Abstract
Thyme extract is known to posses spasmolytic effects on isolated trachea and to increase
ciliary activity. A small part of this effect is mediated via β2 receptors, but other receptors are supposed to be involved. Endothelin has a pathophysiological
impact in asthma with respect to hyper-reagibility and contracting isolated trachea
smooth muscles and was, therefore, investigated. Thyme extract inhibited endothelin-induced
contraction. Emax decreased depending on the concentration of thyme extract indicating a non-competitive
inhibition. Bosentan, an endothelin receptor antagonist (positive control), acted
as a competitive inhibitor. The interaction/combination of thyme extract and bosentan
was additive but not supra-additive indicating an interaction with the endothelin
system. Thymol (one of the major compounds of thyme extract) did not interact with
the endothelin system. It is concluded that thyme extract may help in diseases related
to endothelin hyper-reagibility of the bronchus system such as asthma and COPD (chronic
obstructive pulmonary disease), although thymol is not involved in this effect.
Key words
Thymus vulgaris L. - Lamiaceae - thyme extract - thymol - endothelin - trachea
References
- 1
Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y. et al .
A novel potent vasoconstrictor peptide produced by vascular endothelial cells.
Nature.
1988;
332
411-5
- 2
Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K. et al .
The human endothelin family: three structurally and pharmacologically distinct isopeptides
predicted by three separate genes.
Proc Natl Acad Sci USA.
1989;
86
2863-7
- 3
Kirchengast M, Witte K, Stolpe K, Schilling L, Nedvetsky P I, Schmidt H H. et al .
Effects of chronic endothelin ET(A) receptor blockade on blood pressure and vascular
formation of cyclic guanosine-3′,5′-monophosphate in spontaneously hypertensive rats.
Arzneimittelforschung/Drug Res.
2005;
55
498-504
- 4
Hay D W, Douglas S A, Ao Z, Moesker R M, Self G J, Rigby P J. et al .
Differential modulation of endothelin ligand-induced contraction in isolated tracheae
from endothelin B (ET(B)) receptor knockout mice.
Br J Pharmacol.
2001;
132
1905-15
- 5
D'Agostino B, Advenier C, Falciani M, Gallelli L, Marrocco G, Piegari E. et al .
Endothelin-1 increases cholinergic nerve-mediated contraction of human bronchi via
tachykinin synthesis induction.
Br J Pharmacol.
2001;
134
1447-54
- 6
Filep J G, Battistini B, Sirois P.
Pharmacological modulation of endothelin-induced contraction of guinea-pig isolated
airways and thromboxane release.
Br J Pharmacol.
1991;
103
1633-40
- 7
Yoneyama T, Hori M, Makatani M, Yamamura T, Tanaka T, Matsuda Y. et al .
Subtypes of endothelin ETA and ETB receptors mediating tracheal smooth muscle contraction.
Biochem Biophys Res Commun.
1995;
207
668-74
- 8
Takai M, Umemura I, Yamasaki K, Watakabe T, Fujitani Y, Oda K. et al .
A potent and specific agonist, Suc-[Glu9,Ala11,15]-endothelin-1(8 – 21), IRL 1620,
for the ETB receptor.
Biochem Biophys Res Commun.
1992;
184
953-9
- 9
El-Mowafy A M, Biggs D F.
ET(B) receptor activates adenylyl cyclase via a c-PLA(2)-dependent mechanism: a novel
counterregulatory mechanism of ET-induced contraction in airway smooth muscle.
Biochem Biophys Res Commun.
2001;
286
388-93
- 10
Zhang Y, Adner M, Cardell L O.
Interleukin-1b attenuates endothelin B receptor-mediated airway contractions in a
murine in vitro mdoel of asthma: roles of endothelin converting enzyme and mitogen-activated
protein kinase pathways.
Clin Exp Allergy.
2004;
34
1480-7
- 11
Granstrom B W, Xu C B, Nilsson E, Bengsson U H, Edvinsson L.
Up-regulation of endothelin receptor function and mRNA expression in airway smooth
muscle cells following Sephadex-induced airway inflammation.
