Annals of Medicine

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Serotonin and the heart

William H Frishman & Pam Grewall

To cite this article: William H Frishman & Pam Grewall (2000) Serotonin and the heart, Annals of
Medicine, 32:3, 195-209, DOI: 10.3109/07853890008998827

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Published online: 08 Jul 2009.

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 195

+ SPECIAL SECTION: SEROTONIN +

Serotonin and the heart

William H Frishman and Pam Grewall

Serotonin is a naturally occurring vasoactive substance that has diverse cardio-

physiological effects. These effects can be explained by the existence of serotonin receptor
subtypes which mediate different biological actions. The vasoconstrictive actions of
serotonin are mediated by 5-HT2 serotonergic receptors, and serotonin also amplifies the
release and activities of other vasoconstrictors, such as angiotensin and norepinephrine.
Abnormalities in the serotonergic system may play an important role in the patho-
physiology of multiple cardiovascular disease states such as systemic hypertension,
primary pulmonary hypertension and peripheral vascular disease. Selective 5 -HT,
serotonergic receptor blockers have been developed which appear to be potent
vasodilators with therapeutic potential in various cardiovascular disease states. The
largest clinical experience has been collected with ketanserin, and other agents in this
class are being investigated. Prolongation of the ECG QT interval with 5-HT2
serotonergic receptor blockers may pose a potential risk with these treatments in some
patients.
Key worak cardiovascular disease; hypertension; ketanserin; serotonin antagonism.
Ann Med 2000; 32: 195-209.

Introduction In this article, the cardiovascular effects of

Various circulating substances are involved in blood
pressure control in human beings, and among these
the effects of serotonin are now well recognized. Its
importance in human hypertension and other cardio-
vascular disorders was not appreciated initially as
serotonin antagonism induced by various chemical
substances affected blood pressure in conflicting ways.
The recent discovery of serotonin receptor subtypes
has rekindled interest in examining serotonin antagon-
ism as a pharmacological approach to reducing
elevated blood pressure. A subtype-selective serotonin
blocker, ketanserin (Fig l ) , has been proposed as an
innovative therapy for systemic hypertension and
other cardiovascular disorders (1, 2). The drug has
been studied in extensive clinical trials worldwide.
From the Department of Medicine, New York Medical College,
Valhalla, NY, USA.
Correspondence: William H Frishman MD, Department of
Medicine, New York Medical College, Munger Pavilion, Valhalla,
N Y 10595, USA. E-mail: joanne-pryor@nymc.edu, Fax: +1 914
59441 18.
serotonin will be reviewed, and potential pharmaco-
logical therapies involving serotonin antagonism will
be discussed.
Cardiovascular effects of serotonin
Serotonin, or 5-hydroxytryptamine (5-HT) (Fig l),is
a naturally occurring vasoactive substance found
primarily in the brain, enterochromaffin tissue and
blood platelets. The amine is manufactured predomi-
nantly in the amine precursor uptake and decarboxy-
lation system (APUD) cells of the gastrointestinal tract
(3) where it is then released into the blood. Intra-
vascularly, blood platelets rapidly bind and store the
amine, so that little, if any, exists free in the plasma.
The physiological effects of serotonin were described
by Page in 1954 (4).
Physiological actions
Serotonin has diverse cardiophysiological effects (Table
1; Fig 2) leading to its designation as an amphibaric
molecule (2). The amine either constricts or dilates

0 The Finnish Medical Society Duodecim, Ann Med 2000; 32: 195-209
196 FRISHMAN GREWALL

0
5-hydroxytryptamine 3-[2-[4-(4-fluorobenzoyl)-l-piperidinyl]ethyl]-2,4
(Serotonin) (1H, 3H) - quinazolinedione
(Ketanserin)

Figure 1. Chemical structures of serotonin and the serotonin receptor antagonist ketanserin.

