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Abstract

Even though the underlying mechanisms for the pathophysiology of migraine attacks are not completely understood, little doubt exists that the headache phase is explained by dilatation of cranial, extracerebral blood vessels. In this context, experimental models predictive for anti-migraine activity have shown that both triptans and ergot alkaloids, which abort migraine headache, produce vasoconstriction within the carotid circulation of different species. In contrast to the well-established role of serotonin (5-hydroxytryptamine; 5-HT) 5-HT_1B receptors in the common carotid vascular bed, the role of α-adrenoceptors and their subtypes has been examined only relatively recently. Using experimental animal models and α₁- and α₂-adrenoceptor agonists (phenylephrine and BHT933, respectively) and antagonists (prazosin and rauwolscine, respectively), it was shown that activation of either receptor produces a cranioselective vasoconstriction. Subsequently, investigations employing relatively selective antagonists at α₁- (α_1A, α_1B, α_1D) and α₂- (α_2A, α_2B, α_2C) adrenoceptor subtypes revealed that specific receptors mediate the carotid haemodynamic responses in these animals. From these observations, together with the potential limited role of α_1B-and α_2C-adrenoceptors in the regulation of systemic haemodynamic responses, it is suggested that selective agonists at these receptors may provide a promising novel avenue for the development of acute anti-migraine drugs.

Keywords

α-Adrenoceptors α-adrenoceptor subtypes carotid vascular bed experimental models migraine

Introduction

The pathophysiology of migraine has been a matter of great interest to many researchers over the last decades. Whereas limited information is available concerning the initiation of a migraine attack, subsequent events can be explained by a neurovascular hypothesis, where the headache phase is thought to be mediated by a dilatation of large cranial arteries and arteriovenous anastomoses (1–5). In line with this proposal, several experimental animal models have been developed that may explain the efficacy of acutely acting anti-migraine drugs, as reviewed by De Vries et al. (5). The predictive anti-migraine value of these models is based on (i) the involvement of the trigeminovascular system, i.e. inhibition of plasma protein extravasation (6, 7) or central trigeminal inhibition (2, 8); (ii) constriction of cranial extracerebral blood vessels (4, 5, 9, 10); or (iii) a combination of the two factors. The present review will describe the current pharmacological aspects of vascular α-adrenoceptors and their possible involvement as a potential novel avenue for acute anti-migraine drug development.

Cranial vasoconstriction as a predictor for anti-migraine activity

Based on the pioneering work of Wolff (11) and Heyck (12), there is little doubt that migraine headache is causally associated with cranial extracerebral vasodilatation, involving large arteries and, perhaps, arteriovenous anastomoses as well. Arteriovenous anastomoses (Fig. 1) are large precapillary communications between arteries and veins and they are present in many structures, including the cheeks, lips, forehead skin, nose, ears, nasal mucosa and in the pain-sensitive dura mater, but not in the brain itself (4). In conscious pigs, it has been shown that carotid arteriovenous anastomoses are under a sympathetic constrictor tone (13, 14), normally only shunting a small fraction (<3%) of carotid blood flow (15). A decrease in sympathetic neural discharge, with consequent opening of carotid arteriovenous anastomoses leading to shunting of a large amount of arterial blood directly into the venous circulation, may explain the facial pallor, lowering of facial temperature and increased vascular pulsations observed during the headache phase of migraine (12). Interestingly, Wolff and co-workers (11) reported that the temporal artery pulsations increase during the headache phase in migraineurs and that these pulsations are normalized after treatment with the anti-migraine agent ergotamine.

Figure 1

Schematic representation of an arteriovenous anastomosis (AVA) (4).

Although, admittedly, the subsequent events leading to headache (and associated symptoms) are not completely understood, the increased vascular pulsation may activate stretch receptors (4). This would, in turn, increase the activity of neuropeptide-containing (mainly calcitonin gene-related peptide (CGRP)) perivascular sensory nerves, which may ultimately cause pain and other associated symptoms (2, 4, 5, 8, 10).

