Original Articles
Recent Developments In Noradrenergic
Neurotransmission and its Relevance to the
Mechanism of Action of Certain
Antihypertensive Agents
SALOMON Z. LANGER, M . D . , ICILIO CAVERO, P H . D . , AND R O Y MASSINGHAM, P H . D .
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SUMMARY This report reviews a number of significant developments in the fields of noradrenergic
transmission and adrenergic receptors which suggest that, hi addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate tbe release of norepinephrine (NE) from
peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of
presynaptic a-adrenoceptors reduces this release of transmitter and tbe reverse is observed after blockade of
these receptors. Clearcut pharmacological differences exist between the postsynaptic aradrenoceptors that
mediate the responses of certain organs and the presynaptic aradrenoceptors that modulate the NE release
during nerve stimulation. Therefore, subdassification of a-adrenoceptors into a, and a, subtypes is warranted
but must be considered to be independent of the anatomical location of these receptors.
Some noradrenergic nerve endings have also been shown to possess /3-adrenergic receptors, tbe stimulation
of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors
could be activated by circulating epinepbrine (E) and be involved in essential hypertension. A third type of
catecholamine receptor found at the noradrenergic nerve ending is the Inhibitory dopamine (DA) receptor,
which might be of significance in the development of new antihypertensive agents. Application of these new
concepts of noradrenergic neurotransraission and the subdassification of a-adrenoceptors to tbe treatment of
hypertension is presented. Gonidtne, for example, appears to be a potent aradrenoceptor agonist; the central
receptor involved in its antihypertensive action is pharmacologically an a,-type but located postsynaptically.
Clonidine also induces activation of peripheral presynaptic aradrenoceptors, which might contribute to its
cardiovascular action.
The antihypertensive effects of a-methyldopa are related to tbe formation of a-methylnorepinephrine, a
preferential aradrenoceptor agonist, which can stimulate peripheral presynaptic aradrenoceptors leading to a
decrease of NE release and a reduction in sympathetic tone. Prazosin is a new antihypertensive agent the mechanism of action of which involves a selective blockade of postsynaptic aradrenoceptors. This drug does not antagonize several effects of clonidine that are mediated via aradrenoceptors. The mechanisms presently considered to account for the antihypertensive activity of /3-adrenoceptor blocking agents are numerous. It is
proposed that blockade of peripheral presynaptic fadlltatory ^-adrenoceptors could be of significance in the
antihypertensive action of these drugs. (Hypertension 2: 372-382, 1980)
• a,-adrenoceptors • presynaptic a, and /S-adrenoceptors • prazosin •
• /3-adrenoceptor antagonists • presynaptic dopamine receptors
KEY WORDS
clonidine
M
A N Y drugs used in the therapy of hypertension decrease blood pressure (BP)
either by reducing the sympathetic drive
to the cardiovascular system or by blocking the
transduction of this signal into an effect at the endorgan level (i.e., blockade of the postsynaptic
adrenoceptors). It is still a matter of discussion
whether the effectiveness of these compounds is due to
inhibition of a normal or an increased sympathetic
drive in hypertensive patients, but it is a matter of fact
that the high BP of many patients can be normalized
and stabilized by drugs that effectively reduce sympathetic tone.
During recent years a number of significant
developments have been made in the field of
noradrenergic ncurotransmission and adrenoceptors.
Concepts such as modulation of transmitter release by
presynaptic receptors and the Subdassification of aadrenoceptors into «, and ^-subtype* will be discussed in this review and applied to the understanding
of the mechanism of action of some antihypertensive
•
From the Department of Biology, Laboratoires d'Etudes et de
R
t:i^fo^r^PtzFZ^
M.D.. Department of
Biology, Synthelabo L.E.R.S., 58, me de la Glaciere, 75013 Paris,
France.
372
ANTIHYPERTENSIVE DRUGS AND NEUROTRANSMISSION/Ianger et al.
drugs. We will concentrate on the following groups of
antihypertcnsive drugs:
VARICOSITY
373
EFFECTOR ORGAN
1. Clonidine-type drugs, which may be considered to possess preferential agonist properties for aj-adrenoceptors
2. a-Methyldopa, which is the precursor of amethylnorepinephrine, a preferential a,adrenoceptor agonist
3. Prazosin, a selective aj-adrenoceptor antagonist
4. /3-Adrenoceptor blocking agents, and new
findings on the mechanism of their antihypertensive action.