blood vessels, depending on the vessel site and the probably influenced by the distribution of these
condition of its intimal wall. The vascular effects of receptor subtypes (7).
serotonin are so varied that it can induce different The receptors are characterized by their radio-
contractile responses in separate segments of the same labelled binding specificities: [,H]-S-HT specifically
coronary artery (6). labels the 5-HT, receptors, whereas [3H]-spiperone or
These multiple effects on blood vessels can be [,H]-ketanserin bind to the 5-HT, receptors. A third
explained by the well-defined existence of two seroton- receptor class, 5-HT, is identified by its morphine-
ergic receptor subtypes, 5-HT, and 5-HT, (Table 2). binding capacity. This receptor was formerly termed
The 5-HT, receptor mediates the vasodilator activity the ‘M’ receptor, whereas the 5-HT, and 5-HT,
of serotonin, while the 5-HT, receptor mediates a receptors were previously indistinguishable and termed
vasoconstrictive effect. The different vascular responses ‘D’ receptors for their abilities to bind phenoxy-
observed with serotonin in different vascular beds are benzamine (dibenzyline). Additionally, recent studies
have shown three subtypes of the 5-HT, receptor
called 5-HT,,, 5-HT,,, and 5-HT,,. Evidence also
exists for other classes of serotonin receptors, termed
Table 1. Physiological actions of serotonin (5-HT) in humans.
5-HT, and 5-HT, (8).
The receptor subtype(s) mediating the effect is given in paren- Serotonin causes constriction in large arteries and
theses. precapillary vessels while causing vasodilation in the
arterioles and large veins (6, 9), although numerous
1. Vasoconstriction (5-HTl, 5-HT,) exceptions to both exist. Its vasoconstrictive actions
2. Vasodilation (5-HT1)
3. Potentiation of other vasoactive mediators (5-HT,)
are believed to be largely mediated by 5-HT,
4. increased inotropy serotonergic receptors on platelets and endothelial
5. Increased chronotropy cells; these effects are substantially attenuated by the
6. Increasedgastrointestinal motility serotonin antagonist ketanserin. Serotonin, via the 5 -
7. Central sleep regulation HT, receptor, amplifies the release and augments the
8. Increased blood viscosity/decreased red cell deformability
9. Increased stroke volume
actions of several other vasoconstricting mediators,
10. Increased pulmonary artery pressure including histamine, angiotensin 11, prostaglandin F,=
11. Increased cardiac output (PGF,,) and norepinephrine (2, 7, 10). Serotonin has
been shown to exhibit synergism with these other
(Reproduced from (5) with permission.)
vasoconstrictive substances ( 11). Additionally, it
augments platelet aggregation in conjunction with
Table 2. Agonist actions mediated by peripheral serotonergic other mediators. This in turn causes platelet release of
receptor subtypes. more stored serotonin (12), amplifying its own action.
Recently, the role of serotonin in various cardio-
5-HT, receptor 5-HT2 receptor
vascular diseases has become of interest. Vikenes and
1. Vasodilation 1. Vasoconstriction co-workers have described elevated levels of serotonin
2. Inhibition of norepinephrine 2. Facilitation of platelet
as a risk factor for coronary artery disease and cardiac
release aggregation events. This association was particularly strong in
3. Endothelial-dependent 3. Augmentation of other vaso-
younger patients and persisted even after adjustment
inhibition of vascular constrictors: prostaglandin F2,+ for conventional risk factors (13). Additionally, there
smooth muscle activity norepinephrine, angiotensin 11, has been growing interest in the functional poly-
histamine morphism in the serotonin transporter gene promoter.
4. Vasoconstriction Recent studies in Japan have shown that the poly-
(in some arterial beds)
morphism may be associated with an increased
(Reproduced from (5) with permission.) susceptibility to coronary artery disease, particularly

0 The Finnish Medical Society Duodecim, Ann Med 2000; 32: 195-209
 SEROTONINAND. THE HEART 197

n
Thromboxanes Serotonin promotes
Other vasos ,tic mediators platelet activation
Potentiates action
of All and NE c
*
T 1
Serotonin promotes release of EDRF
nerve terminal
Inhibition of adrenergic
4
EDRF
norepinephrine from Adrenergic neurotransmission
adrenerqic nerve
terminals
+
nerve terminal l-J
All

1 % $ 1
1+15-HT,I
NE

1+ Vascular
smooth
0b Endothelium?
Vascular
smooth
- PGI,

muscle
r
, isoconstriction
0
1*+ -m muscle

Serotonin directlv
Vasodilation
Serotonin directlv
causes vasoconstridtion causes vasodilation

