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`Monographs in Neural Sciences
`
`Nalional Library of Medicine, Caialoging in Publica1ion
`Neuroreceplors in heallh :md dis.case
`Volume editors, J, Marwaha and W.J. Anderson. - Ba,cl; New York: Karger 1984.
`(Monographs in neural sciences; v. 10)
`'This book rtprcscnlS the proceedings of the symposium held in Tme Haute (Indiana) on September 25, 1982." -
`Acknow!edgcmenlS,
`I, Receptors. Sensory - congresses I. Marwaha, J. (Jwahar) U. Anderson, William J. 111. Series
`WI MOS68 C v. IO [WL 102.9 N 4945 1982]
`ISBN 3-8055-3715- 8
`
`Drug Dosage
`The authors and Lht publisher have excrlcd every effort to ensure that drug sclec!ion and dosage set forlh in this tex t
`are in accord with current rtcommcndat.ions and practice at lhe time or publication. However, in view of ongoing
`research, changes in government regula 1ions, and the cooslant flow of )nformalioo relating lo drug lhcrapy and drug
`reactions, the reader is urged to check the package insert for each drug fo r any change in indicalions and dosage and
`for added warnings and precaulions. This i.s p3 rticularly importanl when the recommended agent is a new and/or
`infrcquen1ly employed dru&,
`
`All righ 15 reserved,
`No parl or th.is publication may be translated in10 other languages, reproduced o r uliliz.cd in any form or by any means,
`eJectron.ic.or mechanical, including photocopying, recording, mic roc:opying, orb)' any informuion s1oragc o.nd retrieval
`system, wi(hout permission in writing rrom the publisher.
`
`ru
`
`Copyrighl 19&4 by S. Kargor AO , P.O. 80,, Cfl-4009 Basel (Switzerland)
`Printed in SwiUcrland by ThO.r AG Off,eldruck, Prattcln
`ISBN J-l!OS5-371S-8
`
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`Monogr. neural Sci., vol. IO, pp. 224-253 (Karger, Basel 1984)
`
`a-Adrenoceptors
`
`Robert R. Rujf olo, Jr.
`
`Department of Cardiovascular Pharmacology (MC-304), Lilly Research Laboratories,
`Eli Lilly and Company, Indianapolis, Ind., USA
`
`Introduction
`
`The area of research encompassing a-adrenoceptors and a-adrenergic
`drugs has undergone a rapid growth during the past several years. This stems
`in part from the discovery that a-adrenoceptors do not represent one
`homogeneous population. The existence of presynaptic a-adrenoceptors
`which function as 'autoreceptors' to inhibit neurotransmitter release when
`synaptic levels of norepinephrine are high represents a recent major develop(cid:173)
`ment. Building upon this foundation, potent and highly selective a-adrener(cid:173)
`gic agonists and antagonists have been synthesized and utilized to investigate
`a-adrenergic mechanisms, and this has led to a more universally acceptable
`pharmacological subclassification of a-adrenoceptors. Many of these newer
`selective drugs have found clinical applications particularly in the area of car(cid:173)
`diovascular disorders.
`The intent of this review is to summarize the current status of a-adreno(cid:173)
`ceptors and a-adrenergic drugs. Since a-adrenoceptors exist throughout the
`body and subserve a variety of functions ~oo numerous to address in one
`chapter, only those a -adrenoceptors involved in regulation of the cardiovas(cid:173)
`cular system will be discussed since the functions of these receptors are par(cid:173)
`ticularly well understood, and treatment of a variety of cardiovascular dis(cid:173)
`orders may be achieved with drugs which act upon these a-adrenoceptors.
`In addition, examples of most of the generalizations that may be made about
`a-adrenoceptors, as well as most of the exceptions to these generalizations,
`exist in the cardiovascular system which therefore serves as an excellent
`example of the current status of a-adrenoceptors.