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Modulation of Peripheral and Central Noradrenergic
Neurotransmlssion Through Presynaptic
a-Adrenoceptors
During NE release elicited by the arrival of nerve
impulses, the neurotransmitter interacts with specific
receptors (a or /3-adrenergic type) located in the membrane of the postsynaptic cell to trigger a cell-specific
response at the level of the effector organ. Until a few
years ago, the role of noradrenergic nerve endings in
neurotransmission was considered to be exclusively
concerned with the synthesis, storage, release, and inactivation of NE, and there were no indications that
receptors might also be present on or in the surface of
the membrane of nerve terminals. During the last
decade, evidence has accumulated in favor of the view
that, in addition to the classical postsynaptic
adrenoceptors, there are also presynaptic adrenoceptors of the a-adrenergic type which are involved in the
modulation of the release of NE from peripheral as
well as from central noradrenergic nerve endings.1"" In
support of this view it is now well established that aadrenoceptor agonists inhibit NE release during nerve
stimulation, while a-adrenoceptor blocking agents
enhance the stimulation-evoked release of the
neurotransmitter. These results have been obtained
both under in vitro and in vivo experimental conditions.
The effects of a-adrenoceptor agonists and antagonists on NE release are frequency-dependent (i.e.,
they are most pronounced in the low and intermediate
range of frequencies of nerve stimulation).6-7 In addition, the presynaptic modulation of NE release
triggered by presynaptic a-adrenoceptors is observed
only for calcium-dependent mechanisms of
transmitter release such as the release evoked by nerve
stimulation or potassium depolarization. The calciumindependent NE release induced by tyramine is not
subjected to modulation by presynaptic inhibitory
a-adrenoceptors.
These results support the hypothesis that a-adrenoceptors located on or in the (outer) surface of noradrenergic nerve endings are involved in the regulation of the release of NE through a negative feedback
mechanism mediated by the neurotransmitter itself
FIGURE 1. Diagram of a noradrenergic neuroeffector junction in the peripheral nervous system showing presynaptic
inhibitory aradrenoceptors and dopamine receptors on the
noradrenergic varicosity. In addition, postsynaptic a,-, and
{5-adrenoceptors and dopamine receptors are represented on
the vascular smooth muscle effector cell.
(fig. 1). The presence of presynaptic inhibitory aadrenoceptors on noradrenergic nerve endings has
been found to be independent of the predominant population of a or /3-postsynaptic adrenoceptor present on
the effector cell.
Clearcut pharmacological differences have been
shown to exist between the postsynaptic aadrenoceptors that mediate the response of the effector organ and the presynaptic inhibitory aadrenoceptors that modulate the release of NE during
nerve stimulation. The presynaptic inhibitory aadrenoceptors are generally much more sensitive than
the postsynaptic ones to activation by agonists like
tramazoline or clonidine and to blockade by antagonists like yohimbine or piperoxan.
In contrast, the postsynaptic a-adrenoceptors are
much more sensitive than the presynaptic ones to activation by agonists like phcnylephrine and methoxamine, and to blockade by antagonists like prazosin
and WB 4101. Based on these pharmacological
differences, the subclassification of a-adrenoceptors
into O] and a, subcategories was first proposed1 and
subsequently extended.'1 * Since this first proposal,
considerable evidence has accumulated to support the
view that at least two pharmacologically distinct populations of a-adrenoceptors exist.10"18
While presynaptic receptors as such arc defined by
the function that they control (i.e., modulation of the
stimulation-evoked release of NE), a,-adrenoceptors
are characterized and defined through the relative
order of potencies for agonists and their susceptibility
374
HYPERTENSION
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to certain antagonists.1-18 In fact, aj-adrenoceptors
can be found at sites other than noradrenergic nerve
endings, as for example: 1) sympathetic ganglia
(where they mediate hyperpolarization); 2) platelets
(where they affect platelet aggregation); and 3) human
fat cells (where they inhibit lipolysis). Consequently,
the a-adrenoceptor should be subclassified according
to its pharmacological characteristics, and independent of its anatomical location.
