Pharmacological effects of novel quinone compounds, 6-(fluorinated- phenyl)amino-5,8-quinolinediones, on inhibition of drug-induced relaxation of rat aorta and their putative action mechanism

Abstract

Two 6-(fluorinated-phenyl)amino-5,8-quinolinedione derivatives, OQ21 and OQ1, were newly synthesized as potent inhibitors of endothelial-dependent vasorelaxation. The purpose of the present study was to investigate the effects of OQ21 and OQ1 on different types of vasorelaxation and to pursue their action mechanisms. For acetylcholine both compounds, at a low concentration (0.1 μM), reduced the maximal response with increase of EC50 values. OQ21 is a novel quinone compound and showed a more potent and efficacious inhibitory effect on acetylcholine-induced relaxation of rat aorta than that of LY83583 (6-anilino-5,8-quinolinedione). Relatively high concentrations (1 μM) of OQ21 and OQ1 inhibited the sodium nitroprusside- induced relaxation of endothelium-denuded ring, producing rightward shifts of the curve for sodium nitroprusside without altering the maximal response. They also prevented acetylcholine and sodium nitroprusside-induced elevations of cyclic GMP. In addition, OQ21 and OQ1 (1 μM) significantly decreased (52- 72%) the sensitivity of L-arginine-induced relaxation of precontracted endothelium-denuded aortic rings from lipopolysaccaride-treated (20 mg/kg, i.p.) rats. The inhibitory effect of OQ21 on endothelium-dependent vasodilation was enhanced by N(G)-nitro-L-arginine, which inhibits nitric oxide synthase (NOS) by binding the oxygenase domain of the enzyme, but not by diphenylendiodonium, which inhibits NOS by binding to the reductase domain of the enzyme. Treatment of blood vessels with OQ21 or OQ1 showed a significant increase in chemiluminescence output, which was prevented by adding superoxide dismutase, suggesting that superoxide generation is involved in the action mechanism for OQ21. Present results indicate that a novel naphthoquinone compound, OQ21, potently inhibits endothelial NOS, possibly by interacting with the reductase domain of the enzyme, which leads to induce superoxide formation. The new benzoquinone compounds, OQ21 and OQ1, inhibit not only endothelium-dependent vasorelaxation but also endothelium- independent relaxation induced by exogenous NO generated from a nitrovasodilator via the reduction of cyclic GMP. They also reduced L- arginine-induced vasorelaxation in endotoxin-treated rats, indicating their possession of inhibitory effect on inducible NOS. (C) 2000 Elsevier Science Inc.