In line with the finding that carotid arteriovenous anastomoses dilate and play a role in the pathogenesis of migraine, it is reasonable to believe that compounds which produce a cranioselective vasoconstriction may have potential therapeutic use in the treatment of migraine. For this reason, we developed animal models, using anaesthetized dogs and pigs, in which systemic and carotid haemodynamic responses of current and novel acutely acting anti-migraine agents have been investigated (for further discussion see Refs 5, 16, 17). It is well established that the acutely acting anti-migraine drugs, ergot alkaloids (ergotamine and dihydroergotamine) and triptans (sumatriptan and second-generation triptans), produce potent vasoconstriction in the canine and porcine carotid vasculature (16, 18–20). Furthermore, based on pharmacological, molecular and immunocytochemical investigations (9, 21, 22), it has been clearly demonstrated that mainly 5-HT_1B receptors mediate sumatriptan-induced cranial vasoconstriction, involving carotid arteriovenous anastomoses and temporal and middle meningeal arteries. On the other hand, 5-HT_1D and/or 5-ht_1F receptors, for which sumatriptan displays appreciable affinity, may mediate the presynaptic inhibition of the trigeminovascular inflammatory response (22). In fact, selective 5-HT_1D (e.g. PNU109291, PNU142633, L-775,606) and 5-ht_1F (LY344864 and LY334370) receptor agonists elicit the latter effect, but are devoid of vasoconstrictor properties in human and bovine isolated blood vessels (22). Unfortunately, PNU142633 proved ineffective in the treatment of migraine (23), and LY334370, although found efficacious in migraine (24), had been used in doses providing plasma concentrations in a range where the involvement of 5-HT_1B receptor cannot be ruled out. Therefore, the introduction of potent and selective 5-HT_1B receptor agonists for the treatment of migraine is awaited with interest.

Although the triptans are clearly established as acutely acting anti-migraine agents, effective anti-migraine agents acting via different mechanisms and/or receptors are also being sought with the hope of further improving migraine therapy. As recently reviewed (25, 26), several possible opportunities exist: CGRP receptor antagonists (e.g. BIBN4096BS), neurokinin NK₁ receptor antagonists (e.g. RPR 100,893 or LY 303,870), spreading depression antagonists (e.g. SB220453), drugs that affect nitric oxide biosynthesis (e.g. 546C88) and, finally, selective agonists at vascular α₁- and/or α₂-adrenoceptor subtypes. This last possibility will be discussed in the present review.

Current pharmacological aspects of α-adrenoceptors

The endogenous catecholamines, noradrenaline (norepinephrine) and adrenaline (epinephrine), which are released upon activation of the sympathetic nervous system, play essential roles in the regulation of a host of physiological responses (27). Cardiovascular function is tightly regulated by the autonomic nervous system, i.e. by the sympathetic and parasympathetic nervous system, where sensory nerves monitor the volume and pressure status of the heart and blood vessels, as well as the metabolic state of cardiac and systemic tissues. This information is processed by the nervous system, and impulses sent via the autonomic nerves modulate cardiac rate and contractility, as well as systemic vascular resistance (27). Several decades ago, adrenoceptors (adrenergic receptors) were introduced to explain the difference in actions of noradrenaline and adrenaline. However, it was the revolutionary work of Ahlquist (28) that convincingly established the coexistence of α- (mediating vasoconstriction) and β- (mediating vasodilatation and myocardial contraction) adrenotropic receptors. After this initial division of adrenoceptors, it took many decades to demonstrate that these receptors could be further subdivided into several subtypes. The following section will focus on the current pharmacological aspects of α₁- (α_1A, α_1B and α_1D) and α₂- (α_2A, α_2B and α_2C) adrenoceptor subtypes, whereas those of β-adrenoceptors have been described extensively elsewhere (29–34). However, as reviewed by Hoyer and colleagues (35, 36), it is important to note that the nomenclature for the classification of transmitter receptors is based on three criteria: structural (gene structure or amino acid sequence), operational (ligand-binding or functional responses) and transductional information (receptor–effector coupling). Thus, none of these criteria has priority and as much information as feasible on these three aspects should be collected before a receptor can be classified and named.