Use of receptor-binding techniques has provided
substantial support for the subclassification of aadrenoceptors into a, and a, subtypes in the
peripheral as well as in the central nervous system.
The a-adrenoceptor ligand sH-dihydroergocryptine
(•H-DHE) labels both a, and a, adrenoceptors.1"- "• u
On the other hand, the selective a-adrenoceptor
antagonist 'H-WB 4101 labels preferentially a r adrenoceptors in the periphery11 and in the central nervous
system.10 Figure 2 shows that the relative potencies of
prazosin, phentolamine, and yohimbine in displacing
the specific binding of 'H-WB 4101 in the rat heart
correspond to their pharmacological affinities for a t
and a,-adrenoccptors.
Subclassification of a-adrenoceptors into a! and a,categories is helpful in understanding the overall pharmacological profile of a-adrcnoceptor agonists and
antagonists currently in clinical and experimental use.
In addition, it opens new possibilities in the design and
development of novel agonists and antagonists with
high degrees of selectivity for either receptor as potentially useful agents for the treatment of hypertension.
Presynaptic Fadlitatory /9-Adrenoceptors and
Noradrenergic Neurotransmission
Facilitation of the stimulation-evoked release of NE
through presynaptic /9-adrenoceptors was first
reported under in vitro conditions in peripheral tissues
from the guinea pig and the cat,11-M and in the human
oviduct" and vasoconstrictor nerves." There is also in
vivo evidence for the presence of presynaptic
facilitatory /3-adrenoceptors in the dog heart."
The experimental evidence available so far favors
the view that the presynaptic facilitatory /?adrenoceptors are of the ft rather than 0, type. Low
VOL 2, No 4, JULY-AUGUST 1980
concentrations of epinephrine (E) and terbutaline are
effective in increasing the stimulation-evoked release
of NE.**"8* In addition, propranolol and butoxamine
but not practolol can block these presynaptic 0adrenoceptors.11' *•• *° It is likely that presynaptic 0adrenoceptors are mainly activated by circulating E to
enhance noradrenergic neurotransmission since, when
peripheral noradrenergic nerve endings are labelled
with E instead of NE, propranolol becomes more
effective in reducing transmitter release elicited by
sympathetic nerve stimulation."1" Consequently, it is
possible that E may participate in a positive feedback
mechanism for the release of NE from peripheral
noradrenergic nerve endings. Beta-adrenoceptor antagonists may thus act at this site to cause a decrease
in transmitter release by blocking this positive feedback mechanism, the sensitivity of which could be increased in essential hypertension.
In contrast to the presynaptic inhibition through aadrenoceptors, which is present in peripheral as well
as in central noradrenergic nerve terminals,2-' there is
as yet no evidence for the presence of facilitatory
presynaptic /8-adrenoceptors in certain areas of the
central nervous system involved in the regulation of
cardiovascular function.
Presynaptic Inhibitory Dopamine Receptors and
Noradrenergic Neurotransmission
A DA-sensitive presynaptic inhibitory receptor has
been described for some peripheral noradrenergic
nerve endings.83^0 Stimulation of presynaptic inhibitory DA receptors by agonists like DA, apomorphine, bromocryptine, or N,N-di-n-propyldopamine
reduces the stimulation-evoked release of NE, and this
effect, as in the case of the presynaptic a-adrenoceptor, is frequency-dependent. This reduction in the
stimulation-evoked release of NE obtained by DA
receptor agonists is unaffected by a-adrenoceptor
blockade,*4' *° while it is selectively antagonized by
DA receptor blocking agents like chlorpromazine,
pimozide, or sulpiride. These results indicate that
presynaptic inhibitory DA receptors differ from presynaptic aradrenoceptors, which can be acted upon by
released NE (fig. 1).
FIGURE 2.
DRUG (M)
Displacement of
'H-WB 4101
specific binding in rat heart ventricle by alphaadrenoceptor antagonists. Graph taken from
Raisman et al. {see ref19). Ordinate: Displacement of 'H-WB 4101 binding by the drugs,
expressed as percentage reduction in specific
binding. Abscissa: Molar concentration of the
a-adrenoceptor antagonist. The specific binding of'H-WB 4101 at 6 nM was determined in
the presence of various concentrations ofprazosin (•j, phentolamine (») and yohimbine (A).
