Mydriasis model in rats as a simple system to evaluate α2

Mydriasis model in rats as a simple system to evaluate α2

Pharmacological Reports
Copyright © 2013
2013, 65, 305–312
by Institute of Pharmacology
ISSN 1734-1140
Polish Academy of Sciences
Review
Mydriasis model in rats as a simple system
to evaluate a2-adrenergic activity
of the imidazol(in)e compounds
Joanna Raczak-Gutknecht, Teresa Fr¹ckowiak, Antoni Nasal,
Roman Kaliszan
Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdañsk, Al. Gen. J. Hallera 107,
PL 80-416, Gdañsk, Poland
Correspondence: Joanna Raczak-Gutknecht, e-mail: [email protected]
Abstract:
Imidazol(in)e compounds show the diversity of pharmacological effects including mydriasis, hypotension, sedation, bradycardia
and hypothermia. At first it was postulated that these effects are mediated via a2-adrenoceptors exclusively. Clonidine is well known
as a model agent to produce pupillary dilation in rats. However, it became obvious later that clonidine-like imidazol(in)e adrenoceptor agonists which produced mydriasis in rats, exhibit also a high affinity for imidazoline I1-receptors. That short report attempts to
review the present status of studies to confirm that the mydriasis model in rats can be a selective system to evaluate the a2-adrenergic
activity of potential pharmacologically active compounds of imidazol(in)e structure.
Key words:
mydriatic activity, a-adrenergic receptors, imidazole(in)e receptors, imidazol(in)e derivatives
Abbreviations: CNS – central nervous system, DSP-4 –
N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride,
MAO-A – monoamine oxidase A, RS-79948 – (8aR,
12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy12-(ethylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridine hydrochloride, RX 781094 – 2-(1,4-benzodioxan-2-yl)-2imidazoline
hydrochloride, UK-14,304 – 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline
Introduction
It has been discovered that agents of the imidazol(in)e
structure may interact with different classes of a distinct receptors such as a1, a2-adrenergic, I1, I2-imidazoline as well as with other (e.g., H1, H2-histamine)
receptors [9, 18, 45].
Imidazol(in)e derivatives are mostly known for
having cardiovascular potency. They influence blood
pressure and heart rate, act on the smooth muscle of
blood vessel and on the aggregation of blood platelets
[29]. They might also play an important role in cell
proliferation, the regulation of body fat, neuroprotection, inflammation, and some psychiatric disorders
such as depression [19]. This is all possible because
those agents can also activate (apart from a-adrenoceptors) imidazoline receptors, which belong to two
main classes [12]. The I1-imidazoline receptor mediates sympatho-inhibitory actions to lower blood pressure [7] and the I2-imidazoline receptor shows the important allosteric binding activity towards the
monoamine oxidase A (MAO-A) [48]. Imidazoline
receptors represent important targets for cardiovascular research. So far, a range of new imidazol(in)e agoPharmacological Reports, 2013, 65, 305–312
305
nists and antagonists has been identified showing the
selectivity towards I1- and I2-imidazoline receptors.
Some of those agents show also capability to mediate
pharmacological effects via a-adrenergic mechanism.
Earlier studies suggested that I1-imidazoline receptors
might be engaged in the effect of lowering central
blood pressure evoked by clonidine-like drugs [58].
Another difficulty in studying the physiological role
of imidazoline-binding sites is that the ligands possessing the high affinity for these sites still have some
affinity for a2-adrenoceptors [9]. The basic problem
occurs then to recognize and confirm the specific
pharmacological action mediated via a particular class
of receptor. The affinity of some ligands towards a
specific receptor has been tested by different methods,
e.g., radioligand binding technique. The reliability of
those in vitro methods is limited because they give no
possibility to differentiate between ago- and antagonist properties of the ligands tested. Also, a major obstacle still is the lack of highly selective ligands for
imidazoline receptor subtypes. Recently, many studies were undertaken to pharmacologically determine
if imidazoline I1-receptors can be involved in the
a2-adrenoceptor activity of the ligands of imidazol(in)e structure [43].
