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Zeitschrift für Naturforschung C Contents Vol. 69c (2015)

Z. Naturforsch. 69c, 434 – 442 (2015)

doi:10.5560/ZNC.2014-0017

Mechanisms Underlying the Relaxant Effect of Galetin 3,6-Dimethyl Ether, from Piptadenia stipulacea (Benth.) Ducke, on Guinea-Pig Trachea

Cibério Landim Macêdo¹, Luiz Henrique César Vasconcelos¹, Ana Carolina de Carvalho Correia¹, Italo Rossi Roseno Martins¹, Daysianne Pereira de Lira¹, Bárbara Viviana de Oliveira Santos^1,2, and Bagnólia Araújo da Silva^1,2,*

¹Center of Health Sciences, Federal University of Paraíba (UFPB), Campus I, P. O. Box 5009, 58.051-970, João Pessoa, Paraíba, Brazil. Fax: +55-83-32167502. E-mail: bagnoliasilva@yahoo.com or bagnolia@ltf.ufpb.br

²Department of Pharmaceutical Sciences, Federal University of Paraíba (UFPB), 58.051-970, João Pessoa, Paraíba, Brazil

^*Author for correspondence and reprint requests

Received January 25 / November 28, 2014 / published online January 14, 2015

Galetin 3,6-dimethyl ether (FGAL), a flavonoid from the aerial parts of Piptadenia stipulacea (Benth.) Ducke, was found to exert a relaxant effect on carbachol (CCh)-pre-contracted guinea-pig trachea. Based on cumulative concentration-response curves to CCh, FGAL antagonized muscarinic receptors pseudo-irreversibly and noncompetitively, since it inhibited and shifted these curves towards higher concentrations in a nonparallel manner. In addition, FGAL was more potent in relaxing contractions induced by 18 mm as compared to 60 mm KCl (pD₂ = 5.50 ± 0.36 and 4.80 ± 0.07, respectively), indicating the participation of K⁺ channels. In the presence of 10 mm tetraethylammonium (TEA⁺) chloride, a nonselective K⁺ channel blocker, the relaxant potency of FGAL was reduced (from pD₂ = 5.12 ± 0.07 to 4.87 ± 0.02). Among several selective blockers of K⁺ channel subtypes, only apamin, an SK_Ca (small-conductance Ca²⁺-activated K⁺ channels) blocker, attenuated the relaxant potency of FGAL (pD₂ = 4.85 ± 0.06), suggesting SK_Ca activation. FGAL was equipotent in relaxing trachea contracted by 60 mm KCl (pD₂ = 4.80 ± 0.07) or 10⁻⁶ m CCh (pD₂ = 5.02 ± 0.07), suggesting Ca_V (voltage-gated calcium channel), but not ROCs (receptor-operated calcium channels) participation. Furthermore, aminophylline-induced relaxation (pD₂ = 4.12 ± 0.06) was potentiated around 4-fold (pD₂ = 4.80 ± 0.44) in the presence of FGAL. Moreover, forskolin-induced relaxation (pD₂ = 6.51 ± 0.06) was potentiated around 2.5-fold (pD₂ = 6.90 ± 0.05) by FGAL. Conversely, sodium nitroprusside-induced relaxation was unaffected, indicating that the AC/cAMP/PKA pathway, but not the NO pathway, may be modulated by the flavonoid. These results suggest that, in guinea-pig trachea, FGAL induces relaxation by pseudo-irreversible noncompetitive antagonism on muscarinic receptors, modulation of K⁺ and Ca²⁺ channels, as well as activation of the AC/cAMP/PKA pathway.

Key words: Airway Smooth Muscle, Relaxant Action, Ionic Channels, Galetin 3,6-Dimethyl Ether

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