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Effects of 1,8-cineole (eucalyptol) on the activity of human bronchial
tissue
DOI: https://10.36811/ojprm.2019.110004 OJPRM: November-2019: Page No: 12-22
Page: 12
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Open Journal of Pulmonology and Respiratory
Medicine
Research Article Open Access
Effects of 1,8-cineole (eucalyptol) on the activity of human bronchial tissue
André-Michael Beer1*, Plamen Sagorchev2 and Julian Lukanov2
1Ruhr University Bochum, Im Vogelsang 5-11, 45527 Hattingen, Germany
2Medical University, Biophysics Department, 15-A V. Aprilov Street, 4000 Plovdiv, Bulgaria
*Corresponding Author: Prof. Dr. med. André-Michael Beer, MSc Ruhr-University Bochum, Im
Vogelsang 5-11, 45527 Hattingen, Germany, Phone: 0049 2324 39672487; Fax: 0049 2324 39672497;
Email: andre.beer@klinikum-Bochum.de
Received Date: Nov 12, 2019 / Accepted Date: Nov 22, 2019/ Published Date: Nov 25, 2019
Abstract
1,8-cineole (eucalyptol) is used for the treatment of bronchial complaints, sinusitis and colds.
Experiments have previously shown that 1,8-cineole, a monoterpene (C-10), has a very pronounced
spasmolytic effect on smooth muscle fibre.
In nearly all clinical applications with 1,8-cineole, especially when used in conjunction with allergic
symptoms, histamine receptors prove to be crucial for treatment (use of histamine inhibitors).
Results: The desired 1,8-cineole effects are attained through:
1. specifically blocking H1 histamine receptors, without influencing ACh receptors
2. inhibiting the contractile activity of human bronchial smooth muscle by activating H2
histamine receptors.
The ultimate goal of this study was to address the bronchodilatory effect of this compound, using
human airway smooth muscle in order to demonstrate a possible role for 1,8-cineole in airway
diseases.
Keywords: Smooth muscle fibre; 1,8-cineole (eucalyptol); Human bronchial tissue; Bronchitis;
Monoterpene
Cite this article as: André-Michael Beer, Plamen Sagorchev, Julian Lukanov. 2019. Effects of 1,8-
cineole (eucalyptol) on the activity of human bronchial tissue. Open J Pulm Respir Med. 1: 12-22.
Copyright: This is an open-access article distributed under the terms of the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,
provided the original author and source are credited. Copyright © 2019; André-Michael Beer
Introduction
For many years, medications containing 1,8-
cineole (eucalyptol) have been used for the
treatment of bronchial complaints, sinusitis and
colds. It has been previously shown that 1,8-
cineole, a monoterpene (C-10) [1], has a very
pronounced spasmolytic effect on smooth
muscle fibres (SMF), similar to that of
papaverine [2]. 1,8-cineole was found to have
agonistic effects on the 1 and 2 adrenergic
receptors [3]. These effects can be registered at
low concentrations of up to 3 x10-7 M to 2 x 10-
5 M 1,8-cineole. At higher concentrations, the
Effects of 1,8-cineole (eucalyptol) on the activity of human bronchial
tissue
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well-known spasmolytic effect appears. At
concentrations above 4 x 10-4 M 1,8-cineole, the
effect of 10-5 M acetylcholine is 100%
suppressed. The results of the interactions
between 1,8-cineole and histamine indicate that
1,8-cineole is a reversible antagonist for
histamine receptors. Increasing the
“concentration” of 1,8-cineole by 16-fold (from
0.005 up to 0.080 l) increases this inhibition
from approx. 25% to approx. 66% [4].
However, the various smooth muscles in the
body are characterised by different types and
number of receptors. The aim of this manuscript
is to describe the effect of 1,8-cineole on the
contractile activity of human bronchial smooth
muscles.
Materials and Methods
In in vitro experiments on smooth muscle fibre
of bronchial muscle, the influence of histamine
under normal conditions and using different
concentrations of 1,8-cineole on the
spontaneous contractile activity (SCA) of SMF
was investigated.
2.1 Measurement of the spontaneous contractile
activity of smooth muscle fibre of segmental
bronchi and method of preparation
The measurements were performed according
to the standardised Golenhofen method [5]. The
smooth muscle fibre used in the experiments
was taken from human segmental bronchi.
