RRC ID 42864
Author Kamachi F, Ban HS, Hirasawa N, Ohuchi K.
Title Inhibition of lipopolysaccharide-induced prostaglandin E2 production and inflammation by the Na+/H+ exchanger inhibitors.
Journal J Pharmacol Exp Ther
Abstract We analyzed the effects of the Na+/H+ exchanger (NHE) inhibitor 3,5-diamino-6-chloro-N-(diaminomethylidene)pyrazine-2-carboxamide hydrochloride (amiloride) and its analogs 5-(N,N-dimethyl)-amiloride (DMA) and 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) on the lipopolysaccharide (LPS)-induced production of prostaglandin (PG) E2 in vitro and in vivo. In the mouse macrophage-like cell line RAW 264, these inhibitors suppressed the LPS (1 microg/ml)-induced production of PGE2 at 8 h in a concentration-dependent manner. They also reduced the LPS-induced release of arachidonic acid from membrane phospholipids at 4 h and the LPS-induced increase in the level of cyclooxygenase (COX)-2 protein at 6 h, but not the level of COX-2 mRNA at 3 h. The LPS-induced phosphorylation of mitogen-activated protein kinases and degradation of inhibitor of kappaB-alpha were not inhibited by these drugs. In an air pouch-type LPS-induced inflammation model in mice 30 mg/kg amiloride and 10 mg/kg EIPA as well as the COX inhibitor indomethacin (10 mg/kg), significantly reduced the level of PGE2 in the pouch fluid at 8 h and the vascular permeability from 4 to 8 h. The accumulation of pouch fluid and leukocytes in the pouch fluid at 8 h was significantly inhibited by amiloride and EIPA but not by indomethacin. These findings suggested that the NHE inhibitors suppress the production of PGE2 through inhibiting the release of arachidonic acid and the increase in COX-2 protein levels and thus induce anti-inflammatory activity.
Volume 321(1)
Pages 345-52
Published 2007-4-1
DOI 10.1124/jpet.106.116251
PII jpet.106.116251
PMID 17237260
MeSH Amiloride / analogs & derivatives* Amiloride / pharmacology* Animals Arachidonic Acid / metabolism Blotting, Western Capillary Permeability / drug effects Cell Line Cell Survival / drug effects Cyclooxygenase 2 / biosynthesis Cyclooxygenase 2 / genetics Cyclooxygenase Inhibitors / pharmacology Dinoprostone / biosynthesis* I-kappa B Proteins / metabolism Indomethacin / pharmacology Inflammation / chemically induced Inflammation / prevention & control* Leukocytes / pathology Lipopolysaccharides / antagonists & inhibitors* Lipopolysaccharides / pharmacology Macrophages / drug effects Macrophages / metabolism Mice Mitogen-Activated Protein Kinases / antagonists & inhibitors NF-KappaB Inhibitor alpha Reverse Transcriptase Polymerase Chain Reaction Sodium-Hydrogen Exchangers / antagonists & inhibitors*
IF 3.561
Times Cited 21
Human and Animal Cells RAW 264(RCB0535)