Pharmacological Reports Copyright © 2013 2013, 65, 305312 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 adrenocep- tor 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 – Imidazol(in)e derivatives are mostly known for N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, having cardiovascular potency. They influence blood MAO-A – monoamine oxidase A, RS-79948 – (8aR, pressure and heart rate, act on the smooth muscle of 12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy- blood vessel and on the aggregation of blood platelets 12-(ethylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridine hydro- chloride, RX 781094 – 2-(1,4-benzodioxan-2-yl)-2imidazoline [29]. They might also play an important role in cell hydrochloride, UK-14,304 – 5-bromo-6-(2-imidazolin-2-yl- proliferation, the regulation of body fat, neuroprotec- amino)quinoxaline tion, inflammation, and some psychiatric disorders such as depression [19]. This is all possible because those agents can also activate (apart from a-adrenoce- ptors) imidazoline receptors, which belong to two Introduction main classes [12]. The I1-imidazoline receptor medi- ates sympatho-inhibitory actions to lower blood pres- It has been discovered that agents of the imidazol(in)e sure [7] and the I2-imidazoline receptor shows the im- structure may interact with different classes of a dis- portant allosteric binding activity towards the tinct receptors such as a1, a2-adrenergic, I1,I2-imid- monoamine oxidase A (MAO-A) [48]. Imidazoline azoline as well as with other (e.g.,H1,H2-histamine) receptors represent important targets for cardiovascu- receptors [9, 18, 45]. lar research. So far, a range of new imidazol(in)e ago-
Pharmacological Reports, 2013, 65, 305312 305 nists and antagonists has been identified showing the Engagement of a-adrenergic/imidazoline selectivity towards I1- and I2-imidazoline receptors. receptors in the mechanism of mydriasis Some of those agents show also capability to mediate pharmacological effects via a-adrenergic mechanism. Earlier studies suggested that I1-imidazoline receptors a Role of 2- and imidazoline receptors might be engaged in the effect of lowering central blood pressure evoked by clonidine-like drugs [58]. It was suggested by Warwick in 1954 [62], and con- Another difficulty in studying the physiological role firmed by Silito and Zbro¿yna [55] in 1970 that the of imidazoline-binding sites is that the ligands pos- tonic parasympathetic preganglionic cell bodies that sessing the high affinity for these sites still have some innervate the iris are located in the Edinger-Westphal affinity for a2-adrenoceptors [9]. The basic problem nucleus and antero-median nuclei of the oculomotor occurs then to recognize and confirm the specific complex [55, 62]. Axons emerge in the third cranial pharmacological action mediated via a particular class nerve and synapse in the ciliary ganglion. The main of receptor. The affinity of some ligands towards a tone to the pupil is mediated by the parasympathetic specific receptor has been tested by different methods, system which is modulated by many different inhibi- e.g., radioligand binding technique. The reliability of tory or excitatory central inputs. The predominance of those in vitro methods is limited because they give no parasympathetic tone is particularly true in the cat. possibility to differentiate between ago- and antago- The result of treatment with guanethidine or acute sympathectomy is a minimal miosis of about 0.5 mm nist properties of the ligands tested. Also, a major ob- [4]. Additionally, it was demonstrated by many inves- stacle still is the lack of highly selective ligands for tigators that reflex pupillary dilation, also due to light imidazoline receptor subtypes. Recently, many stud- withdrawal, is mediated only by the inhibition of ies were undertaken to pharmacologically determine parasympathetic tone in examined species [38, 59, if imidazoline I1-receptors can be involved in the 62]. a2-adrenoceptor activity of the ligands of imida- The first to study the light-reflex pathway, the main zol(in)e structure [43]. excitatory influence