It has been proved that imidazol(in)e derivatives
classified as a2-adrenoceptor agonists (so-called
“clonidine-like agents”) cause mydriasis in rats but
also in other laboratory animals (mice, cats). Pupillary
dilation produced by clonidine and related drugs is
mediated via the stimulation of the postsynaptic a2adrenoceptor within the Edinger-Westphal nucleus in
the brain [35]. As was shown by Nasal et al. [46], the
mydriatic activity of imidazol(in)es could be closely
correlated with their hypotensive and bradycardic effects in rats after systemic administration. In many
comparative studies it appeared that the rat clonidine
mydriasis model can be the most sensitive, reliable
test in assessing in vivo a2-adrenoceptor activity.
However, the question arises if clonidine-induced mydriasis could be partly mediated by imidazoline I1receptors. This information may be crucial for the selectivity of the rat mydriasis model. Since Yu and
Koss [65] proved that imidazoline receptors are not
functionally involved in rat clonidine mydriasis, that
in vivo experimental model could be widely applied in
preclinical research to characterize a2-adrenoceptor
activity of drugs.
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Pharmacological Reports, 2013, 65, 305–312
Engagement of a-adrenergic/imidazoline
receptors in the mechanism of mydriasis
Role of a2- and imidazoline receptors
It was suggested by Warwick in 1954 [62], and confirmed by Silito and Zbro¿yna [55] in 1970 that the
tonic parasympathetic preganglionic cell bodies that
innervate the iris are located in the Edinger-Westphal
nucleus and antero-median nuclei of the oculomotor
complex [55, 62]. Axons emerge in the third cranial
nerve and synapse in the ciliary ganglion. The main
tone to the pupil is mediated by the parasympathetic
system which is modulated by many different inhibitory or excitatory central inputs. The predominance of
parasympathetic tone is particularly true in the cat.
The result of treatment with guanethidine or acute
sympathectomy is a minimal miosis of about 0.5 mm
[4]. Additionally, it was demonstrated by many investigators that reflex pupillary dilation, also due to light
withdrawal, is mediated only by the inhibition of
parasympathetic tone in examined species [38, 59,
62].
The first to study the light-reflex pathway, the main
excitatory influence to the tonic pupilloconstrictor
system, were Magoun and Ranson [39, 40]. They defined the excitatory pathway through the pretectum,
the Edinger-Westphal nucleus, and the ciliary ganglion. In later investigations light and electrical stimulation of various loci along this reflex arc was used
and ciliary nerve potentials were recorded. These
studies have contributed much to our understanding
of the neurophysiologic substrates of this autonomic
system [26, 54].
There are several techniques, from the physiological point of view, that have been utilized to evoke mydriasis by inhibition of the central nervous system
(CNS) parasympathetic tone to the iris. One of them
was demonstrated in the studies in cats, where
mydriasis evoked by electrical stimulation of the afferent sciatic nerve is almost exclusively due to CNS
parasympathetic inhibition. Reflex mydriasis is not
changed by sectioning the cervical sympathetic
nerves, but it is stopped following an excision of the
ciliary ganglion or sectioning the oculomotor nerve
[25, 59, 63]. Although not as exclusively mediated by
parasympathetic inhibition, electrical stimulation of
loci in the cerebral cortex, posterior hypothalamus,
and lower brainstem also produce mydriasis. This is
Imidazol(in)es cause mydriasis in rats via a2-adrenoceptors
Joanna Raczak-Gutknecht et al.
mediated in part, by the withdrawal of tonic parasympathetic tone to the iris [47, 53, 63].