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`226
`
`Fig. 2. Relative selectivities for a 1- and aradrenoceptors of a series of a -adrenoceptor
`agonists (a) and antagonists (b) [modified from 8, 132, 151).
`
`Pharmacological Subclassification of a-Adrenoceptors
`Since many exceptions exist to the anatomical subclassification ofpost(cid:173)
`synaptic a 1- and presynaptic aradrenoceptors, criteria for a pharmacological
`subclassification have been developed which employ highly selective
`a-adrenergic agonists and anta,gonists as pharmacological tools. Among
`agonists, phenylephrine, methoxamine and cirazoline have been typically
`employed as selective a 1-adrenergic agonists [8, 65, 73] while clonidine,
`a-methylnorepinephrine, UK-14, 304, B-HT 920 and B-HT 933 are known
`as selective aradrenoceptor agonists [151, 153, 154]. The natural neurotrans(cid:173)
`mitter, norepinephrine, is a relatively nonselective agonist while the hormone,
`epinephrine, displays a slight selectivity for aradrenoceptors [8].
`Antagonists have also proven to be extremely useful tools to probe and
`subclassify a-adrenoceptors. Prazosin, which has been introduced clinically
`to treat hypertension, is a potent and highly selective a 1-adrenoceptor antag(cid:173)
`onist. The dissociation constant of prazosin at a 1-adrenoceptors is typically
`between 1 and 10 nM, and the selectivity for a 1-adrenoceptors ( over a 2) is on
`the order of 100- to 1,000-fold [150]. Other potent and selective competitive
`a 1-adrenoceptor antagonists include WB-4101 and corynanthine [73].
`Yohimbine and rauwolscine are commonly used as potent antagonists of ar
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`a-Adrenoccptors
`
`227
`
`Table /. Radiolabeled a-adrenocepto"r agonists and antagonists commonly used in radio(cid:173)
`ligand binding studies to label the a-adrenoceptor subtypes
`
`Radio ligand
`
`o.rSelective
`[ 3H]-Prazosin
`[ 3H]- WB-4101
`[1251]-BE 2254
`
`o.2-Selec1ive
`[ 3H]-Clonidine
`( 3HJ-para-Aminoclonidine
`[3H]-Guaofacine
`[3HJ-Yohi01bine
`[ 3H]-Epinephrine
`[3H]-Norepinephrine
`
`Nonselective
`[ 3H]-Dihydroergocryptine
`[3H]-Phentolamine
`
`Reference
`
`50
`40
`33,36
`
`40
`95
`146
`49
`157
`157
`
`171
`35
`
`adrenoceptors, with selectivities ranging from approximately 30-fold to more
`than 100-fold [73]. Several of the more common a-adrenergic blocking
`agents, such as phentolamine and tolazoline, are relatively nonselective. The
`a 1 / a 2-adrenoceptor selectivities of several adrenergic agonists and antago(cid:173)
`nists are presented in figure 2.
`As expected, several a-adrenoceptor agonists and antagonists have been
`radiolabeled and proven to be useful ligands to characterize and subclassify
`a-adrenoceptors in binding studies [35, 13 I]. Several tritium and iodine
`labeled a-adrenergic agonists and antagonists with high specific activity and
`proven utility as radioligands are listed in table I. It i~ significant to note that
`3H-norepinephrine and 3H-epinephrine, which are both relatively nonselec(cid:173)
`tive a-adrenoceptor agonists, tend to label predominantly aradrenoceptors
`in radioligand binding studies.
`
`Classes of a-Adrenergic Agonists
`
`There are two major classes of a-adrenoceptor agonists: (I) the
`phenethylamines, which include compounds such as norepinephrine, phen-
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`a -Adrenoceptors
`
`229
`
`not be available for interaction with the a-adrenoceptor for the S(+ )-isomer
`and corresponding desoxy derivative because this functional group is incor(cid:173)
`rectly oriented or absent, respectively. This presumably would account for
`the lower activities of the S(+ )-isomer and desoxy derivative relative to the
`R(-)-isomer and also for the fact that the S( + )-isomer and desoxy derivative
`are equal in activity to each other. The phenethylamines demonstrate a strict
`adherence to the Easson-Stedman hypothesis in all cases studied [85, 86].
