Zn2+ inhibits nitric oxide formation in response to lipopolysaccharides: implication in its anti-inflammatory activity.
There is compelling evidence to indicate an anti-inflammatory action of Zn2+. Most inflammatory diseases are associated with an increase of the inducible form of nitric oxide (NO) synthase. Additionally, inflammatory mediators such as histamine or bradykinin stimulate the constitutive NO synthase. Thus, the present study was undertaken to investigate whether Zn2+ inhibits production of inducible NO synthase and/or constitutive NO synthase activity to produce NO. Lipopolysaccharide, 5 mg/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 significant reduction of their serum Zn2+. The levels of N(G)-nitro-L-arginine methylester (L-NAME)-sensitive cyclic GMP (cGMP) in aortas isolated from ZD or ZG were significantly lower than those obtained from control animals. Zinc (100-150 microM) produced a dose-dependent inhibition of lipopolysaccharide or interleukin-1beta-induced NO formation in isolated rat aortic smooth muscle cells. Compared to cyclohexamide or actinomycin-D, the time course of inhibition of NO formation by 150 microM Zn2+ did not suggest an effect of Zn2+ on inducible NO synthase protein synthesis. Moreover, Zn2+ (150 microM) significantly reduced the rate of conversion of [3H]arginine to [3H]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 microM) caused a significant reduction in basal and bradykinin- or A-23187-induced formation of cGMP. Thus, our results indicate that Zn2+ is capable of inhibiting lipopolysaccharide- or interleukin-1beta-induced NO formation as well as NO formation by constitutive NO synthase basally or in response to bradykinin or A-23187, and may explain the reported anti-inflammatory activity of Zn2+.
Abou-Mohamed
G
G
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta 30912, USA.
Papapetropoulos
A
A
Catravas
J D
JD
Caldwell
R W
RW
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017207:Rats, Sprague-Dawley; D015032:Zinc / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D015032:Zinc