Each point is the mean of three independent
determinations.
ANTIHYPERTENSIVE DRUGS AND NEUROTRANSMISSION/Ianger et al.
Presynaptic inhibitory DA receptors on
noradrenergic nerve terminals might be involved in the
renal vasodilating and BP-lowering effects of DA
receptor agonists.**• *"•" Figure 3 shows the inhibitory effects of the presynaptic DA agonist N,N-di-npropyldopamine on the reductions in renal blood flow
elicited by sympathetic nerve stimulation in anesthetized dogs. Consequently, presynaptic inhibitory
DA receptors could be considered as target receptors
for the development of selective agonists that might be
useful antihypertensive agents.
Antihypertensive and Other Pharmacological
Properties of Qonidlne, a Preferential Alpha*Adrenoceptor Agonist
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Clonidine is an imidazoline that was originally
designed as a nasal vasoconstrictor because of its
ability to stimulate a-adrenoceptors on vascular
smooth muscle.*3 The accidental discovery of its
hypotensive and bradycardic effects may be considered as the starting point for the increasing attention devoted in recent years to the role of central
a-adrenoceptors in the control of cardiovascular function. Several excellent reviews on the pharmacology of
clonidine have recently appeared.*1""
When clonidine is administered intravenously to intact anesthetized animal preparations, it produces an
initial BP rise followed by a longer lasting hypotensive
phase." The initial hypertension results from stimulation of postsynaptic vascular a-adrenoceptors for
which clonidine, as well as structurally related imidazolines, has high affinity, even if it has been shown
to have low efficacy and to behave as a partial
agonist.47- **
The generalized cardiovascular depression (hypotension, bradycardia, and decrease in cardiac output)
produced by clonidine is compatible with an action on
the central nervous system, because administration of
low doses of clonidine into the cisterna magna or
infused into the vertebral artery produces these cardiovascular effects without being preceded by a
pressor response. Furthermore, this central action is
confirmed by the findings that clonidine reduces the
spontaneous discharges in sympathetic preganglionic
fibers of splanchnic nerve and postganglionic fibers of
cardiac nerves.
The central cardiovascular effects of clonidine are
antagonized by a-adrenoceptor blocking agents, and
consequently they are due to activation of aadrenoceptors that appear to be localized postsynaptically. In support of this view, depletion of central endogenous catecholamines does not inhibit the
clonidine-induced decrease in spontaneous discharge
in the splanchnic sympathetic nerves of the cat.**
Furthermore, the hypotensive effects of clonidine are
not affected by degeneration of central noradrenergic
nerve terminals produced by administration of 6hydroxydopamine.60-" The central site of action of
clonidine-induced cardiovascular effects has been
proposed to be in the area of the nucleus tractus
solitarii and in the medulla oblongata. At these sites,
375
100 -i
s.
c
o
X
50 -
"8
o -J
05
1
2
CONTROL
4 Hz
05
1
2
4 Hz
DPOA
FIGURE 3. Effect of close-arterial infusion of the
presynaptic dopamine agonist
N,N-di-n-propyldopamine
(DPDA) on the reduction in renal blood flow induced by
various frequencies of renal sympathetic nerve stimulation
in anesthetized dogs (n = 3). Asterisk indicates a significant (p < 0.05: paired t test) inhibition of responses. Ordinate: Percentage reduction in renal blood flow, which was
measured with an electromagnetic flow probe positioned on
the left renal artery. Abscissa: Control: reductions in renal
blood flow to renal sympathetic nerve stimulation (10 V, I
msec, 0.5-4 Hz for 60 sec) under control conditions.
DPDA = Antagonism of the effects of renal nerve stimulation by an intrarenal artery infusion ofDPDA (6.25 iig/kg/min).
clonidine stimulates a-adrenoceptors, which may be
classified pharmacologically as a^adrcnoceptors,
since its effects are preferentially blocked by a r
adrenoceptor antagonists.
Recent evidence suggests that clonidine reduces
adrenaline turnover in some areas of the rat brain involved in cardiovascular control." Other studies have
indicated that clonidine might possibly act by
stimulating a,-presynaptic autoreceptors present on
adrenaline and/or noradrenaline nerve terminals."