The size of the pupil depends on two types of muscle: the first of these is pupil sphincter muscle, consisting of circularly arranged muscle fibers, the second is the iris dilator, consisting of radially arranged
muscle fibers. Iris sphincter muscle is innervated by
the parasympathetic nervous system, the iris dilator is
controlled by the sympathetic nervous system. Sympathetic stimulation of the adrenergic receptors causes
the contraction of the radial muscle, which is followed
by dilation of the pupil. Parasympathetic stimulation
causes contraction of the circular muscle and, as a result, constriction of the pupil.
In 1971, it was noted that clonidine produce pupillary dilation in some species. Walland and Kobinger
[61], and Kobinger [31] described the mechanism of
the clonidine-induced mydriasis in rats, to a direct
sympathomimetic action on the iris. Since then, many
imidazol(in)e derivatives have been investigated.
Studies performed in rats, by intravenous administration of clonidine, UK-14,304, and guanoxabenz [3,
20, 21] show that a2-adrenoceptor agonists, produce
dose-related pupillary dilation. From these three agonists clonidine has the strongest potency. It was found
that pupillary dilation was produced by analogues of
clonidine that have similar structure [35, 50] and also
by imidazol(in)es from the group of a2-adrenoceptor
agonists. Berridge et al. [3] in their studies demonstrated that intravenous administration of clonidine,
but also UK-14,304, and guanoxabenz (highly selective a2-adrenoceptor agonists [6, 11]) produce a marked
dose-related mydriasis which is competitively antagonized by a2-adrenoceptor antagonists: RX 781094,
RS 21361 and yohimbine. These studies showed, that
RX 781094 antagonizes mydriasis, evoked by guanoxabenz, or atropine. RX 781094 administrated in
small amounts into the lateral cerebral ventricle caused
a rapid dose-related antagonism of the mydriasis produced by guanoxabenz. This was direct evidence that
the mydriatic effect is mediated via a central a2-adrenoceptor mechanism [3]. Further studies supported
this suggestion: the selective a1-adrenoceptor antagonists: prazosin and corynanthine, were ineffective
against this mydriatic response. Gherezghiher and
Koss [16] in previous studies confirmed these results
and showed that yohimbine, excluding phenoxybenzamine (a non-selective a1-adrenoceptor antagonist),
inhibited clonidine-induced mydriasis in the rat. In
later studies, Koss and San [36] suggested that my-
driasis in cat, as a reaction to clonidine administration, was a consequence of the reduction of parasympathetic tone in the constrictor pupillae of the iris
sphincter.
A few years later, Koss [34] presented strong evidence that clonidine-evoked mydriasis is triggered by
postsynaptic a2-adrenergic stimulation of the sciatic
nerve, which produced reflex mydriasis, by the reduction of parasympathetic neural tone to the iris. It was
also shown that some antihypertensive drugs decrease
sympathetic tone by stimulating a2-adrenoceptors
localized in the CNS. It was noted that the same drugs
produce mydriasis in some species: cats, and rats.
Yohimbine-sensitive pupillary dilation became a simple, effective model for quantitatively accessing CNS
a2-adrenoceptor activity [34].
Virtanen et al. [60] compared five azole drugs in
rats, observing their pupillary responses to those
drugs. The potency order found in these studies was:
medetomidine > clonidine = detomidine > UK 14,304
> xylazine. The following experiments confirmed the
mydriatic action of clonidine, detomidine, medetomidine, and xylazine, and demonstrated that other
imidazolines: lofexidine, moxonidine and tiamenidine, also induced a dose-dependent pupillary dilation. It was also proved that the mydriatic effect depends on the hydrophobicity of imidazol(in)es [46].
The a2-adrenomimetic activity of moxonidine and tiamenidine was confirmed by Lindner and Kaiser [37]
and Armah [1] in experiments on isolated organs and
on blood pressure.