Figure 2. In the vascular bed, the immediate source of serotonin (5-HT) is from activated platelets which release Serotonin
along with other vasoactive mediators. Serotonin release promotes platelet activation via 5-HT2 receptors on platelets, leading to a
positive feedback loop. This released serotonin has contradictory effects. Vasoconstrictor actions: 1) via 5-HT2 receptors, serotonin
augments the vasoconstrictor response to norepinephrine (NE) and angiotensin II (All); 2) serotonin displaces NE from adrenergic nerve
terminals, increasing the local concentration of the latter; 3) serotonin acts directly on 5-HT, receptors on vascular smooth muscle to
promote vasoconstriction. Vasodilator effects: 1) via endothelial 5-HT, receptors, serotonin promotes release of endothelial-derived
relaxing factor (EDRF) which acts on smooth muscle to cause vasodilation; 2) serotonin promotes release (and synthesis) of prostacyclin
(PG12), a potent vasodilator; 3) via 5-HT1 receptors, serotonin inhibits release of NE, thereby inhibiting vasoconstriction; 4) via 5-HT1
receptors, serotonin activates autonomic inhibitory neurones which cause vasodilation, probably via release of vasoactive intestinal
peptide (VIP); 5) serotonin acts directly on 5HT, receptors in smooth muscle to cause vasodilation. (Reproducedfrom (5) with permission.)

when combined with smoking (14). Other studies
imply a relationship between the polymorphism and
elevated levels of serum cholesterol (15).
Several factors are involved in the pathogenesis of
common vascular diseases, such as atherosclerosis and
hypertension. Among these changes are development
of collateral vessels, morphological changes in vessel
walls, endothelial dysfunction and altered sensitivity
of vessel walls to circulating substances. The body
often develops collateral circulation to augment blood
flow to ischaemic regions. These collateral vessels are
exquisitely sensitive to the vasoconstrictive effects of
serotonin (16-18). Age, atherosclerosis and hyper-
tension were factors previously thought to augment
serotonin-induced vasoconstriction (19). However,
recent studies on rat coronary vessels have indicated
that contractile responses to serotonin and other
vasoconstrictive agents increase with age but decrease
in hypertension (20).In addition to collateral vessels
being hyper-responsive to circulating serotonin, there
is considerable evidence suggesting the same phenom-
enon in diseased vessels. Doggrell found a selective
increase in sensitivity to serotonin on the aortas of
rats with genetic hypertension, as well as an increase
in affinity for serotonin at the S-HT,,receptors (21).
Benzuly and co-workers (22) demonstrated that
atherosclerosis, and not hyperlipidaemia, increased the
vasoconstrictive effect of serotonin in monkeys. In
their study, nonatherosclerotic, hypercholesterolaemic
monkeys did not exhibit marked vasoconstrictor
responses to serotonin, whereas atherosclerotic,
normocholesterolaemic monkeys did. Additionally,
they demonstrated that serotonin-enhanced vaso-
constriction can return to normal during regression of
atherosclerosis. Curiously, this improvement was
observed even before morphological changes of the
atherosclerotic lesions could be demonstrated. The
authors attributed this phenomenon to improvement
in the function of small resistance vessels and thus
suggested that large artery diameter is a less sensitive
measure of functional improvement than blood flow.
Finally, the authors question the relevance of these
results as atherosclerosis induced in monkeys after 1
year of an atherogenic diet may not be analogous to
the atherosclerosis most commonly seen in humans
that develops over many years. Recent studies in
humans, however, support this phenomenon. Studies
by Heistad and co-workers have shown that athero-
sclerotic and hypertensive patients develop changes
in vascular structure characterized by vessel wall

