Oroxylin-A and its phosphonate derivative potentiate eNOS/NO-mediated relaxation and attenuate vasoconstrictor-induced contraction in the mouse aorta

Abstract

Oroxylin-A (OroA), a flavonoid isolated from Scutellariae baicalensis, alleviates cardiovascular dysfunction. Several procedures for synthesizing OroA have been developed but show low production yield and regioselectivity. We synthesized OroA from baicalin using a one-pot reaction to increase its overall yield. We also determined the chemical properties and mechanism of action of the synthesized OroA and OroA phosphate diethyl ester (OroA-OET) in vascular function. The induction of vascular reactivity by OroA and OroA-OET was evaluated using blood vessel myography and biochemical analysis to assess nitric oxide synthase-mediated nitric oxide production in mouse aortic arteries. OroA and OroA-OET (0.1–30 μM) induced sustained vasorelaxation, which was partly mediated by the endothelium in isolated normal arteries pre-contracted with phenylephrine. OroA and OroA-OET significantly attenuated vasoconstrictors-induced contractile responses. Dilation effects were blocked by the non-selective nitric oxide synthase inhibitor N (omega)-nitro-l-arginine methyl ester but not by tetraethylammonium or 1H-(1,2,4)oxadiazolo [4,3-a]quinoxalin-1-one. Notably, preincubation with OroA and OroA-OET potentiated acetylcholine-induced relaxation and endothelial nitric oxide production in the arteries with the endothelium. OroA and OroA-OET protected against cardiovascular dysfunction. The synthesis and lead compounds used not only improved the yield of OroA from natural sources but also potentially regulated vascular tone.

Keywords

• Oroxylin-A
• Oroxylin-A phosphate diethyl ester
• Endothelial nitric oxide synthase
• Endothelial protection
• Vascular smooth muscle relaxation