7-Epiclusianone, a tetraprenylated benzophenone, relaxes airway smooth muscle through activation of the nitric oxide-cGMP pathway.
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 microM) 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(omega)-nitro-L-arginine methyl ester (L-NAME) (100 microM), or soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 microM). 7-Epiclusianone (1-100 microM) 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 microM), glibenclamide (1 microM), or apamin (1 microM), but not by 9-(tetrahydro-2'-furyl)adenine (SQ22,536) (100 microM), an adenylate cyclase inhibitor. In epithelium-intact tracheal rings, 7-epiclusianone also inhibited Ca(2+)-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.
Coelho
Luciana Pontes
LP
Laboratory of Inflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Av. Brasil, 4365, Manguinhos, CEP 21045-900, Rio de Janeiro, RJ, Brazil.
Serra
Magda Fráguas
MF
Pires
Ana Lúcia de Aguiar
AL
Cordeiro
Renato Sérgio Balão
RS
Rodrigues e Silva
Patrícia Machado
PM
dos Santos
Marcelo Henrique
MH
Martins
Marco Aurélio
MA
D000818:Animals; D001577:Benzophenones / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D006224:Cricetinae; D006152:Cyclic GMP / Q000032:analysis / Q000502:physiology*; D004848:Epithelium / Q000502:physiology; D005260:Female; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D054086:KATP Channels / Q000502:physiology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D010276:Parasympatholytics / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D015398:Signal Transduction; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
C118110:7-epiclusianone; D001577:Benzophenones; D016227:Benzoquinones; D015220:Calcium Channels; D054086:KATP Channels; D010276:Parasympatholytics; D024681:Potassium Channels, Calcium-Activated; D016210:Methacholine Chloride; D009569:Nitric Oxide; D006632:Histamine; D002217:Carbachol; D006152:Cyclic GMP