`However, in marked contrast, optically active imidazolines do not adhere to
`this hypothesis at a 1- or aradrenoceptors [104). Thus, while substitution of
`a hydroxyl group ar the ,B-carbon atom of the phenethylamines increases
`a-adrenergic activity by approximately 100-fold [85, 86), similar hydroxyl
`substitution of an imidazoline produces a decrease in activity ofup to IO-fold
`[99, 101, 103, 104, 112).
`In vasa deferentia completely desensitized to the imidazoline, oxymeta(cid:173)
`zoline, phenethylamines such as norepinephrine, phenylephrine and meth(cid:173)
`oxamine still produce maximal responses, whereas other imidazolines such
`as tetrahydrozoline, xylometazoline and naphazoline either produce no
`response or only a marginal response (106). A similar lack of cross-desensiti(cid:173)
`zation between the phenethylamines and imidazolines has been observed in
`vivo by Kobinger et al. (63) for the hindlimb vasculature of the rat. Finally,
`for the phenethylamines, a single meta or para hydroxyl group on the phenyl
`ring is sufficient to confer full agonist activity at a-adrenoceptors [9, 10, 99).
`However, only those imidazolines with a catechol (i.e. 3,4-dihydroxyphenyl)
`are full agonists [99, 101, 105]. In fact, it has recently been demonstrated that
`aromatic hydroxyl substitutions produce major alterations in intrinsic activity
`or efficacy of the imidazolines, but have no affect on this parameter for the
`phenethylamines [99).
`The differences described above are significant and have led several
`investigators to propose that the imidazolines may interact with the
`a-adrenoceptor in a different manner than the phenethylamines [63, 77, 79,
`96, 99, 101- 106, 112]. These differences in activity may reflect differences in
`the manner in which the phenethylamines and imidazolines bind to and/or
`activate the a-adrenoceptor.
`In addition to the two major classes of a-adrenergic agonists discussed
`above, a relatively novel class of azepine derivatives, such at B-HT 920, have
`recently been developed. Although these compounds are neither phenethyla(cid:173)
`mines nor imidazolines, their pharmacological activity parallels that of the
`imidazolines, and most of the azepines studied to date are highly selective for
`aradrenoceptors [59, 149, 154).
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`a-Adrenoceptors
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`231
`
`cussed in detail since they best illustrate the current status of a -adrenocep(cid:173)
`tors.
`
`Central arAdrenoceptor
`Clonidine is an a-adrenoceptor agonist with antihypertensive activity
`resulting from within in the central nervous system [15, 58, 61, 117, 118, 120,
`161]. The drug is hypothesized to interupt the normal cardiovascular reflex
`loop whose function is to regulate blood pressure and heart rate and maintain
`them within relatively narrow ranges. A highly schematic representation of
`the cardiovascular reflex loop is presented in figure 4. Pressure receptors in
`the carotid sinus and aortic arch _sense changes in peripheral blood pressure
`and initiate the cardiovascular reflex. Afferents from the carotid sinus and
`aortic arch enter the central nervous system through cranial nerves IX (glos(cid:173)
`sopharyngeal) and X (vagus), respectively, and form, in part, the solitary tract
`in the medulla. The first synapse in the cardiovascular reflex loop occurs in
`the nucleus of the solitary tract [ 18], and in this nucleus is believed to be one
`of the primary sites of action of clonidine [22, 42, 69, 70, 93, 94, 119]. Recep(cid:173)
`tors of the arsubtype are postulated to exist postsynaptically on dendrites of
`neurons in the nucleus of the solitary tract. Synapses are made within the
`nucleus of the solitary tract with inhibitory neurons that course to the vaso(cid:173)
`motor center in the reticular formation, and with excitatory neurons which
`send connections to the dorsal motor nucleus of the vagus. When blood pres(cid:173)
`sure is elevated, or when aradrenoceptors in the nucleus of the solitary tract
`are stimulated, several events will occur. Firstly, the inhibitory neurons to the
`vasomotor center are activated and sympathetic outflow, which originates
`from the vasomotor center and innervates the peripheral vasculature, heart,
`and kidney, is reduced. As a result, peripheral vascular tone, heart rate, and
`renin release are decreased producing, in turn, a decrease in total peripheral
`resistance and cardiac output. Secondly, activation of the excitatory neurons
`from the nucleus of the solitary tract which terminate in the dorsal motor
`nucleus of the vagus, causes an enhanced cholinergic outflow to the heart,
`producing a further decrease in heart rate and cardiac output [62]. The result
`of the combined decrease in sympathetic outflow and increase in parasym(cid:173)
`pathetic outflow resulting from central aradrenoceptor stimulation is a
`decrease in blood pressure with a concurrent bradycardia [45, 46].
