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

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 M) 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 M), or soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 M). 7-Epiclusianone (1-100 M) induced a dosedependent increase in the intracellular cGMP levels of cultured tracheal rings. The relaxation effect of 7-epiclusianone was also inhibited by K ϩ channel blockers tetraethylammonium (10 M), glibenclamide (1 M), or apamin (1 M), but not by 9-(tetrahydro-2Ј-furyl)adenine (SQ22,536) (100 M), an adenylate cyclase inhibitor. In epithelium-intact tracheal rings, 7-epiclusianone also inhibited Ca 2ϩ -induced contractions in K ϩ (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.Ginkgo biloba, Artocarpus heterophyllus, Allium sativum, Glycyrrhiza glabra, and Panax ginseng ginseng are examples of plant species that have been used in the so-called complementary and alternative medicine as herbal formulations,

Isolation and evaluation of the antioxidant actity of phenolic constituents of the Garcinia sizygiifolia

“…This class of compounds having phenolic functional groups and ring three cyclic linear, so it has the biological and pharmacological activity of diverse. The groups of these compound gives rise to several interesting pharmacological properties were these constituens have been reported to several biological activities such as antibacterial activity (Dharmaratne, Yoshikazu, Piyasena, & Thevanesam, 2013), anti-inflammatory (Castardo et al, 2008;Santa et al, 2011), antioxidant (Gantijo et al, 2011, antitumour (Coelho et al, 2008) therapies, and anticancer activity (Sales et al, 2014).…”

Estudo farmacobotânico das folhas de Garcinia brasiliensis Mart. (Clusiaceae)

“…Investigações farmacológicas de G. brasiliensis e seus compostos isolados de extratos mostraram atividades antianafiláticas (Neves et al, 2007), antimicrobiana (Almeida et al, 2008;Murata et al, 2008;Naldoni et al, 2009), antiespasmódica (Coelho et al, 2008), antiinflamatória e antioxidante (Martins et al, 2008;Santa-Cecília et al, 2011), antiproteolítica (Martins et al, 2009), antiproliferativa (Murata et al, 2010) e leishmanicida (Pereira et al, 2010), daí a relevância dos estudos realizados com esta espécie.…”

Glucagon induces airway smooth muscle relaxation by nitric oxide and prostaglandin E2

“…3 h before the inhalation of aerosolized methacholine. In some experiments, the animals were pretreated intraperitoneally with L-NAME (20 mg/kg) (Coelho et al 2008), indomethacin (10 mg/kg) (Steiner et al 2001) or SC-560 (5 mg/kg) (Steiner et al 2001) 30 min before glucagon administration. The control animals received the same amount of vehicle i.p.…”

“…In some experiments, epithelial cells were removed mechanically, as described previously (Coelho et al 2008). The contractile response to the cumulative addition of carbachol was measured in intact or denuded epithelium tracheas in the presence or absence of glucagon.…”

“…The contractile response to the cumulative addition of carbachol was measured in intact or denuded epithelium tracheas in the presence or absence of glucagon. To investigate glucagon's antispasmogenic mechanisms of action, tracheas were pretreated with a GcgR antagonist (des-his1-[Glu9]-glucagon amide -1 mM) (Leibiger et al 2012) and with inhibitors of adenylyl cyclase (SQ 22 536 -5 mM), nitric oxide synthase (NOS) (L-NAME -100 mM) (Coelho et al 2008), heme oxygenase (HO) (ZnPP IX -10 mM) (Undem et al 1996), cyclooxygenase (COX) (indomethacin -10 mM) (Coelho et al 2008), COX-1 (SC-560 -1 mM) and COX-2 (NS-398 -0.03 mM) (Schlemper et al 2005). Stimulation-induced isometric contractile responses were measured with a force-displacement transducer (Ugo Basile, Comerio, Italy) and the readout used to assess contractility was obtained by isolated organ data acquisition software (Proto 5; Letica Scientific Instruments, Barcelona, Spain).…”