The muscle tissue had a length of 12-15 mm
and a width of 1.5-2 mm and was taken from
human segmental bronchi. Organ baths (20 mL
volume) contained a Krebs´ solution (KS) with
the following composition: mmol/L: Na+ (143),
K+ (5.94), Mg2+ (1.19); Ca2+ (2.5), Cl- (133),
HCO- (16.7), HPO42- (11.9) and glucose (11.5).
A pH-value within physiological limits of 7.2 to
7.3 (7.2 ± 0.8) was maintained. The organ baths
of Krebs´ solution were kept at 35 °C (± 0.2 °C).
Throughout the experiments the Krebs´
solution was carbonated with carbon dioxide
gas. The response to histamine was measured
under isometric conditions (mN).
Substances
-Acetylcholine chloride (acetylcholine
ophtalmicum dispersa®), Dispersa, Germering,
Germany)
- Substances for Krebs´ solution (Merck comp.,
Darmstadt, Germany): NaCl, KCl, MgCl2 6
H2O, KH2PO4, NaHCO3, CaCl2
- 1,8-cineole, Ph. Eur., Ch.-B: 1,015,309 (purity
99.6%; Klosterfrau Healthcare Group, Berlin).
The following agonists and blockers were used
in the assays:
• 1,8-cineole, Ph.Eur., Ch.-B:10153-09,
Klosterfrau Healthcare Group, Berlin,
Germany
• H1 agonist (2 - (2-pyridyl) -
ethylamine), Sigma-Aldrich Co, USA
• α1/α2 antagonist (benextramine), RBI-
SIGMA, St. Louis, MO, USA
• H2 agonist (dimaprit), Sigma-Aldrich
Chemie GmbH, Germany
• H2 antagonist (famotidine), Sigma-
Aldrich Chemie GmbH, Germany
• α2 agonist (methoxamine), RBI-
SIGMA, St. Louis, MO, USA
• α1 agonist (p-iodoclonidine), RBI-
SIGMA, St. Louis, MO, USA
Substances from Merck (Merck, Darmstadt,
Germany) were used to prepare the prep and
Krebs´ solution.
Cineole solution
At room temperature, 10 µL 1,8-cineole were
added to 2 mL of ethanol (98%). The sample
was homogenised with a vortexer for 2 min.
The transparency of the samples was
determined using standardised methodology at
an illumination of 1500 lux. After proper
solubility was established, 1,8-cineole was
progressively diluted to 100 µL 1,8-cineole in
2 mL of ethanol (98%) (5% solution of cineole
in 98% ethanol). Further dilution with Krebs´
solution was performed. Thereafter, direct
Effects of 1,8-cineole (eucalyptol) on the activity of human bronchial
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comparisons of the absorption spectra of the
concentrations of 1,8-cineole in Krebs´ solution
were determined.
Statistics
To take into account the specific variations and
alterations of the SCA preparation’s measured
values, the concentration-response curves in
each case of N = 10 individual experiments,
always measured the excitation in % of
maximal contractile activity of smooth muscle
tissue when exposed to 10-5 M acetylcholine
(ACh). The changes of the smooth muscle fibre
(SMF) concerning SCA with various
substances are given in Newtons (N). The
processing of experimental data was performed
using the Statistica 4.5 (StatSoft, Inc.
Microsoft, USA) program. For comparison
between two groups, the t-Test (student) for
unpaired samples was implemented. For
comparisons between three or more groups,
variance analysis (ANOVA) was used. The
statistical comparisons were performed at the
5% significance level. The results are expressed
as mean ± standard deviation. In each case n =
7 measurements per experiment were
performed.
Results
To analyse the effects and mechanisms of effect
of 1,8-cineole on the contractile activity of the
segmental bronchi, the tissue was first tested for
the presence of α1, α2 adreno-, H1, H2 histamine
and ACh receptors.
Figure 1: shows that 10-5 M ACh brings about
very good contraction of the smooth muscle
fibre of the segmental bronchi. It corresponds to
the maximal attainable contractile effect of
smooth muscles.
Figure 1: Effect of 10-5 M ACh on the contractile activity of smooth muscle fibre of human segmental
bronchi.
Effects of 1,8-cineole (eucalyptol) on the activity of human bronchial
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Figure 2: (top) shows that 10-7 M p-
iodoclonidine (α2 adrenoreceptor agonist) has a
stimulating effect on these muscle preparations.