`While the antihypertensive activity of clonidine results from its phar(cid:173)
`macological selectivity for central a 2-adrenoceptors in the nucleus of the soli(cid:173)
`tary tract, it is also known that the physicochernical properties of clonidine(cid:173)
`like imidazol(id)ines are also critical to the antihypertensive efficacy of such
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`232
`
`compounds [for review see 154]. Highly lipophilic imidazolidines, such as
`clonidine, which readily penetrate the blood-brain barrier and gain access to
`their site(s) of action in the brain stem, are potent antihypertensive agents.
`Conversely, many imidazolidines with similar selectivities as clonidine for
`ai-adrenoceptors, but with low lipophilicity, do not readily penetrate the
`blood-brain barrier and are either weak antihypertensive agents, or com(cid:173)
`pletely devoid of all antihypertensive activity. Such compounds are still effec(cid:173)
`tive in lowering blood pressure when injected beyond the blood-brain barrier
`into specific brain regions such as the nucleus of the solitary tract [21, 22) or
`into the cerebral ventricles [141) or cistema magna (81, 88, 110, 113). Since
`these compounds with low Iipophilicity are still active when the blood-brain
`barrier is bypassed, it has been concluded that one major factor affecting the
`antihypertensive activity of clonidine-like imidazolidines following systemic
`administration is their ability to penetrate the blood-brain barrier and this,
`in turn, is highly dependent upon overall lipophilicity.
`Many properties of a molecule will determine overall lipophilicity
`which, as indicated above, is critical for antihypertensive efficacy of cloni(cid:173)
`dine-like imidazolidines. For these particular compounds, the most impor(cid:173)
`tant determinant of lipophilicity is the extent of ionization occurring at
`physiological pH, and this property is governed by the ionization constant
`or pKa [147, I 52, 153]. Imidazolidines in the ionized species possess low lipo(cid:173)
`philicity and will penetrate the blood-brain barrier slowly, whereas the un(cid:173)
`ionized form is highly lipophilic and will penetrate the barrier rapidly. Thus,
`the ratio of the un-ionized:ionized species is a major determinant of the anti(cid:173)
`hypertensive efficacy and potency of many clonidine-like imidazolidines.
`There exists an excellent correlation between the antihypertensive potencies
`of a series of clonidine-like imidazolidines and their pKa [115] such that those
`compounds with low pKa, and which are therefore significantly un-ionized
`at physiological pH, will penetrate the blood-brain barrier rapidly and be
`potent antihypertensive agents, whereas those imidazolidines with high pKa
`and which are extensively ionized at physiological pH will penetrate the
`blood-brain barrier to a lesser extent (or at a slower rate) and be weaker anti(cid:173)
`hypertensive agents.