These findings might be relevant to the cardiovascular
effects of this drug.
As already discussed, presynaptic inhibitory a,adrenoceptors are present in peripheral and central
noradrenergic nerve endings, and clonidine is very potent in reducing noradrenergic neurotransmission.**
Impairment of peripheral noradrenergic transmission
by clonidine, more pronounced for low frequencies of
nerve stimulation, was reported for heart rate
responses in rats. M> " Clonidine also decreases the
positive chronotropic effects elicited by cardioaccelerator nerve stimulation in rabbits, cats, and
dogs. This effect was found to be accompanied by a
reduction in NE output in the dog."1 " • " Figure 4
shows the effects of clonidine on the chronotropic
responses and on transmitter release elicited by
stimulation of the cardioaccelerator nerve in spinal
HYPERTENSION
376
HR
( b/min
VOL 2, No 4, JULY-AUGUST
—. )
1980
PLASMA NOREPINEPHRINE
(ng/min
•
)
200
-i
20
16
160
12
120
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80
I
8
U
i
-5
-1 0
STIMULATION
(ihb,2mi«:,10V)
9
11
13
16
18
20
CLONIWNE
(3OOyg/Kg . i.vO
(3OOyg/Kg.i.vO
22
16 18
20
33
38 mm
STIMULATION
OFF
FIGURE 4. Heart rate and coronary sinus plasma norepinephrine overflow in spinal dogs (n = 5) in which
clonidine (20 ng/kg, i.v.) and phentolamine (0.3 mg/kg, i.v.) were administered during electrical stimulation
of the cardioaccelerator nerve. Asterisks indicate that the values of both parameters (heart rate and plasma
norepinephrine) are significantly (p < 0.05: analysis of variance) different from those of the immediately
preceding treatment. Ordinate left: heart rate (HR: beats /min). Ordinateright:plasma norepinephrine concentration (ng/min). Abscissa: time (min). Part of the figure is taken from Cavero et al. (ref. 56).
vagotomized dogs. The reduction of NE release by
clonidine paralleled its effects on the positive
chronotropic effects to nerve stimulation. Both these
effects of clonidine were antagonized by the administration of phentolamine (fig. 4). This peripheral
effect of clonidine on presynaptic aradrenoceptors
appears to be of functional significance, because in intact dogs very small doses of clonidine injected into
the artery perfusing the sino-atrial node region
produce a negative chronotropic effect" which is antagonized by a dose of phentolamine not affecting BP
(fig. 5)." These results support the view that these
effects of clonidine on peripheral presynaptic ar
adrenoceptors are as pronounced as the centrally
mediated inhibition of sympathetic tone to the heart."
If clonidine exhibits similar activity at vascular
presynaptic a,-adrenoceptors, particularly during
chronic treatment, this mechanism could significantly
contribute to its antihypertensive effects. However, it
is more difficult to assess this possibility under experimental in vivo conditions because of the postsynaptic vasoconstrictor effect of clonidine.
Future synthesis of compounds that do not cross the
blood-brain barrier, act selectively on presynaptic a,adrenoceptors, and arc devoid of vasoconstrictor
effects may provide suitable experimental tools to
assess the role of peripheral presynaptic aadrenoceptors in the inhibition of noradrenergic
neurotransmission as a potential mechanism for novel
antihypertensive agents. Such drugs might lack the
undesirable central effects of clonidine.
Involvement of a-adrenoceptors in the production
of sedation and dry mouth by clonidine has been
suggested by many pharmacological studies. In
chicks, for example, the sleep-inducing action of
clonidine is antagonized by a-adrenoceptor blocking
agents with a preferential action on aa-adrenoceptors
but not by prazosin.80 In cats, clonidine was shown to
reduce submaxillary salivation, evoked by peripheral
parasympathetic nerve stimulation, through activation of presynaptic o2-adrenoceptors that inhibit
cholinergic transmission.*1
Potentially dangerous side effects in patients treated
with clonidine, seen with abrupt withdrawal of treatment, are "rebound" hypertension and tachycardia
that may be associated with anxiety, headache, vomiting, and accompanied by increased catecholamine
excretion.83"*4 The mechanism of this syndrome is not
yet fully understood, although it may be due to a
clonidine-induced change in the sensitivity of aaadrenoceptors both in the periphery and the central
nervous system."
