Abstract
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 Nω-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.
Footnotes
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This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação Oswaldo Cruz (PAPES IV), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, IM-INOFAR (BR, 420015/05-1), and Programa de Apoio a Núcleos de Excelência 2006. L.P.C. was supported by a Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro fellowship.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.138032.
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ABBREVIATIONS: DMSO, dimethyl sulfoxide; 5-HT, 5-hydroxytryptamine; l-NAME, Nω-nitro-l-arginine methyl ester; TEA, tetraethylammonium; KAPT, ATP-sensitive K+; IbTX, iberiotoxin; ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; SQ22,536, 9-(tetrahydro-2′-furyl)adenine; TCA, trichloroacetic acid; Penh, enhanced pause; sGC, soluble guanylate cyclase.
- Received February 13, 2008.
- Accepted June 27, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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