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

The superoxide anion ([Formula: see text]) 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 × 10-3 M) inhibited total vascular SOD activity by 46% ( P < 0.0001, n = 6-8 dogs). DETCA (7.6 × 10-3M) significantly reduced relaxations to bradykinin and A-23187 ( P < 0.05, n = 7-11). The inhibitory effect of DETCA was abolished by the [Formula: see text]scavenger 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron; 9.4 × 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 × 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 [Formula: see text]reverses the effect of Cu/Zn SOD inhibition.