Mangiferin Prevents Guinea Pig Tracheal Contraction via Activation of the Nitric Oxide-Cyclic GMP Pathway

Abstract

Previous studies have described the antispasmodic effect of mangiferin, a natural glucoside xanthone (2-C-β-Dgluco-pyranosyl-1,3,6,7-tetrahydroxyxanthone) that is present in mango trees and other plants, but its mechanism of action remains unknown. The aim of this study was to examine the potential contribution of the nitric oxide-cyclic GMP pathway to the antispasmodic effect of mangiferin on isolated tracheal rings preparations. The functional effect of mangiferin on allergic and non-allergic contraction of guinea pig tracheal rings was assessed in conventional organ baths. Cultured tracheal rings were exposed to mangiferin or vehicle, and nitric oxide synthase (NOS) 3 and cyclic GMP (cGMP) levels were quantified using western blotting and enzyme immunoassays, respectively. Mangiferin (0.1–10 µM) inhibited tracheal contractions induced by distinct stimuli, such as allergen, histamine, 5-hydroxytryptamine or carbachol, in a concentration-dependent manner. Mangiferin also caused marked relaxation of tracheal rings that were precontracted by carbachol, suggesting that it has both anti-contraction and relaxant properties that are prevented by removing the epithelium. The effect of mangiferin was inhibited by the nitric oxide synthase inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME) (100 µM), and the soluble guanylate cyclase inhibitor, 1H-[1], [2], [4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 µM), but not the adenylate cyclase inhibitor, 9-(tetrahydro-2-furyl)adenine (SQ22536) (100 µM). The antispasmodic effect of mangiferin was also sensitive to K+ channel blockers, such as tetraethylammonium (TEA), glibenclamide and apamin. Furthermore, mangiferin inhibited Ca2+-induced contractions in K+ (60 mM)-depolarised tracheal rings preparations. In addition, mangiferin increased NOS3 protein levels and cGMP intracellular levels in cultured tracheal rings. Finally, mangiferin-induced increase in cGMP levels was abrogated by co-incubation with either ODQ or L-NAME. These data suggest that the antispasmodic effect of mangiferin is mediated by epithelium-nitric oxide- and cGMP-dependent mechanisms.

Mangiferin: A xanthonoid with multipotent anti‐inflammatory potential

“…In that study mangiferin was also reported to restore the level of eNOS, while the eNOS/iNOS ratio was perturbed in the ischemia reperfusion model of rats. In various other studies regarding the gastro protective effect of mangiferin, it is observed that besides disruption of the redox environment in the gastric tissue, I/R insult enhances the activity of different proinflammatory modulators . It was observed that mangiferin significantly reduces the level of IL‐1β, E‐selectin, and neutrophil infiltration, exhibiting its immunomodulatory and anti‐inflammatory effect .…”

“…Moreover, in acute lung injury, mangiferin is capable in alleviating the inflammatory responses by down regulating the MAP kinase signaling pathways . In addition, mangiferin also exhibits antispasmodic effects by activating the nitric oxide‐cyclic GMP pathway and thereby preventing tracheal contractions is guinea pig . Mangiferin by upregulating heme oxygenase‐1 dose dependently, alleviates lung injury in septic mice models.…”

“…effects by activating the nitric oxide-cyclic GMP pathway and thereby preventing tracheal contractions is guinea pig [101]. Mangiferin by upregulating heme oxygenase-1 dose dependently, alleviates lung injury in septic mice models.…”

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

“…In fact, the epithelium capacity to provide factors to relax the smooth muscle is firmly established. These factors include nitric oxide (NO), carbon monoxide, PGE 2 and prostacyclin, which protect the airway from excessive bronchoconstriction (Barnes 1998, de Sousa et al 2010, Billington et al 2013, Vieira et al 2013. We tested several inhibitors to identify which factors produced by epithelial cells could be involved in the antispasmogenic activity of glucagon in vitro.…”

Mangiferin: An effective therapeutic agent against several disorders (Review)

“…Mangiferin exerts protective effects against bronchial asthma and other allergic diseases. Research has demonstrated that mangiferin inhibits tracheal contractions induced by distinct stimuli, including allergens, histamine, 5-hydroxytryptamine and carbachol, in a dose-dependent manner (95). The antispasmodic effect of mangiferin on allergic and non-allergic tracheal contraction of guinea pig tracheal rings are a result of increased intracellular levels of nitric oxide synthase 3 and cyclic GMP (95).…”