外因性-酸化窒素(NO)による内皮細胞内テトラヒドロビオプテリンの減少を原因とする流れ依存性血管内皮由来NO産生の抑制

抄録

We investigated the effect of exogenous nitric oxide (NO) on the flow-induced endothelium-derived NO production and possible underlying mechanisms including changes in intracellular concentration of tetrahydrobiopterin (BH₄; a cofactor of NO synthase: NOS). Isolated canine femoral arteries were perfused with 100 μM S-nitroso-N-acetylpenicillamine (SNAP; an NO donor) and/or 64 μM BH₄. Perfusion of SNAP suppressed flow-induced NO production (p<0.02 vs control; n=7). Subsequent BH₄ perfusion restored the control-level NO production. Concomitant perfusion of SNAP and BH₄ retained the control-level NO production. Concomitant perfusion of SNAP and 4,5- dihydroxy-1,3-benzene disulfonic acid (Tiron; 1 mM; a membrane-permeable superoxide scavenger) also retained the control-level NO production, while perfusion of Tiron after SNAP could not restore the control-level NO production (p<0.02 vs control; n=7). We also found a significant decrease in BH₄ concentration in the endothelial cells after SNAP perfusion. In conclusion, these results indicate that exogenous NO decreases intracellular BH₄ concentration, resulting in superox-ide release from uncoupled NOS and suppresses the flow-induced endothelium-derived NO produc-tion.