Figure 2: (bottom) shows that also 10-6 M
methoxamine (α2-agonist) induces markedly
stimulating effects.
Figure 2: Effect of 10-7 M p-iodoclonidine
(top) and 10-6 M methoxamine (bottom) on the
contractile activity of smooth muscle fibre of
human segmental bronchi.
Figure 3: illustrates the effects of H1 (bottom)
and H2 (top) histamine agonists. Dimaprit, a H2
histamine receptor agonist, is a strong inhibitor
of the contractile activity of segmental bronchi
(Figure. 3, top).
By contrast, activation of H1 histamine
receptors results in observation of highly
stimulating effects, almost comparable with
those of 10-5 M ACh (Figure. 3, bottom).
Figure 3: Effect of 10-6 M H2 agonist dimaprit
(top) and effect of 10-6 M H1 agonist 2-(-2 -
pyridyl)-ethylamine (bottom) on the contractile
activity of smooth muscle fibre of human
segmental bronchi.
Effects of 1,8-cineole (eucalyptol) on the activity of human bronchial
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Figure 4: (top) shows that, at an effect with
0.001 μl 1,8-cineole (approx. 3 x 10-8 M), the
SCA of the bronchi remains virtually
unchanged. Only a tendency to suppress the
SCA in the effect with 0.005 μl 1,8-cineole
(approx. 1.5 x 10-7 M) can be recorded
(Figure. 4, bottom).
In Figure 4 (top) the inhibitory effects on the
contractile activity of the bronchi are already
clearly visible.
Figure 4: Effect of 0.001 μl 1,8-cineole
(approx. 6 x 10-7 M/L) top, and 0.005 μl
(bottom) on the contractile activity of smooth
muscle fibre of human segmental bronchi.
In the case of a further increase in 1,8-cineole
to 0.01 μl (3 x 10-7 M), a very pronounced
suppression of the SCA of the bronchi is
observed (Figure. 5, top), which however
changes to a stimulating effect after 3-
4 minutes. By contrast, in the case of the effect
with 0.1 μl 1,8-cineole (approx. 3 x 10-5 M),
only a pronounced stimulatory effect can be
registered (Figure. 5, below). It must be taken
into account that short-term effects with 1,8-
cineole levels of 0.1 μl (3 x 10-5 M) lie below
the necessary concentrations for a spasmolytic
effect.
Furthermore, 0.01 μl 1,8-cineole (equivalent to
a concentration of approx. 3 x 10– 6 M) was in
each case used to be able to explain the
mentioned effects of 1,8-cineole on the
contractile activity of the bronchi.
Figure 5: Effect of 0.01 μl (top) and 0.1 μl
(bottom) on the contractile activity of smooth
muscle fibre of human segmental bronchi.
Effects of 1,8-cineole (eucalyptol) on the activity of human bronchial
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Figure 6: (top) shows the effect of 0.01 μl 1,8-
cineole on the SCA of bronchi and with prior
administration of 5 x 10-6 M benextramine (α1
α2 adrenoreceptor blocker) (Figure. 6, bottom).
Blocking of α1 and α2 adrenoreceptors
completely cuts off the stimulating effect of
1,8-cineole on the SCA of the bronchi. Only the
inhibitory components of these effects persist.
Figure 6: Effect of 0.01 μl 1,8-cineole on the
contractile activity of smooth muscle fibre of
human segmental bronchi under normal
conditions (top) and with prior administration
of 5 x 10-6 benextramine (bottom).
Figure 7: shows that the blocking of H2
histamine receptors completely cuts off the
inhibitory components of the 1,8-cineole effect
on the SCA of the bronchi. Only the stimulating
effects of 1,8-cineole on the SCA of the bronchi
remain.
Figure 7: Effect of 0.01 μl 1,8-cineole on the
contractile activity of smooth muscle fibre of
human segmental bronchi under normal
conditions (top) and with prior administration
of 5 x 10-6 M famotidine, a H2 histamine
antagonist (bottom).
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Figure 8: shows that the overall effect of 1,8-
cineole with simultaneous blocking of α1, α2
adreno- and H2 histamine receptors is
completely blocked.
Figure 8: Effect of 0.01 μl 1,8-cineole on the
contractile activity of smooth muscle fibre of
human segmental bronchi (top) and with prior
administration of 5 x 10-6 M benextramine and
5 x 10-6 M famotidine (bottom).
