QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.116251v1 321/1/345    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kamachi, F. Articles by Ohuchi, K. Search for Related Content PubMed PubMed Citation Articles by Kamachi, F. Articles by Ohuchi, K.

INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Inhibition of Lipopolysaccharide-Induced Prostaglandin E₂ Production and Inflammation by the Na⁺/H⁺ Exchanger Inhibitors

Laboratory of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan (F.K., H.S.B., N.H., K.O.); and Yasuda Women's University, Hiroshima, Japan (K.O.)

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 µg/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 B- 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.

Address correspondence to: Dr. Noriyasu Hirasawa, Laboratory of Pathological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan. E-mail: hirasawa{at}mail.pharm.tohoku.ac.jp

This article has been cited by other articles:

				R. Rorato, A. M. Menezes, A. Giusti-Paiva, M. de Castro, J. Antunes-Rodrigues, and L. L. K. Elias Prostaglandin mediates endotoxaemia-induced hypophagia by activation of pro-opiomelanocortin and corticotrophin-releasing factor neurons in rats Exp Physiol, March 1, 2009; 94(3): 371 - 379. [Abstract] [Full Text] [PDF]

				B. Liu, M. Han, and J.-K. Wen Acetylbritannilactone Inhibits Neointimal Hyperplasia after Balloon Injury of Rat Artery by Suppressing Nuclear Factor-{kappa}B Activation J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 292 - 298. [Abstract] [Full Text] [PDF]