ANTIHYPERTENSIVE DRUGS AND NEUROTRANSMISSION/Lan^er et al.
Ill
•—t.
AHRlb/minl
10
CLONIDINE
I
0
r
-10
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-20
_PHENTOLAMINE
-30
-1
10
15
20
2 5 min
FIGURE 5. Changes in heart rate (HR: beats/min) and mean aortic blood pressure (MAP: mm Hg)
produced by clonidine (2 ng: total dose) injected into the artery perfusing the S*A nodi region in intact
thoracotomized dogs (n = 4). The two curves were obtained in the same animals after an interval of 60 min.
Phentolamine (50 ng: total dose) antagonized the effects of clonidine. Initial heart rate was 148 ± 8
beats/min, and MAP was 115 ± 3 mm Hg. Part of the figure is taken from Cavero and Roach (ref. 57).
Stimulation of Alpha,-Adrenoceptors by aMethylnorepinephrine: Possible Relevance to the Antihypertensive Effects of Alpha-Metbyldopa
Alpha-methyldopa (AMD) has been used successfully in the treatment of hypertensive disease for
nearly 20 years." Recently, two reviews on the pharmacology and site of action of this drug have
appeared."1" Initially, the biochemical effect of
AMD in inhibiting L-amino acid decarboxylase was
thought to be causally related to the hypotensive action of the drug, but this hypothesis was proven incorrect." In fact, studies by Henning"- M
demonstrated that decarboxylation of AMD is a
prerequisite for the hypotensive effect.
While AMD lowers BP when administered after a
decarboxylase inhibitor with poor penetration into the
central nervous system (MK 485), hypotension was
abolished when AMD was given following decarboxylase inhibition in both peripheral tissues and in
the central nervous system by using Ro 4-46002. In
addition, pretreatmerit of rats with inhibitors of
dopamine /J-hydroxylase (FLA-63 or disulfiram)
blocks the hypotensive action of AMD. Thus, the formation of a-methylnorepinephrine within the central
nervous system is necessary to mediate the hypotensive effect of AMD."-70 That the site of action of
AMD was within the central nervous system had been
suggested by earlier pharmacological studies where in-
traveftebral artery infusion of low doses of AMD71- n
lowered BP more effectively than via the intravenous
route.
It would appear that it is the direct action of amethylnorepinephrinc that mediates the central
hypotensive effect of AMD rather than the displacement and loss of endogenous NE from central structures, because there is no correlation between the
time-course of effects of AMD on BP and on brain
NE levels after infusion of the drug into the vertebral
artery of cats." Further arguments against the false
transmitter theory in the mechanism of action of
AMD have been discussed previously by Henning.67- "
The suggestion that the hypotension was induced by
stimulation of central adrenoceptors through one of
the metabolites of AMD was first made by Hoyer and
Van Zwieten73-74 and by Henning and Rubenson,"
largely on the basis of results obtained with other sytrtpathomimetic compounds such as clonidine and
amphetamine. Later studies verified this suggestion
when it was found that a-methylnorepincphrine administered directly into the central nervous system
lowered BP and that this effect was antagonized by
a-adrenoceptor blocking drugs.78- ™ Recent evidence,
however, suggests that the 3-0-methylated metabolites
of AMD might participate in the antihypertensive
effect in the rat especially after chronic dosing.77
At present it cannot be completely ruled out that
some of the hypotensive effect of AMD may be
378
HYPERTENSION
peripheral in origin, mediated either by the peripheral
postsynaptic j8s-adrenoceptor stimulation78 and/or by
impairment of peripheral sympathetic neuronal function through the stimulation of presynaptic a^-adrenoceptors by a-methylnorepinephrine.79' *°
Relevance of the Alphai-Adrenoceptor Selectivity of
the Antagonist Prazosin for the Antihypertensive
Profile of the Drug
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Prazosin can be considered the first member of a
new class of antihypertensive drugs having the outstanding pharmacological property of preferentially
blocking peripheral aradrenoceptors. It is this effect
that appears to be responsible for the hypotensive activity of this compound in several models of hypertension. Considerable evidence has accumulated now
against the view initially advanced that a direct vasodilating activity participates in the antihypertensive
effect of prazosin.81 Both pharmacological and receptor
binding studies favor the view that prazosin is a highly
selective postsynaptic aradrenoceptor blocking
agent.4' 8J"M As shown in figure 2, prazosin is very potent in displacing the specific, high affinity binding of
"H-WB 4101, a preferential aradrenoceptor antagonist.