Figure 9: Shows the results of the effects of 10-6
MH1 histamine agonists on the SCA of the
bronchi under normal conditions (top) and with
prior administration of 0.005 μl 1,8-cineole
(approx. 1.5 x 10-6 M). The stimulating effects of
the H1 agonist (top) are clearly reduced (Figure. 9,
bottom).
Figure 9: Effect of 10-6 M H1 agonist (2–(2
pyridil)-ethylamine) on the contractile activity
of smooth muscle fibre of human segmental
bronchi under normal conditions and with prior
administration of 0.005 μl 1,8-cineole.
The effects of 10-5 M ACh under normal
conditions (top) and with prior administration
of 0.01 μl 1,8-cineole are presented in
Figure 10. In the presence of 0.01 μl 1,8-
cineole, the stimulating effects of ACh remain
unchanged.
Effects of 1,8-cineole (eucalyptol) on the activity of human bronchial
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Figure 10: Effect of 10-5 M ACh on the
contractile activity of smooth muscle fibre of
human segmental bronchi (top) and with prior
administration of 0.01 μl 1,8-cineole (bottom).
Figure 11: shows that the stimulating effects of
ACh remain unchanged even after several
effects of 0.01 μl 1,8-cineole.
Figure 11: Effect of 10-5 M ACh on the
contractile activity of smooth muscle fibre of
human segmental bronchi at the start of the
experiment and after 4x administration of
0.01 μl 1,8-cineole.
Discussion
1,8-cineole is a monoterpene known to be a
component of various essential oils, e.g. of the
genus Eucalyptus, Salvia, Rosmarinus, but is
mainly isolated from Eucalyptus species which
produce essential oil rich in cineole. This
saturated terpene has a number of medicinally
useful anti-inflammatory, anti-oxidative and
antimicrobial effects, as recently presented in
an overview by Juergens [6]. An experimental
study provides useful data suggesting that
1,8-cineole is a specific COX-2 blocker [7].
1,8-cineole is used as an active ingredient in
medicinal products and can be inhaled,
topically applied or be taken orally. After
resorption of 1,8-cineole in the small intestine
part of it is eliminated unchanged by exhalation
[8]. In the intestinal as well as the bronchial
tract, 1,8-cineole also comes into contact with
smooth muscle fibre. Investigations of the
effects of 1,8-cineole on SMF, whether
receptor-specific or receptor-independent, are
expected to contribute to understanding of the
clinical efficacy of 1,8-cineole, e.g. in
inflammatory bronchial diseases [9]. Our
results show that the mechanisms of this
inhibition are due to an effect specific to the
human bronchial system. Biologically active
substances can influence the contractile activity
of smooth muscle in various ways. Firstly, the
contractile activity of smooth muscle can be
influenced by an effect on the receptors present
on smooth muscle cells, e.g. through the effects
of histamine, dopamine, acetylcholine, other
mediators or with synthetic substances. For
influences at the receptor level, the effects on
the contractile activity of smooth muscle
typically only occur after several seconds. The
second notable aspect of these effects is that
demonstrable changes in contractile activity are
still observed at concentrations of 10-7 - 10-9 M.
Very often, these are reversible.
Secondly, biologically active substances have
effects on different enzyme systems (e.g.
phosphodiesterases, adenylate cyclases,
cyclooxygenases). For such substances, the
effects typically occur only after several
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minutes and at concentrations above 10-6 M.
Independent of other properties of a substance
(spasmolytic effects etc.), these time and
concentration intervals allow the effects of
biologically active substances to be analysed at
the receptor level. This in particular applies to
substances exhibiting multiple effects on
smooth muscle, such as, for example, some
monoterpenes (1,8-cineole, thymol) with a very
powerful spasmolytic effect. As a result, short-
acting effects and effects at low concentrations,
have allowed identification of previously
unknown effects with 1,8-cineole and other
compounds.
The stimulating effects of histamine continue to
suppress the smooth muscle at 1,8-cineole
concentrations of 3 x 10-6 M. This proves that
the smooth muscle of the segmental bronchi
possesses histamine H1 receptors.
1,8-cineole has an agonistic effect on histamine
H2 receptors, causing very strong suppression
of the contractile activity of smooth muscle.
The smooth muscles of the bronchi also possess
these receptors. It could be shown in the
experiments that 1,8-cineole already exerts a
powerful suppressive effect on the contractile
activity of the bronchi at a concentration of
3 x 10-6 M.