α₁-Adrenoceptors

The general characteristics of α₁-adrenoceptors are shown in Table 1. It is well known that α₁-adrenoceptors are G-protein coupled receptors and mediate their responses via a G_q/11 mechanism, which involves activation of phospholipase C-dependent hydrolysis of phosphatidylinositol 4,5-diphosphate (37–40). Activation of phospholipase C results in the generation of inositol (1,4,5)-triphosphate (IP₃), which acts on the IP₃ receptor in the endoplasmic reticulum to release stored Ca²⁺ and diacylglycerol that (together with Ca²⁺) can activate protein kinase C. Production of these second messengers activates both voltage-dependent and independent Ca²⁺-channels, leading to smooth muscle contraction in both vascular and non-vascular tissues (e.g. prostate, vas deferens, heart) (37).

Table 1

Summary of α₁-adrenoceptor subtype characteristics (modified from Docherty (37), Bylund (84) and Alexander and Peters (33))

	α_1A	α_1B	α_1D
Previous names	α_1a, α_1c	α_1B	α_1A, α_1a/δ
Functional response(s)	Rat vas deferens contraction, rat renal artery contraction, rat caudal artery contraction, rat isolated perfused kidney vasoconstriction, control of blood pressure	Rat spleen contraction, role in rat tail contraction, control of blood pressure?	Rat aorta contraction, control of blood pressure (hypertension)?
Ligand binding assay	Rabbit liver, rat submandibular gland and kidney, human heart and liver	Rat liver, heart and spleen, transfected CHO and HEK 239 cells	Rat aorta, lung and cerebral cortex; transfected CHO and HEK 239 cells
Non-selective agonists	Phenylephrine, cirazoline, methoxamine	Phenylephrine, cirazoline, methoxamine	Phenylephrine, cirazoline, methoxamine
Selective agonists	A61603, oxymetazoline	None	None
Non-selective antagonists	Prazosin	Prazosin	Prazosin
Selective antagonists	e.g. 5-methylurapidil, RS 17053	L-765,314	BMY7378
Potency order	Noradrenaline ≥ adrenaline	Noradrenaline = adrenaline	adrenaline
Receptor distribution	Brain, prostate, vas deferens, heart, blood vessels	Spleen, kidney, brain, heart, blood vessels	Brain, rat aorta, blood vessels
Tissue function(s)	Smooth muscle and myocardial contraction	Smooth muscle contraction	Smooth muscle contraction
Sensitivity to CEC	+/−	+++	++
Second messenger system(s)	Activation of G_q/11, increased PI turnover with elevation of [Ca²⁺]_i, activation of voltage- gated Ca²⁺ channels
Notes	A61603 also displays high affinity at α₂-adrenoceptor subtypes; there are four known isoforms	CEC also affects other receptors	Rat aorta appears to contain other α₁- adrenoceptor subtypes

CEC, Chloroethylclonidine; PI, phosphoinositol; CHO, Chinese hamster ovary; HEK 293, human embryonic kidney cells.

Investigations employing functional, radioligand binding and molecular methods in different species have demonstrated the existence of multiple α₁-adrenoceptor subtypes (α_1A, α_1B and α_1D) throughout the vascular system; this finding substantiates the relevance of α₁-adrenoceptors in blood flow regulation and the maintenance of vascular resistance (37, 41). However, whereas all three α₁-adrenoceptor subtypes are expressed in the heart, the α_1A subtype is the dominant subtype (31, 42). Moreover, around 90% of the total α₁-adrenoceptor mRNA, expressed at very high levels in peripheral arteries, is for the α_1A-adrenoceptor (43). Several lines of evidence, obtained from both in vitro and in vivo studies, show that the α_1A is the main subtype responsible for the sympathetic regulation of vascular tone and blood pressure (37, 41, 44). The human vas deferens and other smooth muscles express both α_1A- and α_1D-adrenoceptors (39). Some α_1B-adrenoceptor message and protein can also be found in vascular smooth muscle (45); however, limited information is available on the exact role of α_1B-adrenoceptors in human peripheral blood vessels (45). Recent findings obtained from experiments using knockout mice (lacking the α_1B-adrenoceptor subtype) demonstrated that the α_1B-adrenoceptors might be involved in the vasopressor and aortic contractile responses induced by α₁-adrenoceptor agonists (46). Whether or not this is a species-dependent phenomenon requires further investigation.

