A synthetic isoquinoline alkaloid, 1-(beta-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (YS 51), reduces inducible nitric oxide synthase expression and improves survival in a rodent model of endotoxic shock.

Abstract

In the present study, the effects of 1-(beta-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (YS 51), a positional isomer of 1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (YS 49), on nitric oxide production and inducible nitric oxide synthase (iNOS) mRNA expression were investigated in RAW 264.7 cells, mouse monocyte macrophage, exposed to lipopolysaccharide (LPS) plus interferon (IFN)-gamma. In addition, the effects of YS 51 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 YS 51 reduced not only nitric oxide production (IC(50), 23.5 microM), but also expression of iNOS mRNA in RAW 264.7 cells in a concentration-dependent manner. Incubation of rat endothelium-denuded thoracic aorta with LPS (300 ng/ml) for 8 h in vitro resulted in suppression of vasoconstrictor effects to phenylephrine, which was restored by coincubation with YS 51. Treatment with YS 51 before (30 min) injection of LPS resulted in significant reduction of the expression of iNOS protein in rat lung tissue and restored the vascular contractility to 9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha) (U46619), ex vivo. The plasma concentration of nitrite/nitrate (NOx) level was significantly (p < 0.01) reduced by YS 51 (10 and 20 mg/kg, i.p) in LPS-treated (10 mg/kg, i.p) rats. Furthermore, YS 51 significantly increased the survival rate in LPS-injected mice. In RAW 264.7 cells, YS 51 inhibited the formation of nuclear factor-kappaB-DNA complex and iNOS promoter activity in a concentration-dependent manner, indicating that iNOS gene expression was modified transcriptionally by YS 51. These data strongly suggest that YS 51, a positional isomer of YS 49, might be beneficial in septic shock and/or endotoxin-induced inflammatory disorders.