VASODILATORY EFFECTS OF A SALEN-MANGANESE COMPLEX WITH POTENT OXYRADICAL SCAVENGER ACTIVITIES

The effects on rat aorta of EUK-8, salen-manganese complex with high s uperoxide dismutase and catalase activities, were investigated. EUK-8 protected the acetylcholine-induced relaxation of rat aortic rings fro m inhibition by superoxide anions and reduced H2O2-induced relaxation. Moreover, EUK-8 dose-dependently relaxed rat aorta precontracted with phenylephrine (10(-6) M) and decreased the vascular the of noncontrac ted aortic rings. The relaxant effect of EUK-8 was significantly poten tiated by endothelium abrasion and/or preincubation with N-nitro-L-arg inine methyl ester (10(-5) M and 5 x 10(-4) M), an inhibitor of nitric oxide synthase. Indomethacin (10(-5) M) had no effect on the action o f EUK-8, showing that it was not dependent on prostacyclin synthesis. Methylene blue (10(-5) M), an inhibitor of soluble guanylate cyclase, partly abolished relaxation induced by EUK-8. Incubation of rat aorta with EUK-8 (10(-4) M) induced an increase in vascular cyclic AMP conte nt. The lack of inhibition by dl-propranolol showed that adenylate cyc lase activation by EUK-8 was not mediated through beta-adrenergic rece ptors. The inhibition of the effects of EUK-8 by tetraethylammonium (1 0(-2) M) and glibenclamide (10(-5) and 2 x 10(-5) M) showed the implic ation of potassium channels in the intracellular cascade triggered by EUK-8. The vasorelaxant activity of EUK-8 was neither affected by xant hine oxidase inhibition (incubation with oxypurinol 25 mu M) nor by su peroxide anion scavenging (incubation with oxypurinol 125 mu M). Final ly, the ligand for EUK-8 (EUK-8 without manganese), which has the same aromatic structure as EUK-8 without its antioxidant activities becaus e of the absence of manganese, conversely potentiated phenylephrine-in duced contraction of aortic rings. We conclude that the vasorelaxant e ffect of EUK-8 observed under our experimental conditions is essential ly mediated through an activation of adenylate cyclase and soluble gua nylate cyclase of smooth muscle cells and is different from a classica l antioxidant effect of protection of nitric oxide.