Inhibitory effects of aclarubicin on nitric oxide production in aortic smooth muscle cells and macrophages

The effects of aclarubicin (ACR), an anthracycline antibiotic, on inducible nitric oxide (NO) synthesis was investigated in rat aortic smooth muscle c ells (RASMCs) and RAW macrophages. ACR at concentrations as low as 0.1 mu M significantly inhibited NO production induced by interleukin-1 beta in RAS MCs. About 5- to 10-fold higher concentrations of ACR were required for inh ibition of interferon-gamma and lipopolysaccharide-induced NO production in RAW cells. When ACR was subsequently administered to inducible NO synthase (iNOS) induction, the NO production was barely suppressed in RASMCs. Moreo ver, ACR (up to 10 mu M) lacked direct inhibitory effects on iNOS activity in homogenates of these cells. ACR (0.1 mu M) inhibited the expression of i NOS protein and mRNA in RASMCs without concomitant cytotoxic effects. ACR ( >0.5 mu M)-induced inhibition of NO production in RAW cells was associated with substantial cytotoxic effects as shown by measurement of lactate dehyd rogenase release. These results suggest that ACR is a potent inhibitor of i NOS induction in vascular smooth muscle, but inhibits iNOS induction in mac rophage only at high cytotoxic concentrations. (C) 2000 Elsevier Science In c.