to the tonic pupilloconstrictor It has been proved that imidazol(in)e derivatives system, were Magoun and Ranson [39, 40]. They de- classified as a2-adrenoceptor agonists (so-called fined the excitatory pathway through the pretectum, “clonidine-like agents”) cause mydriasis in rats but the Edinger-Westphal nucleus, and the ciliary gan- also in other laboratory animals (mice, cats). Pupillary glion. In later investigations light and electrical stimu- dilation produced by clonidine and related drugs is lation of various loci along this reflex arc was used mediated via the stimulation of the postsynaptic a2- and ciliary nerve potentials were recorded. These adrenoceptor within the Edinger-Westphal nucleus in studies have contributed much to our understanding the brain [35]. As was shown by Nasal et al. [46], the of the neurophysiologic substrates of this autonomic mydriatic activity of imidazol(in)es could be closely system [26, 54]. correlated with their hypotensive and bradycardic ef- There are several techniques, from the physiologi- fects in rats after systemic administration. In many cal point of view, that have been utilized to evoke my- comparative studies it appeared that the rat clonidine driasis by inhibition of the central nervous system (CNS) parasympathetic tone to the iris. One of them mydriasis model can be the most sensitive, reliable was demonstrated in the studies in cats, where test in assessing in vivo a2-adrenoceptor activity. mydriasis evoked by electrical stimulation of the af- However, the question arises if clonidine-induced my- ferent sciatic nerve is almost exclusively due to CNS driasis could be partly mediated by imidazoline I1- parasympathetic inhibition. Reflex mydriasis is not receptors. This information may be crucial for the se- changed by sectioning the cervical sympathetic lectivity of the rat mydriasis model. Since Yu and nerves, but it is stopped following an excision of the Koss [65] proved that imidazoline receptors are not ciliary ganglion or sectioning the oculomotor nerve functionally involved in rat clonidine mydriasis, that [25, 59, 63]. Although not as exclusively mediated by in vivo experimental model could be widely applied in parasympathetic inhibition, electrical stimulation of preclinical research to characterize a2-adrenoceptor loci in the cerebral cortex, posterior hypothalamus, activity of drugs. and lower brainstem also produce mydriasis. This is
306 Pharmacological Reports, 2013, 65, 305312 Imidazol(in)es cause mydriasis in rats via a2-adrenoceptors Joanna Raczak-Gutknecht et al.
mediated in part, by the withdrawal of tonic parasym- driasis in cat, as a reaction to clonidine administra- pathetic tone to the iris [47, 53, 63]. tion, was a consequence of the reduction of parasym- The size of the pupil depends on two types of mus- pathetic tone in the constrictor pupillae of the iris cle: the first of these is pupil sphincter muscle, con- sphincter. sisting of circularly arranged muscle fibers, the sec- A few years later, Koss [34] presented strong evi- ond is the iris dilator, consisting of radially arranged dence that clonidine-evoked mydriasis is triggered by muscle fibers. Iris sphincter muscle is innervated by postsynaptic a2-adrenergic stimulation of the sciatic the parasympathetic nervous system, the iris dilator is nerve, which produced reflex mydriasis, by the reduc- controlled by the sympathetic nervous system. Sym- tion of parasympathetic neural tone to the iris. It was pathetic stimulation of the adrenergic receptors causes also shown that some antihypertensive drugs decrease the contraction of the radial muscle, which is followed sympathetic tone by stimulating a2-adrenoceptors by dilation of the pupil. Parasympathetic stimulation localized in the CNS. It was noted that the same drugs causes contraction of the circular muscle and, as a re- produce mydriasis in some species: cats, and rats. sult, constriction of the pupil. Yohimbine-sensitive pupillary dilation became a sim- In 1971, it was noted that clonidine produce pupil- ple, effective model for quantitatively accessing CNS lary dilation in some species. Walland