0 The Finnish Medical Society Duodecirn, Ann Med 2000; 32: 195-209
198 FRISHMAN GREWALL
thickening and vascular ‘remodelling’. In athero-
sclerotic vessels, this remodelling tends to preserve the
lumen size, whereas in hypertension, lumen diameter
is generally diminished. Treatment of hyperlipidaemia
results in the regression of atherosclerotic lesions, but
with inconsistent improvement in maximal vasodilator
capacity. However, endothelial dysfunction improves
with regression of atherosclerosis, and hyper-respon-
siveness to serotonin rapidly subsides. Similarly,
treatment of hypertension induces regression of
vascular hypertrophy while improving endothelium-
dependent relaxation (23). Other studies indicate that
verapamil, by preventing calcium entry, decreases
hyper-responsiveness to 5-HT in rabbits with collared
arteries without decreasing intimal thickening (24).
Further study is needed.
Vascular dilation by serotonin is believed to be
mediated in part by 5-HT, receptors in the endo-
thelium. Bound serotonin causes release of a relaxation
factor called endothelial-derived relaxation factor
(EDRF), which directly relaxes the vascular smooth
muscle cells (2, 12). This observation is substantiated
by the finding that vessels devoid of endothelium show
increased vasoconstriction in the presence of serotonin
(7). Recently, Yokota and co-workers (25) have
challenged the belief that nitric oxide (NO) is the
predominant relaxation factor released in response to
5-HT. In their study of basilar arteries from normo-
tensive and hypertensive rats, the major mechanism
for the attenuation of serotonin-induced smooth muscle
responsiveness was found not to be the release of NO
or cyclooxygenase products, but rather the activation
of K channels, possibly of a Ca2+-dependent type.
Further study has revealed that indeed voltage-gated
Ca2+channels contribute significantly to maintaining
tonic force as well as to agonist responses in mesenteric
rat arteries (26).In fact, chronically elevated blood
pressure has been shown to enhance the serotonin-
stimulated intracellular calcium-dependent aortic
contractions in hypertensive rats (27). Serotonin also
causes the release of other dilator compounds, such as
prostaglandin,, (PGI,) and vasoactive intestinal peptide
(VIP), while inhibiting the release of the vaso-
constrictor norepinephrine (12).
The roles of endothelial dysfunction and abnormal
release of vasoactive substances in these diseases have
been studied extensively. Alterations of flow-dependent
vasodilation in various disease states have been shown
to be predominantly caused by functional changes in
the endothelium, with some evidence for the role of
vascular remodelling of coronary arteries in negatively
affecting these functional changes (28).Recent studies
have indicated that atherosclerotic vessels and re-
generated endothelium undergo functional endothelial
changes including the loss of serotonin-mediated
release of EDRF, which favours the development of
vasospasm, thrombosis and cellular growth (29).In
0 The Finnish Medical Society Duodecirn, Ann Med 2000; 32: 195-209
addition, atherosclerotic vessels are thought to produce
increased amounts of endothelium-derived contracting
factor (EDCF) which contributes to the decrease in
vasodilatory response (30).
Endothelial dysfunction has also been studied in
patients with angina and vasospasm, as well as after
myocardial infarction (MI). Elevated levels of serotonin
have been associated with episodes of nonischaemic
vasospastic angina. Serotonin-mediated release of NO
is thought to be impaired in patients with angina (31).
Additionally, serotonin has been shown to be involved
in the degranulation of platelets in these vessels with
impaired endothelial release of NO, even with
compensatory prostacyclin production (32, 33). While
it has been shown that NO release is impaired in
vasospastic angina, endothelin 1 is not involved in the
serotonin-mediated process (34).Further investigation
is necessary.
Structural and functional changes in coronary
vessels are known to occur during and after MI.
Studies have shown that coronary arteries of rats
exhibit hyper-reactivity, while their mesenteric arteries
demonstrate hyporeactivity (35). Studies in humans
have revealed that patients with recent MI show a
decreased incidence of serotonin-induced occlusive
spasm in the infarct-related artery, but a significantly
higher vasoconstriction in the distal segment of the
infarct-related artery as compared with the same
segment of noninfarcted arteries (36). Other studies
indicate that chronic MI associated with certain
morphological cardiac changes is related to impaired
vasodepressor reflex responses to serotonin (37).
Serotonin also exerts a direct influence on the heart
and cardiopulmonary circulation. Breuer and co-
workers (38) showed a dose-dependent increase in
pulmonary artery pressure, cardiac output, stroke
volume, cardiac contractility and pulmonary vascular
resistance following serotonin infusion in the dog;
serotonin lowered mean aortic pressure and total
peripheral resistance simultaneously and in a dose-
dependent manner. Recent studies by Missouris and
co-workers suggest a positive chronotropic effect and
a possible role for serotonin in the direct regulation of
heart rate in hypertensive patients (39).
There is also a role for sertonin in arterial thrombus
formation. Studies have found that intravenous in-
