A synthetic isoquinoline alkaloid,1-(#beta#-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (YS51),reduces inducible nitric oxide synthase expression and improves survival in a rodent model of endotoix shock

摘要

In the present study,the effects of 1-(#beta#-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline(YS51),a positional isomer of 1-(#alpha#-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (YS49),on nitric oxide production and inducible nitric oxides synthase (iNOS)mRNA expression were investigated in RAW 264.7 cells,mouse monocyte macrophage,exposed to lipopolysaccharide (LPS)plus interforon (IFN)-#gamma#.In addition,the effects of YS51 on vascular reactivity in vitro and ex vivo,iNOS protein expression (rat lung)and survival rate (mice),were also investigated in LPS-treated rodents.Treatment with YS51 reduced not only nitric oxide production (IC_(50),23.5#mu#M),but also expression of iNOS mRNA in RAW 264.7 cells in a concentration-dependent manner.Incubationof rat endothelium-denuded thoracic aorta with LPS(300ng/ml)for 8h in vitro resulted in suppression of vasoconstrictor effects to phenylephrine,which was restored by coincubation with YS51.Treatment with YS51 befor (30min)injection of LPS resulted in significant reductionof the expression of iNOS protein in rat lung tissue and restored the vascular contractility to 9,11-dideoxy-11#alpha#,9#alpha#-epoxymethanoprostaglandin F_(2#alpha#)(U46619),exvivo.The plasma concentration of nitriteitrate (NOx)level was significantly (p<0.01)reduced by YS51(10 and 20mg/kg,i.p)in LPS-treated (10mg/kg,i.p)rats.Furthermore,YS51 significantly increased the survival rate in LPS-injected mice.In RAW 264.7 cells,YS51 inhibited the formationof nuclear factor-kB-DNA complex and iNOS promoter activity in a concentration dependent manner,indicating that iNOS gene expression was modified transcriptionally by YS51.These data strongly suggest that YS51,a positional isomer of YS49,might be beneficical in septic shock and/or enduced inflammatory disorders.