and Kobinger a2-adrenoceptor activity [34]. [61], and Kobinger [31] described the mechanism of Virtanen et al. [60] compared five azole drugs in the clonidine-induced mydriasis in rats, to a direct rats, observing their pupillary responses to those sympathomimetic action on the iris. Since then, many drugs. The potency order found in these studies was: imidazol(in)e derivatives have been investigated. medetomidine > clonidine = detomidine > UK 14,304 Studies performed in rats, by intravenous administra- > xylazine. The following experiments confirmed the tion of clonidine, UK-14,304, and guanoxabenz [3, mydriatic action of clonidine, detomidine, medeto- 20, 21] show that a2-adrenoceptor agonists, produce midine, and xylazine, and demonstrated that other dose-related pupillary dilation. From these three ago- imidazolines: lofexidine, moxonidine and tiamen- nists clonidine has the strongest potency. It was found idine, also induced a dose-dependent pupillary dila- that pupillary dilation was produced by analogues of tion. It was also proved that the mydriatic effect de- clonidine that have similar structure [35, 50] and also pends on the hydrophobicity of imidazol(in)es [46]. by imidazol(in)es from the group of a2-adrenoceptor The a2-adrenomimetic activity of moxonidine and tia- agonists. Berridge et al. [3] in their studies demon- menidine was confirmed by Lindner and Kaiser [37] strated that intravenous administration of clonidine, and Armah [1] in experiments on isolated organs and but also UK-14,304, and guanoxabenz (highly selec- on blood pressure. tive a2-adrenoceptor agonists [6, 11]) produce a marked The experiments on the mydriatic reaction induced dose-related mydriasis which is competitively antago- by a2-adrenoceptor agonists were performed on anes- nized by a2-adrenoceptor antagonists: RX 781094, thetized animals [3, 16, 33, 36]. These studies were RS 21361 and yohimbine. These studies showed, that very important in determining the role of central a2- RX 781094 antagonizes mydriasis, evoked by guan- adrenoceptors in producing mydriasis, but there were oxabenz, or atropine. RX 781094 administrated in some considerations of the potential interference small amounts into the lateral cerebral ventricle caused caused by general anesthesia [8]. In other studies, it a rapid dose-related antagonism of the mydriasis pro- was suggested that ligands producing mydriasis were duced by guanoxabenz. This was direct evidence that less efficacious in conscious animals at normal or the mydriatic effect is mediated via a central a2-adr- moderate laboratory illumination [30, 61]. Studies in enoceptor mechanism [3]. Further studies supported concious mice [20], showed that an intraperitoneal in- this suggestion: the selective a1-adrenoceptor antago- jection of clonidine produces a rapid onset of dose- nists: prazosin and corynanthine, were ineffective dependent pupil dilation. This response was dose- against this mydriatic response. Gherezghiher and dependently reversed by yohimbine and idazoxan. Koss [16] in previous studies confirmed these results Prazosin (a1-adrenoceptor antagonist) and pindolol and showed that yohimbine, excluding phenoxyben- (b-adrenoceptor antagonist) did not have an influence zamine (a non-selective a1-adrenoceptor antagonist), on clonidine-induced mydriasis [20]. These findings inhibited clonidine-induced mydriasis in the rat. In confirm specific mediation by a2-adrenoceptors and later studies, Koss and San [36] suggested that my- are in agreement with other results obtained in con-
