1 The effects of a novel positive inotropic
isoquinoline compound,
YS 49, on NO production and iNOS
protein expression were investigated in cultured rat aortic vascular smooth muscle cells (RAVSMC) and RAW 264.7 cells exposed to
lipopolysaccharide (LPS) plus
interferon-gamma (IFN-gamma). In addition, the effects of
YS 49 on vascular hyporeactivity in vitro and ex vivo, and on survival rate (mice) and serum NOx (rat) levels, were also investigated in LPS-treated animals. 2 Pre- or co-treatment of
YS 49 with LPS plus IFN-gamma, concentration-dependently reduced NO production in RAVSMC and RAW 264.7 cells (IC50 values, 22 and 30 microM, respectively). Although the inhibitory effect on NO production was reduced when
YS 49 was applied 2 and 4 h after
cytokine in RAW 264.7 cells, it was still statistically significant (P<0.05). 3
YS 49 reduced iNOS
mRNA expression in LPS-treated rat aorta in vitro, an effect which was associated with restoration of contractility to the
vasoconstrictor,
phenylephrine (PE), and reduction in
L-arginine-induced relaxation. 4 Serum NOx levels were significantly (P<0.01) reduced by
YS 49 (5 mg kg-1, i.p.) in LPS-treated rats (10 mg kg-1, i.p.). Administration of
YS 49 (10 and 20 mg kg-1) 30 min prior to LPS (10 mg kg-1) also significantly (P<0.01) increased the subsequent survival rates in mice. 5 Finally, expression of iNOS
protein induced by LPS plus IFN-gamma in RAVSMC and RAW 264.7 cells was suppressed by
YS 49, in a concentration-dependent manner. 6 These data strongly suggest that
YS 49 suppresses iNOS gene expression induced by LPS and/or
cytokines in RAVSMC and RAW 264.7 cells at the transcriptional level.
YS 49 could therefore be beneficial in
septic shock and other diseases associated with iNOS over-expression.