The experiments on the mydriatic reaction induced
by a2-adrenoceptor agonists were performed on anesthetized animals [3, 16, 33, 36]. These studies were
very important in determining the role of central a2adrenoceptors in producing mydriasis, but there were
some considerations of the potential interference
caused by general anesthesia [8]. In other studies, it
was suggested that ligands producing mydriasis were
less efficacious in conscious animals at normal or
moderate laboratory illumination [30, 61]. Studies in
concious mice [20], showed that an intraperitoneal injection of clonidine produces a rapid onset of dosedependent pupil dilation. This response was dosedependently reversed by yohimbine and idazoxan.
Prazosin (a1-adrenoceptor antagonist) and pindolol
(b-adrenoceptor antagonist) did not have an influence
on clonidine-induced mydriasis [20]. These findings
confirm specific mediation by a2-adrenoceptors and
are in agreement with other results obtained in con-
Pharmacological Reports, 2013, 65, 305–312
307
Fig. 1. Scheme of mammalian brain showing the main pathways involved in pupil dilation. Solid line – the efferent sympathetic pathway
to the radial muscle of the iris; dotted lines – inhibitory influences ascending from the periphery via the brainstem reticular systems descending from the cortex and hypothalamus impinging on the
Edinger-Westphal complex (the primary mechanism of reflex pupillary dilation); dashed line – efferent parasympathetic path via the
third nerve and ciliary ganglia to the iris sphincter; 1– short ciliary
nerves; 2 – long ciliary nerves; 3 – fornix; 4 – anterior commissure; 5 –
gasserian ganglion; 6 – superior cervical ganglion; 7 – corpus callosum; 8 – massa intermediate; 9 – pons; 10 – posterior commissure;
11 – inferior colliculus; 12 – oculomotor nucleus; modified after references [13] and [17]
scious [8], and anesthetized [3, 22] animals. In further
studies in anesthetized rats it was suggested that mydriasis evoked by clonidine is mediated exclusively
by a2-adrenoceptors located in the CNS [22]. The experiments in cats and rats proved that these receptors
are located in the Edinger-Westphal complex, where
they control parasympathetic tone to the iris [22]. It
has been postulated that the a2-adrenoceptors responsible for the induction mydriasis in several species are
not inhibitory prejunctional autoreceptors controlling
adrenaline, but are part of the postsynaptic to adrenergic neuron population [22, 33]. In agreement with this
hypothesis, Heal et al. [20, 21] demonstrated that mydriasis can also be evoked in conscious rats by the administration of methamphetamine, which by inhibiting
re-uptake and enhancing release, increases noradrenaline outflow [2, 17, 51]. These studies demonstrated
that mydriasis evoked by metamphetamine is also mediated by a2-adrenoceptors, because it is idazoxan
and yohimbine sensitive. It was shown in experiments
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Pharmacological Reports, 2013, 65, 305–312
with the use of DSP-4 neurotoxin, that a2-adrenoceptors are located postsynaptically. DSP-4 was used to
selectively lesion noradrenergic neurons [21]. It depleted noradrenaline in the brain (also at EdingerWestphal nucleus responsible for mydriasis) and also
reduced mydriasis induced by the noradrenaline releasing agent, metamphetamine. Treatment with
DSP-4 did not alter the response to clonidine, which
confirms that in conscious rats mydriasis is also mediated by postsynaptic a2-adrenoceptors. The conclusion of these studies was that metamphetamine acts
indirectly on a2-adrenoceptors by increasing noradrenaline outflow, while clonidine is unaffected because of acting directly on postsynaptic a2-adrenoceptors. These studies showed that mydriasis is specifically mediated by postsynaptic a2-adrenoceptors in
the CNS and it can be evoked directly using specific
agonists, and indirectly with noradrenaline releasing
agents. This made a rapid and simple model for evaluating postsynaptic a2-adrenoceptor function in rats
without interference of anesthesia [46].