`Clonidine is not metabolized to a great extent in man [71] and the limited
`metabolism that does occur does not take place in the brain. As a result, ter(cid:173)
`mination of the central antihypertensive effects of clonidine and clonidine(cid:173)
`like imidazolidines is likely to be by diffusion out of the central nervous sys(cid:173)
`tem. It has recently been demonstrated that the pK. of clonidine-like imi(cid:173)
`dazolidines, and therefore their ratios of un-ionized:ionized species, also
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`Ruffolo
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`234
`
`The antihypertensive activity of a-methyldopa has a similar mechanism
`of action as clonidine [ 162], although physicochemical properties of the mole(cid:173)
`cule play a lesser role. o:-Methyldopa is actively transported into the brain
`by an aromatic amino acid transport mechanism. In the brain, o:-methyldopa
`is sequentially decarboxylated and .8-hydroxylated to form o:-methyl(cid:173)
`norepinephrine which is a potent and selective o:radrenoceptor agonist and
`which interacts with o:radrenoceptors in the nucleus of the solitary tract to
`produce a decrease in blood pressure and heart rate (21, 22]. The effect of
`o:-methylnorepinephrine is not terminated by diffusion out of the central
`nervous system as is the case for clonidine, but rather by enzymatic degrada(cid:173)
`tion by catechol-0-methyltransferase (COMT) and monoamine oxidase
`(MAO).
`
`Peripheral a-Adrenoceptors
`Vasculature. The predominant innervation to the vasculature is adrener(cid:173)
`gic where postganglionic sympathetic nerve terminals liberate norepineph(cid:173)
`rine in response to electrical stimulation. The liberated norepinephrine will
`activate postjunctional a-adrenoceptors which, in turn, mediate vasocon(cid:173)
`striction and a concomitant increase in total peripheral resistance and bood
`pressure. In addition, the liberated neurotransmitter will activate prejunc(cid:173)
`tional o:radrenoceptors which inhibit further norepinephrine release via the
`negative feedback system. The presynaptic autoinhibitory o:radrenoceptor
`at the vascular neuroeffector junction has been studied extensively [ 131, 132]
`and is similar to the o:radrenoceptor found presynaptically in other tissues.
`The nature of the postjunctional o:-adrenoceptor which mediates vaso(cid:173)
`constriction has been the target of many recent investigations. In most non(cid:173)
`vascular tissues, the postjunctional o:-adrenoceptor is of the o: 1 -subtype.
`While postsynaptic o: 1-adrenoceptors in the vasculature were identified early
`on, recent studies in vitro indicate that postsynaptic o:-adrenoceptors in blood
`vessels may not represent one homogeneous population [23, 26, 53, 91, 97,
`108, 109,111,139,140,143, 158].However,themostimportantcontributions
`concerning the nature of the postsynaptic vascular o:-adrenoceptor(s) have
`come from recent studies in vivo. Drew and Whiting [30J identified two types
`of o:-adrenoceptors mediating pressor responses in the cat and rat. One
`type was prazosin-sensitive and classified as a 1, while the second prazosin(cid:173)
`resistant type was not classified at that time. Subsequent investigations
`occuring simultaneously and independently by several groups [24, 25, 29,
`155] indicated that o:1- and aradrenoceptors are both present in the vascu(cid:173)
`lature of the rat and both subtypes are located postjunctionally and mediate
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`236
`
`The physiological role of the vascular postsynaptic junctional o: 1-adreno(cid:173)
`ceptors appears to be in maintaining normal vascular tone. Presumably, these
`receptors which are located in the vicinity of the neurovascular junction
`would interact with endogenous norepinephrine liberated from sympathetic
`nerves. In contrast, the physiological role of the extrajunctional o:i-adreno(cid:173)
`ceptors is not fully understood. It has been argued that the extrajunctional
`o:radrenoceptors would not normally internet with liberated norepinephrine
`since they are located at a distance from the adrenergic nerve terminal [66].
