Inhibition of copper/zinc superoxide dismutase impairs NO·-mediated endothelium-dependent relaxations

Christel O. Wambi-Kiéssé, Zvonimir S Katusic

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Abstract

The superoxide anion (O2/-·) appears to be an important modulator of nitric oxide (NO·) bioavailability. The present study was designed to characterize the role of copper/zinc superoxide dismutase (Cu/Zn SOD) in endothelium-dependent relaxations. Cu/Zn SOD was inhibited with the Cu2+ chelator diethyldithiocarbamic acid (DETCA). In isolated canine basilar arteries, DETCA (7.6 x 10-3 M) inhibited total vascular SOD activity by 46% (P < 0.0001, n = 6-8 dogs). DETCA (7.6 x 10-3 M) significantly reduced relaxations to bradykinin and A-23187 (P < 0.05, n = 7-11). The inhibitory effect of DETCA was abolished by the O2/-· scavenger 4,5-dihydroxy-1,3- benzenedisulfonic acid (Tiron; 9.4 x 10-3 M; P < 0.05, n = 6-13). Tiron significantly potentiated the relaxations to bradykinin in control rings (P < 0.05, n = 13), and the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME; 3 x 10-4 M) abolished these relaxations (P < 0.0001, n = 6). DETCA and Tiron had no effect on the relaxations to diethylamine- NONOate or forskolin (P > 0.05, n = 6). Our results demonstrate that endothelium-dependent relaxations mediated by NO· are impaired after the inhibition of Cu/Zn SOD. Relaxations to bradykinin (but not A-23187) were significantly augmented by Tiron. Pharmacological scavenging of O2/-· reverses the effect of Cu/Zn SOD inhibition.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume276
Issue number3 45-3
StatePublished - Mar 1999

Fingerprint

Ditiocarb
Superoxide Dismutase
Endothelium
Zinc
Copper
Nitric Oxide
1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
Basilar Artery
Calcimycin
Bradykinin
Chelating Agents
Superoxides
Biological Availability
Blood Vessels
Canidae
Pharmacology
Superoxide Dismutase-1

Keywords

  • A-23187
  • Bradykinin
  • Cerebral vessels
  • Inflammation
  • Tiron

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

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title = "Inhibition of copper/zinc superoxide dismutase impairs NO·-mediated endothelium-dependent relaxations",
abstract = "The superoxide anion (O2/-·) appears to be an important modulator of nitric oxide (NO·) bioavailability. The present study was designed to characterize the role of copper/zinc superoxide dismutase (Cu/Zn SOD) in endothelium-dependent relaxations. Cu/Zn SOD was inhibited with the Cu2+ chelator diethyldithiocarbamic acid (DETCA). In isolated canine basilar arteries, DETCA (7.6 x 10-3 M) inhibited total vascular SOD activity by 46{\%} (P < 0.0001, n = 6-8 dogs). DETCA (7.6 x 10-3 M) significantly reduced relaxations to bradykinin and A-23187 (P < 0.05, n = 7-11). The inhibitory effect of DETCA was abolished by the O2/-· scavenger 4,5-dihydroxy-1,3- benzenedisulfonic acid (Tiron; 9.4 x 10-3 M; P < 0.05, n = 6-13). Tiron significantly potentiated the relaxations to bradykinin in control rings (P < 0.05, n = 13), and the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME; 3 x 10-4 M) abolished these relaxations (P < 0.0001, n = 6). DETCA and Tiron had no effect on the relaxations to diethylamine- NONOate or forskolin (P > 0.05, n = 6). Our results demonstrate that endothelium-dependent relaxations mediated by NO· are impaired after the inhibition of Cu/Zn SOD. Relaxations to bradykinin (but not A-23187) were significantly augmented by Tiron. Pharmacological scavenging of O2/-· reverses the effect of Cu/Zn SOD inhibition.",
keywords = "A-23187, Bradykinin, Cerebral vessels, Inflammation, Tiron",
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T1 - Inhibition of copper/zinc superoxide dismutase impairs NO·-mediated endothelium-dependent relaxations

AU - Wambi-Kiéssé, Christel O.

AU - Katusic, Zvonimir S

PY - 1999/3

Y1 - 1999/3

N2 - The superoxide anion (O2/-·) appears to be an important modulator of nitric oxide (NO·) bioavailability. The present study was designed to characterize the role of copper/zinc superoxide dismutase (Cu/Zn SOD) in endothelium-dependent relaxations. Cu/Zn SOD was inhibited with the Cu2+ chelator diethyldithiocarbamic acid (DETCA). In isolated canine basilar arteries, DETCA (7.6 x 10-3 M) inhibited total vascular SOD activity by 46% (P < 0.0001, n = 6-8 dogs). DETCA (7.6 x 10-3 M) significantly reduced relaxations to bradykinin and A-23187 (P < 0.05, n = 7-11). The inhibitory effect of DETCA was abolished by the O2/-· scavenger 4,5-dihydroxy-1,3- benzenedisulfonic acid (Tiron; 9.4 x 10-3 M; P < 0.05, n = 6-13). Tiron significantly potentiated the relaxations to bradykinin in control rings (P < 0.05, n = 13), and the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME; 3 x 10-4 M) abolished these relaxations (P < 0.0001, n = 6). DETCA and Tiron had no effect on the relaxations to diethylamine- NONOate or forskolin (P > 0.05, n = 6). Our results demonstrate that endothelium-dependent relaxations mediated by NO· are impaired after the inhibition of Cu/Zn SOD. Relaxations to bradykinin (but not A-23187) were significantly augmented by Tiron. Pharmacological scavenging of O2/-· reverses the effect of Cu/Zn SOD inhibition.

AB - The superoxide anion (O2/-·) appears to be an important modulator of nitric oxide (NO·) bioavailability. The present study was designed to characterize the role of copper/zinc superoxide dismutase (Cu/Zn SOD) in endothelium-dependent relaxations. Cu/Zn SOD was inhibited with the Cu2+ chelator diethyldithiocarbamic acid (DETCA). In isolated canine basilar arteries, DETCA (7.6 x 10-3 M) inhibited total vascular SOD activity by 46% (P < 0.0001, n = 6-8 dogs). DETCA (7.6 x 10-3 M) significantly reduced relaxations to bradykinin and A-23187 (P < 0.05, n = 7-11). The inhibitory effect of DETCA was abolished by the O2/-· scavenger 4,5-dihydroxy-1,3- benzenedisulfonic acid (Tiron; 9.4 x 10-3 M; P < 0.05, n = 6-13). Tiron significantly potentiated the relaxations to bradykinin in control rings (P < 0.05, n = 13), and the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME; 3 x 10-4 M) abolished these relaxations (P < 0.0001, n = 6). DETCA and Tiron had no effect on the relaxations to diethylamine- NONOate or forskolin (P > 0.05, n = 6). Our results demonstrate that endothelium-dependent relaxations mediated by NO· are impaired after the inhibition of Cu/Zn SOD. Relaxations to bradykinin (but not A-23187) were significantly augmented by Tiron. Pharmacological scavenging of O2/-· reverses the effect of Cu/Zn SOD inhibition.

KW - A-23187

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KW - Cerebral vessels

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JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

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