title: Nifedipine protects against overproduction of superoxide anion by monocytes from patients with systemic sclerosis.
abstract: We have reported previously that dihydropyridine-type calcium-channel antagonists (DTCCA) such as nifedipine decrease plasma markers of oxidative stress damage in systemic sclerosis (SSc). To clarify the cellular basis of these beneficial effects, we investigated the effects in vivo and in vitro of nifedipine on superoxide anion (O2*-) production by peripheral blood monocytes. We compared 10 healthy controls with 12 patients with SSc, first after interruption of treatment with DTCCA and second after 2 weeks of treatment with nifedipine (60 mg/day). O2*- production by monocytes stimulated with phorbol myristate acetate (PMA) was quantified by the cytochrome c reduction method. We also investigated the effects in vitro of DTCCA on O2*- production and protein phosphorylation in healthy monocytes and on protein kinase C (PKC) activity using recombinant PKC. After DTCCA had been washed out, monocytes from patients with SSc produced more O2*- than those from controls. Nifedipine treatment considerably decreased O2*- production by PMA-stimulated monocytes. Treatment of healthy monocytes with nifedipine in vitro inhibited PMA-induced O2*- production and protein phosphorylation in a dose-dependent manner. Finally, nifedipine strongly inhibited the activity of recombinant PKC in vitro. Thus, the oxidative stress damage observed in SSc is consistent with O2*- overproduction by primed monocytes. This was decreased by nifedipine treatment both in vivo and in vitro. This beneficial property of nifedipine seems to be mediated by its cellular action and by the inhibition of PKC activity. This supports the hypothesis that this drug could be useful for the treatment of diseases associated with oxidative stress.
authors.affiliation: Rheumatology A Department, Paris V University, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, Paris, France. yannick.allanore@cch.ap-hop-paris.fr
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
authors.forename: Didier
authors.initials: D
authors.lastname: Borderie
authors.forename: Axel
authors.initials: A
authors.lastname: Périanin
authors.forename: Hervé
authors.initials: H
authors.lastname: Lemaréchal
authors.forename: Ohvanesse Garabed
authors.initials: OG
authors.lastname: Ekindjian
authors.forename: André
authors.initials: A
authors.lastname: Kahan
mesh_terms: D000368:Aged; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002121:Calcium Channel Blockers; D011993:Recombinant Fusion Proteins; D013481:Superoxides; D011493:Protein Kinase C; D009543:Nifedipine; D013755:Tetradecanoylphorbol Acetate