Original Articles
Copyright ©The Author(s) 2001. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 15, 2001; 7(3): 331-334
Published online Jun 15, 2001. doi: 10.3748/wjg.v7.i3.331
Effects of aminoguanidine on nitric oxide production induced by inflammatory cytokines and endotoxin in cultured rat hepatocytes
Guo-Liang Zhang, Ye-Hong Wang, Hui-Ling Teng, Zhi-Bin Lin
Guo-Liang Zhang, Ye-Hong Wang, Hui-Ling Teng, Zhi-Bin Lin, Department of Pharmacology, School of Basic Medical Sciences, Beijing University, Beijing 100083, China
Author contributions: All authors contributed equally to the work.
Correspondence to: Dr. Guo-Liang Zhang, Department of Pharmacology, School of Basic Medical Sciences, Beijing University, Beijing 100083, China. yuankui@public.bta.net.cn
Telephone: +86-10-62091421 Fax: +86-10-62015681
Received: February 6, 2001
Revised: April 3, 2001
Accepted: May 8, 2001
Published online: June 15, 2001
Abstract

AIM: To study the effects of aminoguanidine (AG) and two L-arginine analogues Nω-nitro-L-arginine methyl ester (L-NAME) and Nω-nitro-L-arginine (L-NNA) on nitric oxide (NO) production induced by cytokines (TNF-α, IL-1β, and IFN-γ) and bacterial lipopolysaccharide (LPS) mixture (CM) in the cultured rat hepatocytes, and examine their mechanisms action.

METHODS: Rat hepatocytes were incubated with AG, L-NAME, L-NNA, Actinomycin D (ActD) and dexamethasone in a medium containing CM (LPS plus TNF-α, IL-1β, and IFN-γ) for 24 h. NO production in the cultured supernatant was measured with the Griess reaction. Intracellular cGMP level was detected with radioimmunoassy.

RESULTS: NO production was markedly blocked by AG and L-NAME in a dose-dependent manner under inflammatory stimuli condition triggered by CM in vitro. The rate of the maximum inhibitory effects of L-NAME (38.9%) was less potent than that obtained with AG (53.7%, P < 0.05). There was no significant difference between the inhibitory effects of AG and two L-arginine analogues on intracellular cGMP accumulation in rat cultured hepatocytes. Non-specific NOS expression inhibitor dexamethasone(DEX) and iNOS mRNA transcriptional inhibitor ActD also significantly inhibited CM-induced NO production. AG (0.1 mmol·L-1) and ActD (0.2 ng·L-1) were equipotent in decreasing NO production induced by inflammatory stimuli in vitro, and both effects were more potent than that induced by non-selectivity NOS activity inhibitor L-NAME (0.1 mmol·L-1) under similar stimuli conditions (P < 0.01).

CONCLUSION: AG is a potent selective inhibitor of inducible isoform of NOS, and the mechanism of action may be not only competitive inhibition in the substrate level, but also the gene expression level in rat hepatocytes.

Keywords: nitric-oxide synthase/antagonists and inhibitors; nitric oxide/biosynthesis; liver/cytology; cells, cultured/drug effects; endotoxins/pharmacology; immunologic and biological factors/pharmacology