`Langer and Shepperson [66] indicate that the highly efficient neuronal uptake
`pump (fig. 6) keeps synaptic levels of norepinephrine sufficiently low and
`thereby prevents diffusion of the neurotransmitter to the extrajunctional
`sites. It has been proposed that the extrajunctional o:radrenoceptors may
`respond to circulating epinephrine acting as a blood-borne hormone [66].
`While circulating catecholamines may be below the levels required to exert
`a physiological effect, it has been suggested that in times of stress, these levels
`may be elevated to threshold levels where postsynaptic vascular o:radreno(cid:173)
`ceptors are activated [19, 66). It has also been postulated that the circulating
`levels of catecholamines acting as hormones may not need to be as high as
`expected to elicit effects from extrajunctional vascular o:radrenoceptors
`since these receptors, which are located at a distance from th e sympathetic
`nerve endings, may behave more like 'denervated' receptors and exhibit an
`exaggerated sensitivity to catecholamines [66]. Consistent with this hypoth(cid:173)
`esis is the observation that rat aorta, which is not innervated [84], exhibits an
`exaggerated response to several aradrenoceptor-selective agents, whereas
`aortas from other species which are innervated do not exhibit such an exag(cid:173)
`gerated sensitivity [97, 108, 109, 111).
`It has recently been established that junctional o: 1-adrenoceptors do not
`rely upon extracellular calcium to produce a vasoconstrictor response,
`whereas the extrajunctional o:2-adrenoceptors are highly dependent upon
`extracellular calcium to produce vasoconstriction (fig.6) [151, 159, 160). As
`a result, o: 1-adrenoceptor-mediated vasoconstriction is not altered by the new
`class of compounds, the calcium entry blockers (or calcium slow channel(cid:173)
`blocking agents), whereas vasoconstriction mediated by extrajunctional a 2-
`adrenoceptors is highly sensitive to blockade by the calcium entry block(cid:173)
`ers [159, 160). It has been postulated that the efficacy of the calcium entry
`blockers in hypertension, angina, and certain vasospastic disorders, such
`as Raynaud's syndrome, may result from the ability of these agents to in(cid:173)
`hibit the vasoconstrictor response mediated by extrajunctional o:2-adreno(cid:173)
`ceptors.
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`a-Adrenoceptors
`
`237
`
`Heart. The cardiac adrenergic neuroeffector junction is in many respects
`similar to neuroeffector junctions in other tissues as far as a-adrenoceptors
`are concerned. Presynaptic a 2-adrenoceptors on postganglionic sympathetic
`nerve terminals have been identified in isolated hearts from many species.
`As in other organs, the presynaptic ai-adrenoceptors, when activated, medi(cid:173)
`ate an inhibitory effect on neurotransmitter release [27, 44]. In vivo studies
`in pithed rats also indicate the existence of presynaptic aradrenoceptors
`which modulate stimulation-evoked norepinephrine release [28, 66]. As such,
`a-adrenoceptor antagonists may produce positive inotropic and chrono(cid:173)
`tropic responses [5; 6] by enhancing neurotransmitter liberation [ 134, 135]
`which results from loss of the autoinhibition mediated by presynaptic ar
`adrenoceptors. In electrically driven hearts, in vivo and in vitro, selective a 2-
`adrenoceptor agonists, such as clonidine, decrease heart rate in conjunction
`with inhibition of transmitter release (1 28, 129].
