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Nifedipine protects against overproduction of superoxide anion by monocytes from patients with systemic sclerosis.

Allanore Y, Borderie D, Périanin A, Lemaréchal H, Ekindjian OG, Kahan A - Arthritis Res. Ther. (2004)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Rheumatology A Department, Paris V University, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, Paris, France. yannick.allanore@cch.ap-hop-paris.fr

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.

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Superoxide anion production by monocytes after induction with phorbol myristate acetate (PMA; 100 nM) for 15 min. From healthy controls (n = 10), patients with systemic sclerosis (SSc) after disruption of calcium-channel blocker treatment (n = 12) (baseline) and patients with SSc after 14 days of treatment with 60 mg/day nifedipine (NIF) (n = 12) (a), from healthy donors (n = 5) treated with or without various concentrations of nifedipine for 30 min before stimulation with PMA (b) and from healthy donors treated with or without calcium-channel blockers (10 µM) before stimulation with PMA (c). *P < 0.05; **P < 0.01 relative to controls.
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Figure 1: Superoxide anion production by monocytes after induction with phorbol myristate acetate (PMA; 100 nM) for 15 min. From healthy controls (n = 10), patients with systemic sclerosis (SSc) after disruption of calcium-channel blocker treatment (n = 12) (baseline) and patients with SSc after 14 days of treatment with 60 mg/day nifedipine (NIF) (n = 12) (a), from healthy donors (n = 5) treated with or without various concentrations of nifedipine for 30 min before stimulation with PMA (b) and from healthy donors treated with or without calcium-channel blockers (10 µM) before stimulation with PMA (c). *P < 0.05; **P < 0.01 relative to controls.

Mentions: Monocytes from patients with SSc (n = 12) not treated by nifedipine produced a significantly greater amount of O2•- than controls (n = 10) after stimulation ex vivo with the PKC activator PMA for 15 min (9.1 ± 1.7 versus 5.4 ± 0.7 nmol per 106 cells; P < 0.01; Fig. 1a). This difference was also observed when monocytes were stimulated with PMA for 10 min (7.6 ± 2.3 versus 4.3 ± 0.8 nmol per 106 cells; P < 0.01) but not when they were stimulated for 5 min (2.7 ± 0.8 versus 2.1 ± 0.4 nmol per 106 cells; not significant). These observations suggest that the biochemical modifications affecting monocytes from patients with SSc might not affect the kinetics of NADPH oxidase but rather its late regulatory mechanisms.


Nifedipine protects against overproduction of superoxide anion by monocytes from patients with systemic sclerosis.

Allanore Y, Borderie D, Périanin A, Lemaréchal H, Ekindjian OG, Kahan A - Arthritis Res. Ther. (2004)

Superoxide anion production by monocytes after induction with phorbol myristate acetate (PMA; 100 nM) for 15 min. From healthy controls (n = 10), patients with systemic sclerosis (SSc) after disruption of calcium-channel blocker treatment (n = 12) (baseline) and patients with SSc after 14 days of treatment with 60 mg/day nifedipine (NIF) (n = 12) (a), from healthy donors (n = 5) treated with or without various concentrations of nifedipine for 30 min before stimulation with PMA (b) and from healthy donors treated with or without calcium-channel blockers (10 µM) before stimulation with PMA (c). *P < 0.05; **P < 0.01 relative to controls.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1064885&req=5

Figure 1: Superoxide anion production by monocytes after induction with phorbol myristate acetate (PMA; 100 nM) for 15 min. From healthy controls (n = 10), patients with systemic sclerosis (SSc) after disruption of calcium-channel blocker treatment (n = 12) (baseline) and patients with SSc after 14 days of treatment with 60 mg/day nifedipine (NIF) (n = 12) (a), from healthy donors (n = 5) treated with or without various concentrations of nifedipine for 30 min before stimulation with PMA (b) and from healthy donors treated with or without calcium-channel blockers (10 µM) before stimulation with PMA (c). *P < 0.05; **P < 0.01 relative to controls.
Mentions: Monocytes from patients with SSc (n = 12) not treated by nifedipine produced a significantly greater amount of O2•- than controls (n = 10) after stimulation ex vivo with the PKC activator PMA for 15 min (9.1 ± 1.7 versus 5.4 ± 0.7 nmol per 106 cells; P < 0.01; Fig. 1a). This difference was also observed when monocytes were stimulated with PMA for 10 min (7.6 ± 2.3 versus 4.3 ± 0.8 nmol per 106 cells; P < 0.01) but not when they were stimulated for 5 min (2.7 ± 0.8 versus 2.1 ± 0.4 nmol per 106 cells; not significant). These observations suggest that the biochemical modifications affecting monocytes from patients with SSc might not affect the kinetics of NADPH oxidase but rather its late regulatory mechanisms.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Rheumatology A Department, Paris V University, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, Paris, France. yannick.allanore@cch.ap-hop-paris.fr

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.

Show MeSH
Related in: MedlinePlus