Pharmacological Reports, 2013, 65, 305312 307 with the use of DSP-4 neurotoxin, that a2-adrenoce- ptors are located postsynaptically. DSP-4 was used to selectively lesion noradrenergic neurons [21]. It de- pleted noradrenaline in the brain (also at Edinger- Westphal nucleus responsible for mydriasis) and also reduced mydriasis induced by the noradrenaline re- leasing agent, metamphetamine. Treatment with DSP-4 did not alter the response to clonidine, which confirms that in conscious rats mydriasis is also medi- ated by postsynaptic a2-adrenoceptors. The conclu- sion of these studies was that metamphetamine acts indirectly on a2-adrenoceptors by increasing nora- drenaline outflow, while clonidine is unaffected be- cause of acting directly on postsynaptic a2-adrenoce- ptors. These studies showed that mydriasis is specifi- cally mediated by postsynaptic a2-adrenoceptors in the CNS and it can be evoked directly using specific agonists, and indirectly with noradrenaline releasing Fig. 1. Scheme of mammalian brain showing the main pathways in- agents. This made a rapid and simple model for evalu- volved in pupil dilation. Solid line – the efferent sympathetic pathway to the radial muscle of the iris; dotted lines – inhibitory influences as- ating postsynaptic a2-adrenoceptor function in rats cending from the periphery via the brainstem reticular systems de- without interference of anesthesia [46]. scending from the cortex and hypothalamus impinging on the Edinger-Westphal complex (the primary mechanism of reflex pupil- Dexamphetamine produces dose-related mydriasis via lary dilation); dashed line – efferent parasympathetic path the sensitive to a2-adrenoceptor agonists in anesthetized third nerve and ciliary ganglia to the iris sphincter; 1– short ciliary nerves; 2 – long ciliary nerves; 3 – fornix; 4 – anterior commissure; 5 – rats, by stimulating the CNS. This activity is antago- gasserian ganglion; 6 – superior cervical ganglion; 7 – corpus callo- nized by idazoxan, and yohimbine. Pretreatment with sum; 8 – massa intermediate; 9 – pons; 10 – posterior commissure; 11 – inferior colliculus; 12 – oculomotor nucleus; modified after refer- the a1-adrenoceptor antagonist – phenoxybenzamine, ences [13] and [17] does not alter the pupillary response. These experi- ments demonstrated that dexamphetamine acts mainly as an indirect sympathomimetic agent to release en- scious [8], and anesthetized [3, 22] animals. In further dogenous stores of a monoaminergic neurotransmitter studies in anesthetized rats it was suggested that my- which is supposedly noradrenaline [23]. Studies per- driasis evoked by clonidine is mediated exclusively formed by Nasal et al. in a group of eight imida- zol(in)es classified as a2-adrenoceptor agonists: clo- by a2-adrenoceptors located in the CNS [22]. The ex- periments in cats and rats proved that these receptors nidine, lofexidine, moxonidine, tiamenidine, xylazine, medetomidine and detomidine, show that these agents are located in the Edinger-Westphal complex, where cause both mydriasis (after intravenous administra- they control parasympathetic tone to the iris [22]. It tion to anesthetized rats) and human blood platelet has been postulated that the a2-adrenoceptors respon- aggregation in vitro. A statistically significant correla- sible for the induction mydriasis in several species are tion was also found between centrally mediated my- not inhibitory prejunctional autoreceptors controlling driatic activity and both the hypotensive and brady- adrenaline, but are part of the postsynaptic to adrener- cardic activity of the compounds studied. Moreover, gic neuron population [22, 33]. In agreement with this the mydriatic activity depended on the lipophilicity of hypothesis, Heal et al. [20, 21] demonstrated that my- those imidazol(in)es, but platelet aggregation did not. driasis can also be evoked in conscious rats by the ad- Similarly, the human platelet antiaggregatory effects ministration of methamphetamine, which by inhibiting observed correlated with neither the mydriatic, nor re-uptake and enhancing release, increases noradrena- cardiovascular activity of the agents. The dependence line outflow [2, 17, 51]. These studies demonstrated of the centrally induced effects of imidazol(in)es on that mydriasis evoked by metamphetamine is also me- lipophilicity and the lack of such a dependence in the diated by a2-adrenoceptors, because it is idazoxan case of such effects in in vitro a2-adrenoceptor medi- and yohimbine sensitive. It was shown in experiments ated platelet aggregation may be interpreted as result-
308 Pharmacological Reports, 2013, 65, 305312 Imidazol(in)es cause mydriasis in rats via a2-adrenoceptors Joanna Raczak-Gutknecht et al.