`The predominant adrenergic receptor located postsynaptically in the
`heart is the /3 1-adrenoceptor which mediates a large positive inotropic and
`chronotropic response [3, 11 ]. However, the existence of postsynaptic
`a-adrenoceptors was suggested many years ago [37-39, 168]. Recent studies
`indicate that postsynaptic a-adrenoceptors do exist in the hearts of many
`mammalian species, including man, and mediate a positive inotropic
`response with little or no change in heart rate [3, 7, 78, 82, 83, 125, 126, 163-
`166; for reviews, see 4, 11, 121]. The mechanism by which cardiac a-adreno(cid:173)
`ceptors increase force of contraction has not been established, but it appears
`not to be associated with the accumulation of cAMP or stimulation of adeny(cid:173)
`late cyclase (2, 12, 13, 89] and in this respect, a-a,drenoceptors differ from
`/3 1-receptors in the myocardium. Other differences between the a- and
`/3-adrenergic effects in the heart include the rate of onset and duration of
`action which are particularly long for a-adrenoceptor-mediated inotropic
`effects (14, 124]. Differences in various electrophysiological actions mediated
`by a- and /3-adrenoceptors have also been observed [38; for review see 11 ].
`Furthermore, while /31-adrenoceptor-mediated inotropic responses occur at
`all frequencies of stimulation, the effect mediated by a-adrenoceptors is
`apparent only at low rates [4, 11].
`The subtype of the cardiac a-adrenoceptor has been the topic of some
`controversy. Using classical techniques to characterize the postsynaptic car(cid:173)
`diac a -adrenoceptor, Schumann and Endoh [123] and Schumann et al. [125]
`observed differences between postsynaptic a -adrenoceptors in the heart and
`postsynaptic a-adrenoceptors in other organs. Most of the physiological and
`radio ligand binding data indicate that the postsynaptic a-adrenoceptor of the
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`
`heart is of the a 1-subtype [17, 32, 47, 48, 55, 90, 122, 123, 156, 172]. However,
`since differences may exist between the cardiac a-adrenoceptor and the post(cid:173)
`synaptic a-adrenoceptor in other organs [ 121, 125], in addition to the fact that
`norepinephrine does not stimulate this receptor [ 165), the possibility that the
`cardiac a-adrenoceptor may represent an atypical subset of the a 1 -type must
`be considered [ 137).
`Several recent reports indicate that postsynaptic a 1-adrenoceptors in the
`heart may undergo marked and rapid changes in number in response to vari(cid:173)
`ous disease states. Myocardial ischemia in the cat has been reported to result
`in an acute and reversible increase in postsynaptic myocardial a 1-adrenocep(cid:173)
`tors [ 17). These findings are consistent with the observation that enhanced
`a-adrenergic responses have been obtained in ischemic myocardium [127].
`Chronic heart failure in the guinea pig produced by aortic constriction like(cid:173)
`wise resulted in an increase in myocardial a 1- (and /3i-) adrenoceptors [54).
`It has been proposed that the increase in the number of myocardial a 1-
`adrenoceptors results from an apparent compensatory up-regulation second(cid:173)
`ary to the decrease in endogenous catecholamine levels that accompanied the
`induction of heart failure. Finally, Woodcock and Johnston [173) have
`observed a decrease in the number of myocardial a-adrenoceptors in rats
`made hypertensive by surgical removal of one kidney and contralateral con(cid:173)
`striction of the renal artery.
`
`Kidney. The existence of a-adrenoceptors in the kidney has been sus(cid:173)
`pected for many years since a -adrenergic drugs produce a variety of renal
`effects. The functions and locations of the renal a-adrenoceptors are now
`only beginning to be understood [for review, see 144]. Radioligand binding
`studies indicate that a 1- and a:radrenoceptors coexist in the kidneys of a
`variety of mammalian species; however, the number, proportion and distri(cid:173)
`bution of each a-adrenoceptor subtype may vary from species to species [51,
`75, 144].