α₂-Adrenoceptors

The general characteristics of α₂-adrenoceptors are shown in Table 2. Since the 1970s it has been known that α₂-adrenoceptors are located both pre- and post-synaptically. Combining ligand binding and molecular cloning studies, four distinct subtypes of α₂-adrenoceptors have been identified, namely the α_2A-, α_2B-, α_2C- and α_2D-adrenoceptor subtypes (31, 47). Nevertheless, the α_2D-adrenoceptor subtype (found in the rat, mouse and cow) is believed to be a species homologue of the α_2A-adrenoceptor subtype found in human, dog, rabbit and pig. α₂-Adrenoceptors are part of the large family of G-protein coupled receptors and mediate their functions through a variety of G-proteins, including G_i/o (48). Both pre- and post-synaptic α₂-adrenoceptors are negatively coupled to adenylyl cyclase, decreasing cyclic AMP production in target cells (37). Nevertheless, depending on the species and vascular bed under study, alternative mechanisms may be involved; for example, the α₂-adrenoceptor-mediated vasoconstriction of the porcine palmar lateral vein is dependent on an influx of extracellular calcium (49). In certain cell lines, ectopic expression of α₂-adrenoceptors has revealed a pertussis toxin-insensitive increase in adenylyl cyclase via coupling to G_s (50).

Table 2

Summary of α₂-adrenoceptor subtype characteristics (modified from Docherty (37), Bylund (84) and Alexander and Peters (33))

	α_2A/α_2D	α_2B	α_2C
Previous name(s)	α₂-C10, RG20	α₂-C2, RNG	α₂-C4
Functional response(s)	Prejunctional inhibition in most adrenergic nerves, central hypotensive action in several species	Pressor responses in mutated mouse, pressor responses in pithed rat	Contraction of human saphenous vein, inhibition of neurotransmitter release, inhibition of adenylyl cyclase in cell lines
Ligand binding assay	Human platelet (α_2A), rat submandibular gland (α_2D)	Neonatal rat lung, rat kidney	Different cell lines
Non-selective agonists	Clonidine, BHT933, UK 14304, BHT920	Clonidine, BHT933, BHT920	Clonidine, BHT933, BHT920
Selective agonists	Oxymetazoline (partial agonist), moxonidine?	None	None
Non-selective antagonists	Rauwolscine	Rauwolscine	Rauwolscine
Selective antagonists	BRL44408, BRL48962	ARC239, imiloxan	MK912
Potency order	noradrenaline	noradrenaline	noradrenaline
Receptor distribution	Platelet, brain, spinal cord, adipocyte cells, aorta, kidney, brain, spleen (human and rat)	Liver, spleen, heart (human), kidney, neonatal rat lung (rat), thalamus, olfactory tubercle, septum, cerebellum (rat)	Brain human and (rat), heart, lung, aorta, kidney, brain (human)
Tissue function(s)	Hypotension, sedation, analgesia, anaesthesia	Vasoconstriction	Not established
Second messenger system(s)	Activation of G_i/o, inhibition of adenylyl cyclase, decrease in cAMP levels, inhibition of voltage-gated Ca²⁺ channels, activation of Ca²⁺-dependent K⁺ channels (except for α_2B- adrenoceptors)
Notes	α_2A- (human, dog, pig and rabbit) and α_2D-adrenoceptors (rat, mouse and cow) are species homologues	ARC239 also displays moderate affinity for α_2C- adrenoceptors, prazosin displays moderate affinity

cAMP, Cyclic adenosine monophosphate.