Dexamphetamine produces dose-related mydriasis
sensitive to a2-adrenoceptor agonists in anesthetized
rats, by stimulating the CNS. This activity is antagonized by idazoxan, and yohimbine. Pretreatment with
the a1-adrenoceptor antagonist – phenoxybenzamine,
does not alter the pupillary response. These experiments demonstrated that dexamphetamine acts mainly
as an indirect sympathomimetic agent to release endogenous stores of a monoaminergic neurotransmitter
which is supposedly noradrenaline [23]. Studies performed by Nasal et al. in a group of eight imidazol(in)es classified as a2-adrenoceptor agonists: clonidine, lofexidine, moxonidine, tiamenidine, xylazine,
medetomidine and detomidine, show that these agents
cause both mydriasis (after intravenous administration to anesthetized rats) and human blood platelet
aggregation in vitro. A statistically significant correlation was also found between centrally mediated mydriatic activity and both the hypotensive and bradycardic activity of the compounds studied. Moreover,
the mydriatic activity depended on the lipophilicity of
those imidazol(in)es, but platelet aggregation did not.
Similarly, the human platelet antiaggregatory effects
observed correlated with neither the mydriatic, nor
cardiovascular activity of the agents. The dependence
of the centrally induced effects of imidazol(in)es on
lipophilicity and the lack of such a dependence in the
case of such effects in in vitro a2-adrenoceptor mediated platelet aggregation may be interpreted as result-
Imidazol(in)es cause mydriasis in rats via a2-adrenoceptors
Joanna Raczak-Gutknecht et al.
ing from the heterogeneity of the rat cerebral and human blood platelet a2-adrenoceptors [46].
It is well known that clonidine – like other a2-adrenoceptor agonists, can evoke autonomic nervous system reactions causing sedation, hypotension, anesthesia, hypothermia and mydriasis [28, 57].
In 2003, Koss [35] undertook studies on rilmenidine, an a2/imidazoline-I1 receptor agonist. In previous studies, it was demonstrated that this drug, in contrast to clonidine, is a CNS I1-imidazoline receptor
agonist, rather than an a2-adrenoceptor agonist [5,
14]. This relative selectivity for I1-imidazoline receptors gives rilmenidine the advantage of decreasing
arterial blood pressure, with fewer unwanted side effects than seen with an a2-adrenoceptor agonist [15].
In Koss studies [35], experiments were undertaken
which determined that pupillary dilation is induced by
inhibition of parasympathetic tone to the iris sphincter
and that this CNS parasympatho-inhibition is mediated by a2-adrenoceptors, rather than imidazoline
receptors. In these studies, it was shown that rilmenidine produced long lasting, dose-dependent mydriasis, which is more likely caused by CNS parasympatho-inhibition. The experimental results showed
that parasympathetic innervation, excluding sympathetic innervation to the pupil, prevents the pupillary
dilation actions of rilmenidine. In independent studies, it has been shown that RS-79948 antagonizes the
rilmenidine-induced mydriatic action [27, 41], while
highly selective I1-imidazoline agonists had no
physiological effect when administered [44].
Studies undertaken by Koss [35] may suggest that
rilmenidine produce mydriasis as an a2-adrenoceptors
agonist, without acting on I1-imidazoline receptors.
The latter receptors are not involved in the rat clonidine mydriasis model, and support this in vivo system as a useful model for studies of a2-adrenoceptors.
In 1997, Ernsberger et al. [13] showed that antihypertensive drugs: rilmenidine and moxonidine have
a high affinity towards imidazoline I1-receptors. This
highly selective affinity to I1-imidazoline receptors
was used to explain a decrease in side effects caused
by rilmenidine and moxonidine (sedation, dry mouth)
[10, 13].
In 2005, Yu and Koss [65] confirmed that the clonidine mydriasis model is mediated by a2-adrenoceptors, and I1-imidazoline receptors are not engaged in
this effect.
Role of a1-adrenoceptors
In the in vitro studies with the use of radioligand techniques the presence of a1-adrenoceptors has been
proved in the rabbit iris-ciliary body [42] and in the
rabbit iris dilator muscle [32]. Experiments in cats
showed that a1-adrenoceptor agonists contracted the
smooth dilator muscle causing mydriasis, but a1-adrenoceptor antagonists had the opposite effect [52]. According to the results of other experiments [10, 24,
66], the a1-adrenoceptors are classified into three subtypes called: a1A, a1B and a1D. These subtypes do not
react similarly to different agonists and antagonists.
