Effects of esculetin (6,7-dihydroxycoumarin) on guinea-pig tracheal chains in vitro

doi:10.1016/1043-6618(89)90237-5

Pharmacological Research

Volume 21, Issue 2, March–April 1989, Pages 183-192

https://doi.org/10.1016/1043-6618(89)90237-5 Get rights and content

Abstract

Esculetin (6,7-dihydroxycoumarin) was tested in isolated guinea-pig tracheal chains from normal and ovalbumin-sensitized animals. The drug showed a concentration-dependent relaxant effect, with an EC50 of 60 μm. Pretreatment with esculetin (30–60 μm) was not able to reduce the contractile response induced by either carbachol (0.1 μm), histamine (10 μm), BaCl₂(10 mm) or K⁺ (80 mm).

Esculetin increased the contraction evoked by PGF_2α and by histamine, but reduced A23187-induced contraction. Mepacrine (10 μm), a phospholipase A₂ inhibitor, reduced the relaxant effect of the lower esculetin concentrations (3–60 μm). Indomethacin (0.1 μm) increased the relaxation induced by esculetin (3–10 μm).

In tracheal chains from ovalbumin-sensitized guinea-pigs, esculetin (60 μm) significantly reduced the duration of the recovery phase after antigen challenge contraction.

In conclusion, in our in vitro conditions, this natural coumarin derivative seems to act by interfering with the arachidonic acid cascade.

References (35)

PJ Piper et al.
The mechanism of action of leukotriene C₄ and D₄ in guinea-pig isolated perfused lung and parenchymal strips of guinea-pig, rabbit and rat
Prostaglandins
(1981)
JF Burka et al.
Evidence for lipoxygenase pathway involvement in allergic tracheal contraction
Prostaglandins
(1980)
JF Burka et al.
The effects of SRS-A and histamine antagonists on antigen-induced contraction of guinea-pig trachea
Eur J Pharmac
(1981)
MH Saad et al.
Release of leukotriene C₄ from guinea-pig trachea
Prostaglandins
(1983)
PJ Piper et al.
Interaction of leukotrienes with cyclooxygenase products in guineapig isolated trachea
S Kitamura
Arachidonic acid metabolites and control of airway smooth muscle
SE Dahlen et al.
Leukotrienes and other eicosanoids as mediators of airway obstruction
Respiration
(1986)
NC Barnes et al.
Leukotrienes and asthma
GD Raphael et al.
Mediators of airway inflammation
Eur J Resp Dis
(1986)
FP Nijkamp et al.
Reversal of arachidonic acid-induced guinea-pig tracheal relaxation into contraction after epithelium removal
Eur J Pharmac
(1987)

NF Voelkel

Species variations in the pulmonary response to arachidonic acid metabolites

Prostaglandins

(1985)

GK Adams et al.

Antagonism of antigen-induced contraction of guinea-pig and human airways

Nature

(1977)

RA Lewis et al.

Slow-reacting substances of anaphylaxis: identification of leukotrienes C and D from human and rat

HR Morris et al.

Structure of slow-reacting substance of anaphylaxis from guinea-pig lung

Nature

(1980)

M Kumlin et al.

Differences in the formation and metabolism of leukotrienes B₄ and C₄ in the human lung

D Raeburn et al.

Lack of effect of leukotriene D₄ on Ca-uptake in airway smooth muscle

Br J Pharmac

(1984)

PJ Piper et al.

Stimulation of arachidonic acid metabolism and generation of thromboxane A₂ by leukotriene B₄, C₄ and D₄ in guinea-pig lung in vitro

Br J Pharmac

(1982)

Cited by (6)