As reviewed by Docherty (37) and Hieble (34), prejunctional α₂-adrenoceptors (probably the α_2A- and/or α_2C-subtypes, depending on species) are located on most adrenergic nerves and primarily mediate prejunctional inhibition. Since both presynaptic α_2A- and α_2C-adrenoceptors are targets for the neural release of noradrenaline, at least when the noradrenaline transporter is inhibited, it would be interesting to elucidate their individual pharmacological profiles (e.g. binding properties to known compounds), signal transduction pathways, second messengers and their potential differences in function (51). A valuable tool in dissecting the role of these receptors in the regulation of a variety of physiological responses, e.g. blood pressure (52), is the use of genetically engineered mice deficient in each of the α₂-adrenoceptor subtypes (53–55). The use of these knock-out mice confirmed the earlier findings that the α_2A-adrenoceptor (34, 37), which appears to be the major subtype in brain areas involved in cardiovascular regulation (56), plays a critical role in regulating sympathetic outflow (55). On the other hand, post-junctional α₂-adrenoceptors are located on the vascular smooth muscle and activation results in vasoconstriction (52), but the individual contribution of the three known α₂-adrenoceptors subtypes is poorly understood. However, the central distribution of α_2B-adrenoceptors is restricted to certain areas, such as the thalamus and the nucleus tractus solitarius (56), and it is abundant in arterial vascular smooth muscle, producing peripheral vasoconstriction (57–59). In agreement with the latter, recent findings demonstrated that α_2B-adrenoceptor-deficient anephric mice are unable to raise their blood pressure in response to an acute hypertonic saline stimulus (52, 55). These data are in agreement with studies using pithed rat preparations, where the α_2B is the main subtype mediating hypertension (34, 60–62). In contrast, Duka et al. (63) recently reported that vasoconstriction mediated by direct activation of vascular α₂-adrenoceptors in mice is attributable to the post-synaptic α_2A-adrenoceptor subtype, which is consistent with the finding that mRNA for the α_2A-adrenoceptor, but not α_2B-adrenoceptor, was detected in the arterial wall of rabbits (64). In fact, the pressor response attributed to α_2B-adrenoceptor stimulation (57–59) could in fact be due to central, rather than peripheral, α_2B-adrenoceptors (63). Interestingly, the human isolated saphenous vein is a preparation in which the postsynaptic α_2C-adrenoceptor predominantly mediates contraction, whereas the involvement of α₁-adrenoceptors is limited (65). It may be noted that so far only limited information exists on haemodynamic responses mediated by α_2C-adrenoceptors (34, 37, 55, 58).

α₁- and α₂-adrenoceptor mediating vasoconstriction in the carotid circulation

Several in vitro studies have shown that stimulation of α-adrenoceptors produces contraction of isolated carotid artery rings, including those of the dog (66), rabbit (67, 68) and pig (69). Nevertheless, few studies have addressed the question whether these receptors are operative in the carotid circulation in vivo. Verdouw et al. (70) reported that intracarotid bolus injection of noradrenaline elicited short-lasting and phentolamine-sensitive decreases in total as well as arteriovenous anastomotic conductances in pigs; in marked contrast, intracarotid infusion of noradrenaline was devoid of constriction in this vascular bed. Notwithstanding, the detailed mechanisms involved in this response to noradrenaline were not further analysed. However, in anaesthetized dogs it has been shown that the external carotid vasoconstrictor responses are mediated by (i) α₁-adrenoceptors in response to intracarotid infusions of the anxiolytic agents, buspirone and ipsapirone (71), and (ii) α₂-adrenoceptors in response to intracarotid infusions of ergotamine and dihydroergotamine (72). Since these experimental models have been shown to be of predictive value in the development of anti-migraine drugs (5, 10, 16, 19), we decided to elucidate the subtypes of α-adrenoceptors (α₁ and/or α₂) mediating vasoconstriction in the porcine (arteriovenous anastomotic) and canine (external) carotid circulation, using intracarotid infusions of selective ligands (73, 74). As shown in Fig. 2, intracarotid infusions of α₁- (phenylephrine) as well as α₂- (BHT933) adrenoceptor agonists produced a marked reduction in external carotid vascular conductance in anaesthetized dogs, and these effects were selectively blocked by their respective antagonists, prazosin and rauwolscine (75). Thus, both α₁- and α₂-adrenoceptors mediate vasoconstriction within the canine carotid bed.

