Vasodilatory effects of a salen-manganese complex with potent oxyradical scavenger activities.
The effects on rat aorta of EUK-8, a salen-manganese complex with high superoxide dismutase and catalase activities, were investigated. EUK-8 protected the acetylcholine-induced relaxation of rat aortic rings from 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 tone of noncontracted aortic rings. The relaxant effect of EUK-8 was significantly potentiated by endothelium abrasion and/or preincubation with N-nitro-L-arginine 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 of 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 content. The lack of inhibition by dl-propranolol showed that adenylate cyclase activation by EUK-8 was not mediated through beta-adrenergic receptors. The inhibition of the effects of EUK-8 by tetraethylammonium (10(-2) M) and glibenclamide (10(-5) and 2 x 10(-5) M) showed the implication of potassium channels in the intracellular cascade triggered by EUK-8. The vasorelaxant activity of EUK-8 was neither affected by xanthine oxidase inhibition (incubation with oxypurinol 25 microM) nor by superoxide anion scavenging (incubation with oxypurinol 125 microM). Finally, the ligand for EUK-8 (EUK-8 without manganese), which has the same aromatic structure as EUK-8 without its antioxidant activities because of the absence of manganese, conversely potentiated phenylephrine-induced contraction of aortic rings. We conclude that the vasorelaxant effect of EUK-8 observed under our experimental conditions is essentially mediated through an activation of adenylate cyclase and soluble guanylate cyclase of smooth muscle cells and is different from a classical antioxidant effect of protection of nitric oxide.
Barandier
C
C
Groupe de Physiopathologie Cellulaire Cardiaque, CNRS-ESA 5077, Universite Joseph Fourier, Grenoble, France.
Boucher
F
F
Malfroy
B
B
de Leiris
J
J
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D005029:Ethylenediamines / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D008297:Male; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D005029:Ethylenediamines; D016166:Free Radical Scavengers; D009942:Organometallic Compounds; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II)