Blockade of presynaptic a2-adrenoceptors increases
the stimulation-evoked release of NE, which may
counteract the blockade of postsynaptic a r
adrenoceptors at the level of the vascular bed. It is
possible that the effectiveness of prazosin in the
chronic treatment of hypertension is at least partly
due to the fact that it lacks or,-adrenoceptor blocking
properties. Classical a-adrenoceptor antagonists, by
blocking aj-receptors, increase the neuronal release
of NE and thereby reduce their potential antihypertensive effects.
Most drugs that decrease BP through a peripheral
mechanism of action trigger a number of reflexes at
the cardiovascular level, leading to tachycardia and an
increase in cardiac output. Alpha-adrenoceptor antagonists like phentolamine, which block both a, and
a2-adrenoceptors and direct vasodilators such as
hydralazine, increase basal heart rate in the conscious
dog, but this effect is not observed with prazosin.811"
The absence of tachycardia when prazosin is administered to man represents a therapeutic advantage.8* The
fact that prazosin has a very low or negligible affinity
for the blockade of presynaptic aj-adrenoceptors in
the heart may contribute to this effect. To explain the
lack of tachycardia in response to the BP fall
produced by prazosin, however, other mechanisms
must be invoked such as changes in baroreceptor sensitivity83' M and absence of right atrial pressure increases.
The selectivity of prazosin in blocking a,adrenoceptors may also explain why this drug does
not increase renin release when administered in doses
that decrease BP.8'87- M
VOL 2, No 4, JULY-AUGUST
1980
Prazosin was reported to be a more effective antagonist of the pressor responses to phenylephrine
compared to NE under in vivo experimental conditions in various species. These results are compatible
with the presence of two different types of postsynaptic a-adrenoceptors in vascular smooth muscle.*0-*1
Although prazosin can cross the blood-brain
barrier, there is no evidence to support a central
mechanism of action for its antihypertensive
effect.""" Due to its selectivity for aj-adrenoceptors,
prazosin does not antagonize clonidine-induced sleep
in young chicks80 or the sedative effects of clonidine in
rats.9*
Antihypertensive Effects of Beta-Adrenoceptor
Blocking Agents
These compounds are becoming the most widely
used drugs in the treatment of essential hypertension
provided that patients with obstructive disease of the
airways and heart failure are excluded." The first use
of propranolol in the treatment of hypertension was
reported by Prichard and Gillam.*8 The effectiveness
of /8-adrenoceptor blocking agents in the treatment
of hypertension appears to be due to their /8-antagonist properties and not to some other associated
effect.99' 10°
Beta-adrenoceptor blocking agents include the
following groups: 1) cardioselective (ft) like
metoprolol, atenolol and betaxolol; 2) noncardioselective (ft and ft) like propranolol; and 3) noncardioselective /S-adrenoceptor blocking agents like
labetolol which also possess ^-receptor antagonist
properties. The first two groups above have a further
subclassification according to the presence or absence
of intrinsic sympathomimetic activity and the degree
of membrane stabilizing properties.
Different mechanisms have been proposed for the
antihypertensive action of /9-adrenoceptor blocking
agents; they could well be complex and vary with the
patient, since essential hypertension has a complex
etiology. Reduction in cardiac output as the sole
responsible mechanism of antihypertensive action of
/3-adrenoceptor blockers101 has been challenged.
Evidence has been presented that chronic administration of ft-adrenoceptor blocking drugs reduces
peripheral resistance.101 The sympathetic nervous
system controls the release of renin from juxtaglomerular cells in the kidney via /S-adrenoceptors.