ing from the heterogeneity of the rat cerebral and hu- a Role of 1-adrenoceptors man blood platelet a2-adrenoceptors [46]. It is well known that clonidine – like other a2-adre- noceptor agonists, can evoke autonomic nervous sys- In the in vitro studies with the use of radioligand tech- tem reactions causing sedation, hypotension, anesthe- niques the presence of a1-adrenoceptors has been sia, hypothermia and mydriasis [28, 57]. proved in the rabbit iris-ciliary body [42] and in the In 2003, Koss [35] undertook studies on rilmen- rabbit iris dilator muscle [32]. Experiments in cats showed that a1-adrenoceptor agonists contracted the idine, an a2/imidazoline-I1 receptor agonist. In previ- smooth dilator muscle causing mydriasis, but a1-adre- ous studies, it was demonstrated that this drug, in con- noceptor antagonists had the opposite effect [52]. Ac- trast to clonidine, is a CNS I1-imidazoline receptor cording to the results of other experiments [10, 24, agonist, rather than an a2-adrenoceptor agonist [5, 66], the a1-adrenoceptors are classified into three sub- 14]. This relative selectivity for I1-imidazoline recep- types called: a1A, a1B and a1D. These subtypes do not tors gives rilmenidine the advantage of decreasing react similarly to different agonists and antagonists. arterial blood pressure, with fewer unwanted side ef- The existence of the atypical subtype of a1-adrenoce- fects than seen with an a2-adrenoceptor agonist [15]. ptor, a1L, is also postulated. The experiments were In Koss studies [35], experiments were undertaken performed to characterize the a-adrenoceptor sub- which determined that pupillary dilation is induced by type, which is responsible for mediating sympatheti- inhibition of parasympathetic tone to the iris sphincter cally elicited mydriasis in rats. In these studies, the and that this CNS parasympatho-inhibition is medi- preganglionic cervical sympathetic nerve was stimu- ated by a2-adrenoceptors, rather than imidazoline lated in pentobarbital anesthetized rats. Evoked receptors. In these studies, it was shown that rilmen- responses were inhibited by the systemic administra- idine produced long lasting, dose-dependent mydria- tion of the nonselective a-adrenergic antagonists, sis, which is more likely caused by CNS parasym- phentolamine (0.3–10 mg/kg) and phenoxybenzamine patho-inhibition. The experimental results showed (0.03–1 mg/kg). The selective a1-adrenergic antago- that parasympathetic innervation, excluding sympa- nist, prazosin (0.01–1 mg/kg), was also effective, but thetic innervation to the pupil, prevents the pupillary the a2-adrenergic antagonist, rauwolscine, had no ef- fect. The conclusion was drawn that sympathetically dilation actions of rilmenidine. In independent stud- evoked mydriasis in rats is mediated by typical a1A- ies, it has been shown that RS-79948 antagonizes the adrenoceptors [64]. The adrenergic mechanism of the rilmenidine-induced mydriatic action [27, 41], while iris dilator muscle appears to agree with the adrenergic highly selective I1-imidazoline agonists had no regulation of the vascular smooth muscle. Although physiological effect when administered [44]. many a1-adrenoceptors have been found in peripheral Studies undertaken by Koss [35] may suggest that arteries, more often than not, a single a1-adrenoceptor rilmenidine produce mydriasis as an a2-adrenoceptors subtype (a1A and a1D) is responsible for mediating the agonist, without acting on I1-imidazoline receptors. contraction of each blood vessel type [49]. The latter receptors are not involved in the rat clo- Suzuki et al. [56] examined adrenoceptor subtypes nidine mydriasis model, and support this in vivo sys- in the rabbit eye and mainly found the a1A-adrenoce- tem as a useful model for studies of a2-adrenoceptors. ptor subtype in the iris. These findings prove that the In 1997, Ernsberger et al. [13] showed that antihyper- a1A-adrenoceptor is probably the exclusive subtype tensive drugs: rilmenidine and moxonidine have that mediates the mydriasis. 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) Conclusions [10, 13]. In 2005, Yu and Koss [65] confirmed that the clo- The clonidine mydriasis model in rats can play a phar- nidine mydriasis model is mediated by a2-adrenoce- macologically important role as a simple in vivo sys- ptors, and I1-imidazoline receptors are not engaged in tem to test the a2-adrenergic activity of drugs. this effect. Clonidine-like imidazol(in)e agents produce diverse
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