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1 Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021; and 2 Departments of Psychiatry and Human Behavior, Pharmacology, and Physiology, University of Mississippi Medical Center, Jackson, Mississippi 39216-4505
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ABSTRACT |
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Clonidine, moxonidine, and rilmenidine
are centrally acting antihypertensive agents that lower arterial
pressure by inhibiting the tonic activity of sympathoexcitatory neurons
in the rostral ventrolateral medulla. Competing hypotheses have been
put forward by different investigators to explain the
sympathoinhibition evoked by "imidazoline drugs": either via
central actions at 
2-adrenergic receptors or novel I1-imidazoline
receptors. These different perspectives are presented in the
accompanying reviews.
ventrolateral medulla; arterial pressure; 2-adrenergic
receptors
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ARTICLE |
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Abstract
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CLONIDINE, an
2-adrenergic receptor agonist,
lowers arterial pressure (AP) by centrally inhibiting sympathetic nerve
activity. The sympathoinhibitory action of clonidine, and related drugs rilmenidine and moxonidine, are believed to result from inhibition of
tonically active sympathoexcitatory reticulospinal neurons of the
rostroventrolateral medulla reticular nucleus of the medulla oblongata
(RVLM) (24). Central inhibition of sympathetic activity has advantages
in the treatment of hypertension by decreasing release of renin as well
as peripheral resistance (5). In peripheral tissues, clonidine is an
agonist at 2-adrenergic
receptors (2AR) (26). It was
therefore originally assumed that clonidine's hypotensive actions were
attributable to stimulation of central
2AR. However, even as early as
1976, Karppanen et al. (15) hypothesized that the antihypertensive
actions of clonidine administered intracerebroventricularly related to
nonadrenergic receptors, possibly histaminergic. More recently, the
central effects of clonidine have been attributed to novel imidazoline
receptors (6, 28, 32), some of which might be related to amine oxidases
(21) or nicotinic ion channels (20).
In an important structure-function analysis in 1984, Bousquet et al.
(2) directly tested the non-2AR
hypothesis of clonidine's action. They compared the ability of a panel
of drugs to lower AP when microinjected into the RVLM of anesthetized
cats. The drugs differed in their functions at known catecholaminergic
receptors and in their chemical structures. It was noted that the
hypotensive potencies of these drugs related to whether or not they
contained an imidazoline ring structure, not necessarily to their
affinities at 2AR. It was
therefore proposed that clonidine lowered AP by an interaction in the
ventral medulla with "sites preferring the imidazoline structure"
(I sites).
The original concept for imidazoline receptors proposed by Bousquet et
al. (2) has been supported by two principal lines of investigation.
First, the antihypertensive actions of agents injected into the RVLM of
conscious animals have been correlated with radioligand binding
affinities to I sites, but not
2AR, as measured in membranes
of ventral medulla (6). Although Bousquet's initial study was
criticized because of the possible metabolism of microinjected
norepinephrine (29) and because of other possible pathways of action
(27), recent studies (3, 12) have upheld the proper rank ordering of
affinities to subtype I1-binding
sites versus hypotensive efficacies, without including catecholamines or imidazole acetic acid in the correlation. Second, the central administration of imidazolines, either intracerebroventricularly (4,
13) or by microinjection into RVLM (9, 22), blocks the antihypertensive
actions of systemically administered clonidine and/or
rilmenidine or moxonidine. In contrast, a number of selective 2-antagonists appear to have
either weak or no blocking effects. Finally, the concept that
hypotension relates to stimulation of an imidazoline receptor has found
therapeutic use. The development of rilmenidine and moxonidine, by
favoring binding to I sites rather than
2AR, has minimized the most
limiting side effect of clonidine, namely somnolence, attributable to
2AR (30).
The evidence appears strong that imidazoline-binding sites and
2AR are physically distinct
entities. Candidate proteins for imidazoline receptors have been
isolated (32) that are not related to
2AR. Second,
2AR- and imidazoline-binding
sites (I1 and
I2) can be differentially
downregulated by chronic drug treatments in vivo (11).
I1- and
2AR-binding sites also differ
in regard to their responses to GTP (8). Recently,
I1 receptor activation was linked
to diacylglycerol accumulation via phosphatidylcholine-phospholipase C
activation, making ultimate expression via arachidonic acid release
(28). This pathway has not been previously ascribed to an
2-adrenoceptor.
On the other hand, other studies have suggested that the effects on AP
of clonidine-like drugs may be entirely attributable to stimulation of
2AR. The first line of evidence
is that when selective
2-antagonists are administered
systemically, rather than centrally, the antihypertensive responses to
intraventricular clonidine are totally blocked (14, 31). Second, the
discharges of neurons (single cells) in RVLM, expressing
2AR (25), are inhibited by
systemic and/or iontophoretic application of either catecholamines or clonidine (1, 29). Moreover, these effects are
antagonized by iontophoretic application of methoxy-idazoxan, a drug
that most investigators, except Ernsberger and Haxhiu (7), believe is a
selective 2-antagonist. Third,
transgenic mice expressing mutated
2AAR, with intact
2BAR and
2CAR subtypes of
2AR, were reported (17, 18) to
lack hypotensive responses to two imidazolines, one of which was
clonidine (Dr. Lee Limbird, Vanderbilt University; personal
communication).
It is also noteworthy to realize that ligands for I sites are not
limited to imidazolines, but include guanidiniums (e.g., guanabenz,
agmatine), an oxazole (e.g., rilmenidine), and a bicycloheptane, AGN-192403 (19). Most I site ligands potently agonize or antagonize hypotensive responses when administered centrally, except agmatine (a
putative endogenous ligand for I sites) and the bicycloheptane (19,
23). The latter two drugs possess moderate (agmatine) to high
(AGN-192403) affinities at I sites but lack hypotensive potencies in
vivo (16, 19). However, selective
2-agonists (e.g., guanabenz)
and 2-antagonists (e.g.,
SKF-86466) exist that are nearly devoid of affinity at
I1-binding sites.
In two accompanying articles (7, 10), these divergent viewpoints are
presented. Dr. Patrice Guyenet presents the traditional viewpoint that
clonidine's hypotensive action can be explained sufficiently by
postsynaptic 2AR. On the other
side of the debate, Drs. Paul Ernsberger and Musa A. Haxhiu contend
that clonidine and other imidazolines act primarily via imidazoline
receptors in the RVLM.
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FOOTNOTES |
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Address for reprint requests: D. J. Reis, Cornell University Medical College, 411 East 69th St., Rm. KB410, New York, New York 10021.
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REFERENCES |
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