It was also demonstrated that 1,8-cineole, at a
concentration of 3 x 10-6 M, has agonistic
effects on α1 und α2 adrenoreceptors [3].
Activation of α1 and α2 adrenoreceptors, which
also occurs with other monoterpenes, e.g. with
thymol, is observed at very high concentrations
[10]. This is the reason for the existence of
contradictory reports on the effect of 1,8-
cineole on the bronchi. At a low doses, the
stimulating effects of 1,8-cineole dominate
through the activation of the α1 and α2
adrenoreceptors. Additional intensification of
the bronchial spasmolytic properties results as a
consequence of the mentioned effects. At
somewhat higher concentrations, an
equilibrium occurs between the stimulating and
suppressive effects on the contractile activity of
the bronchi. A pronounced spasmolytic effect
on the bronchi is recorded at higher
concentrations.
At sufficiently high concentrations of 1,8-
cineole (approx. 10-5 M in vitro), contraction is
blocked due to the stimulation of α1 and α2
adrenoreceptors by its spasmolytic effect, as
there are insufficient free Ca2+ ions available.
The spasmolytic effect of 1,8-cineole cannot
influence the effects on the H1 and H2 histamine
receptors and the blocking of cyclooxygenase.
As a result, the desired 1,8-cineole effects are
attained:
1. A specific blocker of H1 histamine
receptors, with no effect on ACh receptors.
2. Inhibition of the contractile activity of
human bronchial smooth muscle through
activation of H2 histamine receptors.
These results are in line with former
investigations indicating the spasmolytic effect
of 1,8-cineole on SMF in our results [3]. A
study by Wagner [11] showed, however, that
terpenes, when administered to patients with
bronchial asthma, resulted in paradoxical
bronchoconstriction reactions. We believe that
these contradictory reports are based on the
special properties of terpenes: Monoterpenes
are known to have both specific and non-
specific effects on smooth muscle fibre,
dependent on the dose. Some monoterpenes,
such as 1,8-cineole and thymol [10], at
concentrations of up to 5 x 10-7 M, lead to
constricting effects on almost all smooth
muscle fibre. These effects are due to the
agonistic effects on α1 and α2 adrenoreceptors.
However, they can only be observed up to an
administered dose of a concentration of 5 x 10-
7 M. Exceeding this amount, the pronounced
spasmolytic effect of cineole appears, which no
longer allows the registration of specific
effects. Low concentrations of 1,8-cineole
allow observations of bronchoconstriction.
Here, we recorded the stimulating effects of
1,8-cineole on smooth muscle fibre (due to the
excitation effects on H1 receptors). At higher
concentrations very pronounced spasmolytic
effects can be observed and, of course,
inhibition of H1 receptor activity. The
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concentration-response curve of the effects of
histamine indicates that the maximum
excitation effects are achieved at a
concentration of 5 x 10-6 M. The results of the
interaction between 1,8-cineole and histamine
indicate that 1,8-cineole is a reversible
antagonist of histamine H1 receptors. Regarding
the clinical relevance of the use of 1,8-cineole,
the well-known spasmolytic effect of 1,8-
cineole in therapeutic concentrations could be
particularly valuable in inflammatory airway
diseases with bronchoconstriction symptoms,
which has already been confirmed in clinical
trials with patients suffering from asthma or
COPD [7].
Conclusions
The ultimate goal of this study was to address
the bronchodilatory effect of this compound,
using human airway smooth muscle in order to
demonstrate a possible role for 1,8-cineole in
airway diseases. Human airway smooth muscle
is an appropriate substrate because the
pharmacological properties of airway smooth
muscle could differ in several aspects from
those of gastric and other types of smooth
muscle.
List of Abbreviations
Acetylcholine (ACh).
Krebs´ solution (KS)
Newtons (N)
Smooth muscle fibres (SMF)
Spontaneous contractile activity (SCA)
All experiments were approved by the
Bulgarian Food Safety Agency (approval
number: 21/19.03.2012) and the Ethics
Committee of the Medical University of
Plovdiv, Bulgaria (approval number:
2/13.03.2014).
Funding
Prof. J. Lukanov reported receiving financial
support by Klosterfrau Company used for
reagents and animals to perform the study. All
other authors declare that they have no
competing interests.
Acknowledgements
We thank the Klosterfrau Company for their
financial support in making this study possible.
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