Consequently drugs blocking these receptors reduce
plasma renin levels both in normotensive and
hypertensive subjects. 10S~1'a It was suggested that the
antihypertensive effects of /8-adrenoceptor blocking
agents was most pronounced in patients with high
plasma renin activity.108 Yet, after intravenous administration of propranolol, there is a rapid fall in
plasma renin levels but no decrease in BP,105> m In addition, several clinical studies failed to show a correlation between the BP fall induced by /S-adrenoceptor
antagonists and renin levels in plasma.99
ANTIHYPERTENSIVE DRUGS AND NEUROTRANSMISSION/La/iger et al.
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Experiments in dogs have shown that chronic
propranolol therapy reduces the pressor responses to
carotid occlusion, while short-term therapy is without
effect.108 These results could be related to an increased
baroreceptor sensitivity or due to central nervous
system effects of /S-adrenoceptor blocking agents.
Intracerebroventricular injection of propranolol
leads to BP reduction; consequently, it was proposed
that blockade of central £-adrenoceptors might be involved in the antihypcrtensive effects of this compound.10*"111 Yet relatively large doses of propranolol
were employed in these studies, and leakage into the
periphery could contribute to the observed effects.
Lewis and Haeusler"2 demonstrated that the intravenous administration of propranolol to conscious
rabbits reduces the splanchnic nerve discharge as well
as the BP. Similar decreases in splanchnic nerve discharges were reported in cats treated with propranolol
or pindolol administered centrally.118 In conscious
rabbits, intravenous administration of propranolol
reduces BP but has no effect on resting renal sympathetic nerve discharge, although it does reduce the
threshold of the renal baroreflex.114
Drugs like practolol116 and sotalol11* penetrate
poorly into the central nervous system, yet these /3adrenoceptor blocking agents are effective antihypertensive drugs in man. The question of a central
effect of ^-receptor blocking agents remains open, but
it is of interest to note that side effects like sedation
and vivid dreams are observed particularly with many
nonselective /J-adrenoceptor antagonists.
Recent studies have shown that prolonged treatment of spontaneously hypertensive rats with /3adrenoceptor blocking agents reduces the responses
of the portal vein to electrical stimulation without
affecting the sensitivity to exogenous NE.117 The
reduced release of NE per nerve impulse could be
related to the blockade of the presynaptic facilitatory
/3-adrenoceptors on noradrenergic nerve terminals."- »• " • "
Since E is more effective than NE in enhancing
transmitter release through the activation of
presynaptic facilitatory jS-adrenoceptors,17-n it is
possible that circulating E as well as E released from
noradrenergic nerve endings as a cotransmitter with
NE may be the physiological stimulus for presynaptic
/3j-adrenoceptors.ai> " Recent studies indicate that the
plasma levels of circulating E are significantly increased in hypertensive patients.118 In addition, it is
well known that stress triggers an increase in plasma E
levels. It is therefore possible that circulating E can be
incorporated into noradrenergic nerve endings for
storage and subsequent release. The increase in the
responsiveness of certain cardiovascular effector
tissues in hypertensive patients may be due to activation of this presynaptic 0-adrenoceptor-mediated
positive feedback loop by circulating or neuronally
released E. Under these conditions, a decrease in NE
released from peripheral noradrenergic nerve endings
due to the blockade of presynaptic facilitatory /?adrenoceptors could contribute to the antihypertensive effects of /3-adrenoceptor antagonists.
379
Conclusions
Our understanding of the mechanism of action of
several antihypertensive drugs has been improved by
recent developments concerning presynaptic regulation of norepinephrine release and through the subclassification of a-adrenoceptors into a t and ^-subcategories.
Most of the antihypertensive effects of clonidine
and a-methyldopa are mediated through the activation of aj-adrenoceptors. On the other hand, the selective blockade of aj-adrenoceptors by prazosin may explain the effectiveness of this drug in the treatment of
hypertension and partly the lack of tachycardia as a
side effect. It is possible that blockade of presynaptic
facilitatory /8-adrenoceptors may contribute to the antihypertensive effects of /3-adrenoceptor antagonists.
Finally, it is suggested that presynaptic inhibitory
ctj-adrenoceptors and presynaptic dopamine receptors
might become important target receptors in the
development of novel, selective agonists with potential
antihypertensive properties.
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mechanism of action of certain antihypertensive agents.
S Z Langer, I Cavero and R Massingham
Hypertension. 1980;2:372-382
doi: 10.1161/01.HYP.2.4.372
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