The existence of the atypical subtype of a1-adrenoceptor, a1L, is also postulated. The experiments were
performed to characterize the a-adrenoceptor subtype, which is responsible for mediating sympathetically elicited mydriasis in rats. In these studies, the
preganglionic cervical sympathetic nerve was stimulated in pentobarbital anesthetized rats. Evoked
responses were inhibited by the systemic administration of the nonselective a-adrenergic antagonists,
phentolamine (0.3–10 mg/kg) and phenoxybenzamine
(0.03–1 mg/kg). The selective a1-adrenergic antagonist, prazosin (0.01–1 mg/kg), was also effective, but
the a2-adrenergic antagonist, rauwolscine, had no effect. The conclusion was drawn that sympathetically
evoked mydriasis in rats is mediated by typical a1Aadrenoceptors [64]. The adrenergic mechanism of the
iris dilator muscle appears to agree with the adrenergic
regulation of the vascular smooth muscle. Although
many a1-adrenoceptors have been found in peripheral
arteries, more often than not, a single a1-adrenoceptor
subtype (a1A and a1D) is responsible for mediating the
contraction of each blood vessel type [49].
Suzuki et al. [56] examined adrenoceptor subtypes
in the rabbit eye and mainly found the a1A-adrenoceptor subtype in the iris. These findings prove that the
a1A-adrenoceptor is probably the exclusive subtype
that mediates the mydriasis.
Conclusions
The clonidine mydriasis model in rats can play a pharmacologically important role as a simple in vivo system to test the a2-adrenergic activity of drugs.
Clonidine-like imidazol(in)e agents produce diverse
Pharmacological Reports, 2013, 65, 305–312
309
autonomic nervous system effects including (apart
from mydriasis) hypotension, bradycardia, sedation,
anesthesia and hypothermia. The main disadvantage
of these drugs appeared to be many adverse reactions.
On the other hand, the imidazoline receptor agonists
showed more optimal pharmacological effects due to
the relative better selectivity for I1-receptors. These
features have been used to explain the decrease in side
effects caused by rilmenidine or moxonidine, such as
sedation and dry mouth. However, there are still many
controversies concerning the engagement of imidazoline I1-receptors versus a2-adrenoceptors in the
central regulation of blood pressure. In order to better
elucidate the mechanism of hypotensive activity and
to select of the most active potential drugs of an imidazol(in) structure it is necessary to perform a test for
highly selective ligands of the imidazoline I1-receptors. Considering this, it is important to note that the
mydriatic activity of a group of imidazol(in)es can be
closely correlated to both the hypotensive and bradycardic responses in rats. In view of this, the negative
result of the clonidine-induced mydriasis model might
suggest the potential role of imidazoline receptors in
the mediation of mydriasis.
Pharmacologically, this simple system in rats can
be routinely used as an in vivo model to test the potential a2-adrenergic activity of imidazol(in)e drugs.
Also, this model appears to be superior to other in
vivo testing systems, such as clonidine-induced sleep
in chickens and clonidine-induced reduction of motor
activity in rats or mice.
The latest report of Yu and Koss [65], based on
a multi-dose quantitative approach, stated that imidazoline I1-receptors are not involved in the central regulation of pupillary size. Therefore, this functional model
remains to be a useful system which could be widely applied in preclinical research for the in vivo assessment of
a2-adrenergic drugs. The advantage of this model is also
the fact that the whole experiment is performed in vivo
and the whole animal is involved. In comparison to the
variety of other methods, this particular model of assessing the a2-adrenergic properties of imidazol(in)e ligands
seems to be simple, easy, reliable and reproducible.
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Received: June 6, 2012; accepted: October 24, 2012.