Basic Clin Pharmacol Toxikcol.
2004;
95
43-8
- 12
Chalmers G W, Little S A, Patel K R, Thomson N C.
Endothelin-1-induced bronchoconstriction in asthma.
Am J Respir Crit Care Med.
1997;
156
382-8
- 13
Henry P J.
Endothelin-1 (ET-1)-induced contraction in rat isolated trachea: involvement of ETA
and ETB receptors and multiple signal transduction systems.
Br J Pharmacol.
1993;
110
435-41
- 14
Turner N C, Power R F, Polak J M, Bloom S R, Dollery C T.
Endothelin-induced contractions of tracheal smooth muscle and identification of specific
endothelin binding sites in the trachea of the rat.
Br J Pharmacol.
1989;
98
361-6
- 15
Van den Broucke C O, Lemli J A.
Pharmacological and chemical investigation of thyme liquid extracts.
Planta Med.
1981;
41
129-35
- 16
Meister A, Bernhardt G, Christoffel V, Buschauer A.
Antispasmodic activity of Thymus vulgaris extract on the isolated guinea-pig trachea: discrimination between drug and ethanol
effects.
Planta Med.
1999;
65
512-6
- 17
Boskabady M H, Aslani M R, Kiani S.
Relaxant effect of Thymus vulgaris on guinea-pig tracheal chains and its possible mechanism(s).
Phytother Res.
2006;
20
28-33
- 18 Wienkötter N. Pharmakologische Untersuchungen zum Spasmolytischen Wirkmechanismus
von Thymian-haltigen Extrakten: Beeinflussung des β2-adrenergen Systems [disseration]. Münster;
University of Münster 2006
- 19
Wienkötter N, Begrow F, Kinzinger U, Schierstedt D, Verspohl E J.
The effect of thyme extract on beta2-receptors and mucociliary clearance.
Planta Med.
2007;
73
629-35
- 20
Devadason P S, Henry P J.
Comparison of the contractile effects and binding kinetics of endothelin-1 and sarafotoxin
S6b in rat isolated renal artery.
Br J Pharmacol.
1997;
121
253-63
- 21
Bremnes T, Paasche J D, Mehlum A, Sandberg C, Bremnes B, Attramadal H.
Regulation and intracellular trafficking pathways of the endothelin receptors.
J Biol Chem.
2000;
23
17 596-604
- 22
Freedman N J, Ament A S, Oppermann M, Stoffel R H, Exum S T, Lefkowitz R J.
Phosphorylation and desensitization of human endothelin A and B receptors. Evidence
for G protein-coupled receptor kinase specificity.
J Biol Chem.
1997;
272
17 734-43
- 23
Wu-Wong J R, Chiou W J, Magnuson S R, Opgenorth T J.
Endothelin receptor agonists and antagonists exhibit different dissociation characteristics.
Biochim Biophys Acta.
1994;
1224
288-94
- 24
Chun M, Lin H Y, Henis Y I, Lodish H F.
Endothelin-induced endocytosis of cell surface ETA receptors. Endothelin remains intact
and bound to the ETA receptor.
J Biol Chem.
1995;
270
10 855-60
- 25
Burgess G, Hoogkamer H, Collings L, Dingemanse J.
Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil.
Eur J Clin Pharmacol.
2008;
64
43-50
- 26
Sudoh K, Yuyama H, Noguchi Y, Fujimori A, Ukai M, Ohtake A. et al .
Pharmacological characterization of YM598, a selective endothelin-A receptor antagonist.
J Cardiovasc Pharmacol.
2004;
44
390-3
- 27
Clozel M, Breu V, Gray G A, Kalina B, Löffler B M, Burri K. et al .
Pharmacological characterization of bosentan, a new potent orally active nonpeptide
endothelin receptor antagonist.
J Pharmacol Exp Ther.
1994;
270
228-35
Prof. Dr. E. J. Verspohl
Department Pharmacology
Institute for MedicinalChemistry
University of Münster
Hittorfstr. 58–62
48149 Münster
Germany
Fax: +49-251-83-32144
eMail: verspoh@uni-muenster.de