ZN2-OXIDE FORMATION IN RESPONSE TO LIPOPOLYSACCHARIDES - IMPLICATION IN ITS ANTIINFLAMMATORY ACTIVITY( INHIBITS NITRIC)

There is compelling evidence to indicate an anti-inflammatory action o f Zn2+. Most inflammatory diseases are associated with an increase of the inducible form of nitric oxide (NO) synthase. Additionally, inflam matory mediators such as histamine or bradykinin stimulate the constit utive NO synthase. Thus, the present study was undertaken to investiga te whether Zn2+ inhibits production of inducible NO synthase and/or co nstitutive NO synthase activity to produce NO. Lipopolysaccharide, 5 m g/kg i.v., administered to Zn2+-deficient (ZD) rats, rats supplemented with Zn2+ sulfate(ZG), 10 mg/kg s.c., or controls resulted in a signi ficant reduction of their serum Zn2+. The levels of N-G-nitro-L-argini ne methylester (L-NAME)-sensitive cyclic GMP (cGMP) in aortas isolated from ZD or ZG were significantly lower than those obtained from contr ol animals. Zinc (100-150 mu M) produced a dose-dependent inhibition o f lipopolysaccharide or interleukin-1 beta-induced NO formation in iso lated rat aortic smooth muscle cells. Compared to cyclohexamide or act inomycin-D, the time course of inhibition of NO formation by 150 mu M Zn2+ did not suggest an effect of Zn2+ on inducible NO synthase protei n synthesis. Moreover, Zn2+ (150 mu M) significantly reduced the rate of conversion of [H-3]arginine to [H-3]citrulline in lung homogenates from lipopolysaccharide-treated rats. Incubation of rat aortic smooth muscle cells and bovine pulmonary artery endothelial cell co-cultures with Zn2+ (150 mu M) caused a significant reduction in basal and brady kinin-or A-23187-induced formation of cGMP. Thus, our results indicate that Zn2+ is capable of inhibiting lipopolysaccharide-or interleukin- 1 beta-induced NO formation as well as NO formation by constitutive NO synthase basally or in response to bradykinin or A-23187, and may exp lain the reported anti-inflammatory activity of Zn2+. (C) 1998 Elsevie r Science B.V.