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

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.138032v1 327/1/206    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 Google Scholar Google Scholar Articles by Coelho, L. P. Articles by Martins, M. A. Search for Related Content PubMed PubMed Citation Articles by Coelho, L. P. Articles by Martins, M. A.

INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

7-Epiclusianone, a Tetraprenylated Benzophenone, Relaxes Airway Smooth Muscle through Activation of the Nitric Oxide-cGMP Pathway

Laboratory of Inflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Rio de Janeiro, Brazil (L.P.C., M.F.S., A.L.d.A.P., R.S.B.C., P.M.R.e.S., M.A.M.); and Laboratory of Phytochemistry and Medicinal and Chemistry, Department of Pharmacy, Alfenas, Federal University of Alfenas, Minas Gerais, Brazil (M.H.d.S.)

This study was undertaken to investigate the putative mechanism(s) underlying the antispasmodic effect of 7-epiclusianone, a naturally occurring compound isolated from the plant Garcinia brasiliensis. Guinea pig tracheal rings were mounted in tissue baths filled with Krebs' solution, and the contractile response to distinct stimuli was measured in the presence or absence of 7-epiclusianone. We also tested the effect of 7-epiclusianone on methacholine-evoked airways obstruction in BALB/c mice using barometric plethysmography. 7-Epiclusianone (10 µM) inhibited epithelium-intact tracheal ring contraction induced by allergen, histamine, 5-hydroxytryptamine, or carbachol challenge. The relaxation effect was abrogated by epithelium removal, the presence of nitric-oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) (100 µM), or soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 µM). 7-Epiclusianone (1–100 µM) induced a dose-dependent increase in the intracellular cGMP levels of cultured tracheal rings. The relaxation effect of 7-epiclusianone was also inhibited by K⁺ channel blockers tetraethylammonium (10 µM), glibenclamide (1 µM), or apamin (1 µM), but not by 9-(tetrahydro-2'-furyl)adenine (SQ22,536) (100 µM), an adenylate cyclase inhibitor. In epithelium-intact tracheal rings, 7-epiclusianone also inhibited Ca²⁺-induced contractions in K⁺ (60 mM)-depolarized preparations, but it seemed ineffective in assays in which epithelium-denuded tracheal ring preparations were used. Oral administration of 7-epiclusinone (25–100 mg/kg) dose-dependently inhibited airway obstruction triggered by aerosolized methacholine (6–25 mg/ml), in a mechanism sensitive to L-NAME (20 mg/kg). In conclusion, the relaxation effect of 7-epiclusinone seems to be mediated by epithelium-, nitric oxide-, and cGMP-dependent mechanisms. Furthermore, oral administration of 7-epiclusianone reduces episodes of bronchial obstruction, warranting further research on this compound regarding a putative application in asthma therapy.

Address correspondence to: Dr. Marco Aurélio Martins, Laboratory of Inflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Av. Brasil, 4365, Manguinhos, CEP 21045-900, Rio de Janeiro, RJ, Brazil. E-mail: mmartins{at}ioc.fiocruz.br