Inhibition of Lipopolysaccharide-induced Prostaglandin E2 Production and Inflammation by the Na+/H+ Exchanger Inhibitors.
From: Laboratory of Pathological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba Aramaki, Sendai, Miyagi 980-8578, Japan.
The Journal of pharmacology and experimental therapeutics
- Publish Date: Apr 2007
- ISSN: 0022-3565
- Volume: 321
- Issue: 1
- Pages: 345-52
- Medium: Print
- Language: English
- Citation (JAMA): Kamachi Fumitaka, Ban Hyun Seung, Hirasawa Noriyasu, et al. Inhibition of Lipopolysaccharide-induced Prostaglandin E2 Production and Inflammation by the Na+/H+ Exchanger Inhibitors.. J. Pharmacol. Exp. Ther. Apr 2007;321:345-52
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.
Mesh Headings (Keywords): Amiloride, Animals, Arachidonic Acid, Blotting, Western, Capillary Permeability, Cell Line, Cell Survival, Cyclooxygenase 2, Cyclooxygenase Inhibitors, Dinoprostone, I-kappa B Proteins, Indomethacin, Inflammation, Leukocytes, Lipopolysaccharides, Macrophages, Mice, Mitogen-Activated Protein Kinases, Reverse Transcriptase Polymerase Chain Reaction, Sodium-Hydrogen Antiporter
Check for Full Text / PubMed Unique Identifier (PMID): 17237260
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