Esculetin attenuates receptor activator of nuclear factor kappa-B ligand-mediated osteoclast differentiation through c-Fos/nuclear factor of activated T-cells c1 signaling pathway
2015, Biochemical and Biophysical Research Communications
Citation Excerpt :
In response to RANKL and M-CSF, bone marrow-derived macrophages (BMMs) are differentiated into bone resorbing osteoclasts via multiple downstream pathways such as the nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs), and phospholipase C gamma 2 (PLCγ2)-Ca2+ signaling pathways and the subsequent nuclear translocation of two main transcription factors, c-Fos and nuclear factor of activated T cell c1 (NFATc1) [12–14]. Esculetin (6,7-dihydroxycoumarin) is a naturally occurring coumarin compound that is isolated from various plant species such as Artemisia scoparia, Artemisia capillaries, Euphorbia lathyris, and Citrus limonia [15,16]. Coumarins, containing fused benzene and α-pyrone rings, belong to a group of phenolic substances, which can influence their bioactivities through the type of substitutions in their basic rings.
Esculetin exerts various biological effects on anti-oxidation, anti-tumors, and anti-inflammation. However, the involvement of esculetin in the bone metabolism process, particularly osteoclast differentiation has not yet been investigated. In the present study, we first confirmed the inhibitory effect of esculetin on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation. We then revealed the relationship between esculetin and the expression of osteoclast-specific molecules to elucidate its underlying mechanisms. Esculetin interfered with the expression of c-Fos and nuclear factor of activated T cell c1 (NFATc1) both at the mRNA and protein level with no involvement in osteoclast-associated early signaling pathways, suppressing the expression of various transcription factors exclusively expressed in osteoclasts such as tartrate-resistant acid phosphatase (Trap), osteoclast-associated receptor (Oscar), dendritic cell-specific transmembrane protein (Dcstamp), osteoclast stimulatory transmembrane protein (Ocstamp), cathepsin K, αvβ3 integrin, and calcitonin receptor (Ctr). Additionally, esculetin inhibited the formation of filamentous actin (F-actin) ring-positive osteoclasts during osteoclast differentiation. However, the development of F-actin structures and subsequent bone resorbing activity of mature osteoclasts, which are observed in osteoclast/osteoblast co-culture systems were not affected by esculetin. Taken together, our results indicate for the first time that esculetin inhibits RANKL-mediated osteoclastogenesis via direct suppression of c-Fos and NFATc1 expression and exerts an inhibitory effect on actin ring formation during osteoclastogenesis.
Effect of a total extract from Fraxinus ornus stem bark and esculin on zymosan- and carrageenan-induced paw oedema in mice
1995, Journal of Ethnopharmacology
This study investigates the total ethanol extract (TE) of the stem bark of Fraxinus ornus and its constituent esculin (EN). They inhibited classical pathway (CP) and alternative pathway (AP) of complement activation in mouse serum. After intraperitoneal administration the total extract displayed antiinflammatory activity in both zymosan- and carrageenan-induced paw oedema in mice. The results suggest that the traditional use of Fraxinus ornus stem bark extracts in the treatment of inflammatory disorders is at least partially due to its coumarin constituents.
In vitro effects of naphthoquinones isolated from drosera species
1993, Pharmacological Research
The study of natural compounds targeting RANKL signaling pathway for the treatment of bone diseases
2020, Current Drug Targets
Esculetin restores mitochondrial dysfunction and reduces allergic asthma features in experimental murine model
2009, Journal of Immunology
Anti-inflammatory and smooth muscle relaxant activities of the hydroalcoholic extract and chemical constituents from Amburana cearensis A. C. Smith
2003, Phytotherapy Research

View full text

Effects of esculetin (6,7-dihydroxycoumarin) on guinea-pig tracheal chains in vitro

Abstract

Prostaglandins

Prostaglandins

Eur J Pharmac

Prostaglandins

Interaction of leukotrienes with cyclooxygenase products in guineapig isolated trachea

Arachidonic acid metabolites and control of airway smooth muscle

Leukotrienes and other eicosanoids as mediators of airway obstruction

Respiration

Leukotrienes and asthma

Mediators of airway inflammation

Eur J Resp Dis

Reversal of arachidonic acid-induced guinea-pig tracheal relaxation into contraction after epithelium removal

Eur J Pharmac

Species variations in the pulmonary response to arachidonic acid metabolites

Prostaglandins

Antagonism of antigen-induced contraction of guinea-pig and human airways

Nature

Slow-reacting substances of anaphylaxis: identification of leukotrienes C and D from human and rat

Structure of slow-reacting substance of anaphylaxis from guinea-pig lung

Nature

Differences in the formation and metabolism of leukotrienes B4 and C4 in the human lung

Lack of effect of leukotriene D4 on Ca-uptake in airway smooth muscle

Br J Pharmac

Stimulation of arachidonic acid metabolism and generation of thromboxane A2 by leukotriene B4, C4 and D4 in guinea-pig lung in vitro

Br J Pharmac

Differences in the formation and metabolism of leukotrienes B₄ and C₄ in the human lung

Lack of effect of leukotriene D₄ on Ca-uptake in airway smooth muscle

Stimulation of arachidonic acid metabolism and generation of thromboxane A₂ by leukotriene B₄, C₄ and D₄ in guinea-pig lung in vitro