Figure 2

Effect of intravenous (i.v.) administration of saline (0.03 and 0.1 ml/kg), prazosin (Praz; 100 µg/kg) or rauwolscine (Rauw; 100 and 300 µg/kg) on canine external carotid vasoconstrictor responses elicited by consecutive 1-min intracarotid (i.c.) infusions of phenylephrine and BHT933. ∗Significantly different from the corresponding control response (P < 0.05). Data taken from Willems et al. (75).

Using the radioactive microsphere method (4, 76), we demonstrated that the decrease in porcine carotid vascular conductance by both phenylephrine and BHT933 is exclusively produced by constriction of carotid arteriovenous anastomoses (74) (Fig. 3). Consistent with the closure of carotid arteriovenous anastomoses (77), both agonists increased arteriovenous jugular oxygen saturation difference (74). The involvement of α₁-adrenoceptors in the vasoconstriction of carotid arteriovenous anastomoses is strengthened by the finding that prazosin completely blocked the effects of phenylephrine (74). On similar grounds, the fact that rauwolscine completely antagonized BHT933-induced responses (74) establishes that α₂-adrenoceptors also mediate constriction of carotid arteriovenous anastomoses in the pig. This latter conclusion is substantiated by previous results demonstrating that clonidine can constrict porcine carotid arteriovenous anastomoses (70) and that α₂-adrenoceptors partly mediate canine external carotid vasoconstriction by ergotamine and dihydroergotamine (19, 72).

Figure 3

Percent changes in carotid arteriovenous anastomotic (AVA) vascular conductance induced by 10-min intracarotid (i.c.) infusions of phenylephrine or BHT933 in anaesthetized pigs treated intravenously with vehicle (○), prazosin (• 100 µg/kg) or rauwolscine (▪; 300 µg/kg). Statistical significance: ∗P < 0.05 vs. baseline; ∗∗P < 0.05 vs. vehicle group. Data taken from Willems et al. (74).

Involvement of specific subtypes of α₁- and α₂-adrenoceptor

Having established that both α₁- and α₂-adrenoceptors are operative in vivo mediating vasoconstriction in the carotid circulation, we further investigated which subtypes (α_1A, α_1B, α_1D and α_2A, α_2B, α_2C) are involved. For this purpose, the effects were studied of the selective antagonists 5-methylurapidil (α_1A), L-765,314 (α_1B), BMY7378 (α_1D), BRL44408 (α_2A), imiloxan (α_2B) and MK912 (α_2C) on the carotid vasoconstriction induced by phenylephrine and BHT933, respectively. Table 3 shows the affinity constants of these antagonists at the different, recombinant human α₁- and α₂-adrenoceptor subtypes. Although the doses of the various antagonists have been chosen on the basis of the affinity constants, it has to be conceded that the absolute selectivity of the compounds cannot be guaranteed in in vivo experiments.

