Cologne, Gleueler Str. 24, 50931 Cologne, Germany. Reinhard.Berkels@uni-duesseldorf.de
Breitenbach
Thomas
T
Bartels
Henning
H
Taubert
Dirk
D
Rosenkranz
Anke
A
Klaus
Wolfgang
W
Roesen
Renate
R
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology*; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D009924:Organ Culture Techniques; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013552:Swine
D000975:Antioxidants; D015220:Calcium Channels; D004095:Dihydropyridines; D017382:Reactive Oxygen Species