`The anatomical location of the renal a-adrenoceptors and the functions
`they subserve are not completely understood. It is believed that a-adrenocep(cid:173)
`tors of the a: 1-subtype exist in the renal vasculature and mediate a vasocon(cid:173)
`strictor response [43] and thereby modulate, in part, renal blood flow. In the
`rat, a:i-adrenoceptors of the juxtaglomerular apparatus have been proposed
`to inhibit renin release [87, 144]. a-Adrenoceptors also enhance sodium and
`water reabsorption in the proximal convoluted tubules. While the a-adreno(cid:173)
`ceptor subtype responsible for this effect has not been definitely established,
`recent findings tend to implicate the a:rsubtype [144]. In addition, gluconeo-
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`Ruffolo
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`240
`
`azolines and phenethylamines, and their relative significance at a 1- and ar
`adrenoceptors, are summarized in figure 7. Aromatic ring hydroxylation of
`the phenethylamines and imidazolines is critical for the a 2-adrenergic effects
`of both classes of agonists, but especially so for the imidazolines [99]. At a 1-
`adrenoceptors, aromatic ring hydroxylation of the phenethylamines affects
`largely affinity (i.e. binding to the receptor), whereas for the imidazolines,
`both affinity and efficacy (i.e. ability to activate the receptor subsequent to
`binding), but especially efficacy, are affected by aromatic hydroxylation [99].
`For both classes of compounds, aromatic ring hydroxylation produces the
`following rank order of potencies at a 1-adrenoceptors: 3,4-dihydroxy > 3-
`hydroxy >4-hydroxy > non phenolic (i.e. nonhydroxyl substituted). At both
`a 1- and aradrenoceptors, aromatic hydroxyl substitution appears to be more
`critical for the imidazolines than for the phenetylamines.
`The most important substitution at the benzylic carbon atom is also the
`hydroxyl group. Most interesting is the fact that benzylic hydroxyl substitu(cid:173)
`tion produces opposite effects on the activities of the phenethylamines and
`imidazolines [99, 101, 112]. While benzylic hydroxyl substitution of a phen(cid:173)
`ethylamine produces an increase in activity of approximately two orders of
`magnitude [86}, the analogous substitution of the imidazolines results in a
`decrease in activity ofup to 10-fold [99, 101, 112). Recent studies indicate that
`the reason for the opposite effects that benzylic hydroxyl substitution has
`on the phenethylamines and imidazolines is that the phenethylamines
`adhere strictly to the Easson-Stedman hypothesis while the imidazolines do
`not [98, 104), and this represents a major difference between the imidazolines
`and phenethylamines. While benzylic hydroxyl substitution of the phen(cid:173)
`ethylamines no doubt produces an enhancement in agonist activity at both
`a-adrenoceptor subtypes, the effect is greater at aradrenoceptors (99}.
`Substitution at the a-carbon atom can produce dramatic effects in the
`agonist activity of phenethylamines (the imidazolines cannot be substituted
`at this position). The most important substitution at the a-position of
`phenethylamines is the methyl group. This substitution produces a dramatic
`increase in activity at aradrenoceptors while producing no change, or even
`a decrease in activity at a 1-adrenoceptors [98, 114, 133). As a result,
`a-methyl-substituted phenethylamines are highly selective for aradreno(cid:173)
`ceptors relative to their a-desmethyl analogs. This position of substitution,
`therefore, represents a critical point of divergence in the structural require(cid:173)
`ments of a 1- and a 2-adrenoceptors for phenethylamines. Similar observa(cid:173)
`tions have been made for phenethylamines possessing the a-ethyl substitu(cid:173)
`tion [9}.
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`a-Adrenoceptors
`
`241
`
`Many phenethylamine and imidazoline derivatives have been syn(cid:173)
`thesized with N-substituents or imidazoline ringsubstituents, respectively. In
`general, N-methyl substitution of phenethylamines produces a slight
`increase in activity at a 1- and ai-adrenoceptors [l, 169]. Larger N-substitu(cid:173)
`ents produce a decrease in activity at both a 1- and aradrenoceptors [1, 169;
`for review see 96]. For the imidazolines, virtually any manipulation or substi(cid:173)
`tution of the imidazoline ring reduces activity at a 1- and aradrenoceptors
`[96]. However, one interesting difference between a 1- and aradrenoceptors
`has been reported for N-substituted imidazolin