Table 3

Binding affinity constants (pK_i values) of antagonists at recombinant human α₁- and α₂-adrenoceptor subtypes

Antagonist	α₁ receptors			α₂ receptors
Antagonist	α_1a	α_1b	α_1d	α_2a	α_2b	α_2c
Prazosin	9.8–9.9	9.5–9.6	10.2–10.4	5.3–5.7	6.4–6.5	6.7–7.2
5-Methylurapidil	9.0–9.1	7.4–7.4	7.9–8.0	6.2	6.4	6.9
L-765 314	6.4	8.7	7.5	ND	ND	ND
BMY7378	6.6–6.8	7.0–7.2	9.0–9.4	5.1∗	5.1∗	5.1∗
Rauwolscine	5.1–6.3	5.3–6.3	5.3–6.3	8.9–9.5	8.9–9.4	9.3–9.9
BRL44408	ND	ND	ND	7.6–8.2	6.0–6.2	6.4–6.8
Imiloxan	<4†	<4†	<4†	5.8–6.5	6.9–7.2	6.0–6.8
MK912	ND	ND	ND	8.9–9.1	8.9–9.1	10.2

Data collated by Willems et al. (73).

^∗Value for rat receptor.

^†pA₂ value.

ND, Not determined.

Nevertheless, as shown in Fig. 4, both 5-methylurapidil and BMY7378 markedly attenuated phenylephrine-induced response, while L-765,314 remained ineffective. Moreover, a combination of both antagonists abolished these responses to phenylephrine (73). These data suggest that both α_1A- and α_1D-adrenoceptor subtypes exclusively mediate the vasoconstriction in the canine carotid vascular bed produced by stimulation of α₁-adrenoceptors. In contrast, the α₁-adrenoceptor subtypes that mediate the vasoconstrictor responses to phenylephrine in porcine carotid vasculature resembled α_1A- and α_1B-adrenoceptors, since 5-methylurapidil (partially) and L-765,314 (markedly) attenuated this response (78). This apparent discrepancy in the involvement of α_1B-adrenoceptors may be explained by a species variance in receptor distribution. However, another likely explanation may be a difference in potency of these antagonists at these receptor subtypes in the two species.

Figure 4

The effect of subsequent intravenous administration of 5-methylurapidil (5MU), L-765,314 (L), BMY7378 (BMY), BRL44408 (BRL), imiloxan (IMI) or MK912 (MK) on the external carotid vasoconstrictor responses produced by consecutive 1-min intracarotid (i.c.) infusions of phenylephrine in anaesthetized dogs. The numbers in parentheses represent the respective doses of the antagonists administered intravenously in µg/kg. Statistical significance: ∗P < 0.05 vs. corresponding dose in control curve. Data taken from Willems et al. (75).

Figure 5 shows that the canine carotid vascular responses to BHT933 were markedly attenuated by BRL44408 (α_2A) and MK912 (α_2C), given either alone or in combination, while imiloxan remained ineffective (73). Similarly, the carotid vasoconstrictor responses produced by BHT933 in anaesthetized pigs were markedly attenuated by MK912, while the other antagonists were ineffective (Willems et al., unpublished observations). These results suggest that mainly α_2C-adrenoceptors mediate vasoconstriction in the carotid circulation of both species.

Figure 5

The effect of subsequent intravenous administration of 5-methylurapidil (5MU), L-765,314 (L), BMY7378 (BMY), BRL44408 (BRL), imiloxan (IMI) or MK912 (MK) on the external carotid vasoconstrictor responses produced by consecutive 1-min intracarotid (i.c.) infusions of BHT933 in anaesthetized dogs. The numbers in parentheses represent the respective doses of the antagonists administered intravenously in µg/kg. Statistical significance: ∗P < 0.05 vs. corresponding dose in control curve. Data taken from Willems et al. (73).

Possible clinical implications for acute migraine therapy

To date, all acutely acting specific anti-migraine agents, including the triptans and ergot alkaloids, produce vasoconstriction within the carotid circulation in several species, including the dog (16, 19, 21, 72) and pig (10, 16). In contrast to the well-established role of serotonin 5-HT_1B receptors in the carotid vasoconstrictor effects of the triptans (21), the ergots seem to involve both 5-HT_1B and α₂-adrenoceptors (19, 72). Recently, it has been shown that the adrenergic system does not play a significant role in neurogenic dural vasodilatation produced by electrical stimulation of periarterial nerves in anaesthetized rats, a model predictive for anti-migraine activity (79). However, irrespective of the lack of attenuation of neurogenic vasodilatation, a selective vasoconstriction within the carotid circulation is in its own right an important property of acutely acting anti-migraine drugs (16). Moreover, as reviewed by May and Goadsby (26), current clinical and experimental evidence supports the view that peripheral trigeminal nerve inhibition is insufficient as a sole mechanism to relieve acute migraine.

