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

The superoxide anion (O-2.) 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 O-2. 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 Nomega-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 O-2. reverses the effect of Cu/Zn SOD inhibition.