POTENTIATION OF NITRIC OXIDE-MEDIATED VASCULAR RELAXATION BY SC52608,A SUPEROXIDE-DISMUTASE MIMIC

Nitric oxide (NO) produced by the vascular endothelium is an endogenou s contributor to the regulation of vascular relaxation and the mainten ance of blood pressure, The effective half-life of NO and the relaxati on of aortic rings by NO is enhanced by a reduction in the concentrati on of superoxide radicals with superoxide dismutase (SOD), In the curr ent study, SC52608, a newly synthesized SOD mimic with a manganese cor e, was tested for its ability to potentiate the activity of NO both in vitro and in vivo, SC52608 relaxation of rat aortic segments was endo thelium dependent as well as concentration dependent. The maximum rela xation following KCI contraction was 44% with 300 mu M SC52608. Cyclic GMP concentrations in the segments were increased 1,6- and 3.2-fold w ith 5 and 300 mu M SC52608, respectively, N-monomethyl-I-arginine pret reatment of aortic rings abolished the relaxation and cyclic GMP accum ulation mediated by SC52608. In a smooth muscle cell reporter system o f nitric oxide synthase activity, SC52608 potentiated the increase in cyclic GMP elicited by NO in a concentration dependent manner with a m aximum increase of 5.2-fold at 100 mu M Injection of SC52608 into cons cious, restrained rats resulted in a dose-dependent decrease of blood pressure. Therefore, the data suggest that SC52608 potentiates the act ions of nitric oxide on vascular tone, cyclic GMP, and blood pressure by enhancing the half-life of NO through a mechanism that mimics the a ction of SOD.