The presented data show that specific α₁- and α₂-adrenoceptor subtypes mediate vasoconstriction in the carotid circulation of anaesthetized dogs and pigs, implying that selective agonists at these receptors are likely to be effective in aborting migraine attacks. Since selective agonists at these receptors are not yet available, it is not possible to verify this hypothesis. Admittedly, vasoconstriction within the canine or porcine carotid vascular bed by a compound does not automatically imply that such a compound will be efficacious in migraine patients. This will ultimately depend on (i) verification that the human carotid vasculature has a preponderance of a specific subtype of α₁- or α₂-adrenoceptors that are relatively lacking in other parts of the body; (ii) the ability of such agonists to cause selective carotid (and arteriovenous anastomotic) vasoconstriction without producing systemic side-effects; and (iii) the pharmacokinetic properties of the compounds, namely long half-life and good oral bioavailability (16).

Since the α_1A is the main subtype of α₁-adrenoceptors regulating systemic resistance and blood pressure (37, 41), it is rather unlikely that a selective α_1A-adrenoceptor agonist would be useful in the treatment of migraine. In this sense, the α_1B-adrenoceptor is an interesting target for future anti-migraine drugs, especially when considering that this receptor does not seem to be much involved in the constriction of the peripheral blood vessels (41, 45). Indeed, predominantly α_1A-, but not α_1B- (or α_1D-), adrenoceptors mediate the hypertensive effect produced by intravenous administration of phenylephrine in anaesthetized pigs (78). Thus, a selective α_1B-adrenoceptor agonist may have advantages over the currently available acute anti-migraine drugs, which all constrict the human isolated coronary artery (80, 81), which do not seem to respond to α-adrenoceptors (31), particularly the α_1B-adrenoceptors (82). However, this issue will have to be studied in more detail.

Furthermore, to the best of our knowledge our recent investigation (73) seems to be one of the first to show in vivo functional contractile responses mediated by α_2C-adrenoceptors. As mentioned before, the human isolated saphenous vein is a preparation in which predominantly α_2C-adrenoceptors mediate contraction (65). Interestingly, Khasar et al. (83) have shown that the α_2C-adrenoceptor exclusively mediates the anti-nociceptive effect of α₂-adrenoceptor agonists (such as clonidine) in rats. This property, together with the fact that these receptors mainly mediate vasoconstriction in both anaesthetized pigs (Willems et al., unpublished observations) and dogs (73), favours the potential usefulness of selective α_2C-adrenoceptor agonists in migraine therapy. However, our studies have mainly been based on the effects of antagonists. It is therefore crucial to develop potent and selective agonists at the different α₁- and α₂-adrenoceptor subtypes. The latter should be particularly focused on α_1B- and α_2C-adrenoceptors, in order to verify our hypothesis and for their possible clinical implications in acute migraine therapy.

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Possible Role of α-Adrenoceptor Subtypes in Acute Migraine Therapy

Abstract

Keywords

Introduction

Cranial vasoconstriction as a predictor for anti-migraine activity

Current pharmacological aspects of α-adrenoceptors

α1-Adrenoceptors

α2-Adrenoceptors

α1- and α2-adrenoceptor mediating vasoconstriction in the carotid circulation

Involvement of specific subtypes of α1- and α2-adrenoceptor

Possible clinical implications for acute migraine therapy

References

α₁-Adrenoceptors

α₂-Adrenoceptors

α₁- and α₂-adrenoceptor mediating vasoconstriction in the carotid circulation

Involvement of specific subtypes of α₁- and α₂-adrenoceptor