jection of serotonin stimulates arterial thrombus
formation in rats (40). Endogenous serotonin acts
synergistically with ADP to activate platelets, leading
to thrombus formation. This mechanism of action is
believed to be inhibited by 5-HT,, receptor antagonists
(41).
Serotonin in systemic hypertension
Peripheral effects. Serotonin may be responsible for
causing, or at least perpetuating, some forms of
 SEROTONIN
AND THE HEART
systemic hypertension. Elderly individuals and hyper-
tensive patients show increased serotonin sensitivity
(2, 12,23).Increased circulating serotonin could cause
increased capacitance bed constriction, thereby raising
blood pressure (42). In diseased and damaged vessels
(commonly seen in the elderly and in hypertensive
patients in association with atherosclerosis), the
degenerating wall elasticity, as well as the increased
pressures and blood turbulence, tend to damage the
intima. The vessel wall loses its protective endothelial
barrier with its 5-HT, receptors, as well as the EDRF
and, with it, much of the dilator activity of serotonin
(9, 12).Therefore, the 5-HT, receptor will be more or
less unopposed by the loss of 5-HT, dilator activity,
resulting in augmented constriction. This may explain
a decrease in tachyphylaxis seen with serotonin in the
vasculature of hypertensive animals (12).Additionally,
damaged intima tends to attract and adsorb platelets,
causing increased release of serotonin, thereby per-
petuating the cycle (2).
Hypertensive patients have been shown to exhibit
an increase in P-thromboglobulin, suggesting acceler-
ated platelet turnover (9). In the hypertensive person,
there is both a diminished ability of platelets to bind
serotonin and a decreased platelet survival time (4).
Baudouin-Legros and co-workers showed diminished
platelet levels of serotonin in hypertensive individuals
(43). One interpretation could be augmented release,
with decreased uptake of serotonin in the presence of
increased platelet turnover in those vessels subject to
increased blood pressure and turbulence. This would
lead to increased serotonin at sites of platelet
aggregation.
Another feature in hypertension that tends to
enhance the blood pressure-elevating effects of
serotonin is the impaired clearing of the monoamine
by the monoamine oxidase (MAO) system (9).
Along with its direct vasoactive actions, serotonin
interacts at another site in the hypertensive scheme. It
has known aldosterone-stimulating properties in both
man and rat (44), leading to increased sodium and
water retention, and possibly elevating blood pressure
by this mechanism.
Central effects. Serotonin also aids in central blood
pressure regulation. Unlike platelet serotonin manu-
factured in the APUD cells of the gastrointestinal tract,
this serotonin is manufactured locally. Radiolabelling
studies in the rat (45) localize serotonergic neurones
to specific areas of the brainstem, most of which
correspond to the raphe nuclei. Two of these areas,
the B7 (dorsal) and B8 (lateral) raphe nuclei of the
midbrain, and the B3 group in the medulla maintain
important functions in central blood pressure control.
The B7-B8 group projects to the preoptic area of
the hypothalamus. In the normotensive rat, as little as
20 ng of serotonin injected locally in this area
0 The Finnish Medical Society Duodecim, Ann Med 2000; 32: 195-209
199
produces significant elevations in blood pressure (46).
This hypertensive response can be antagonized by
pretreatment with methysergide or metergoline, non-
specific serotonergic antagonists. Additionally, prior
depletion of noradrenergic input to this area produces
a hypertensive response which requires the presence of
a functioning serotonergic system. This suggests an
interaction between these two systems at the
hypothalamic level. Finally, the output of this system
travels, at least partially, through the sympathetic
nervous system, as pretreatment of rats with bretylium
tosylate, which depletes catecholamines from post-
synaptic nerve terminals, attenuates this pressor
response.
The medullary group, B3, can be further subdivided
into lateral and midline components. The lateral
projects to the intermediolateral cell column of the
thoracic spinal cord, ie the cell bodies of preganglionic
sympathetic nerves. Electrical or chemical stimulation
of this area is associated with an increase in systemic
blood pressure and increased renal nerve activity (45).
Therefore, these serotonergic neurones may increase
sympathetic activity. These neurones may also inhibit
vagal depressor responses via a projection to the
nucleus of the solitary tract, thereby dampening the
baroreceptor reflex arc. Evidence exists that methyl-
dopa and clonidine may act by inhibiting these
serotonergic neurones (46).In contrast, stimulation of
the midline group leads to a vasodepressor response
(45).
Which serotonergic subtypes are involved in these
pathways needs clarification. Most studies have used
either nonspecific antagonists, such as methysergide,
or synthesis inhibitors, such as paraclorophenylalanine
(46). Much evidence exists that serotonin acts on
receptors in the rostra1 ventrolateral medulla to inhibit
sympathetic nerve activity and, thereby, decreases blood
pressure and heart rate as well as renal sympathetic
nerve activity. This sympatholytic effect is thought to
occur via a process of ‘disfacilitation’, or removal of
serotonergic excitatory output (47).Additionally SHT,,
agonists act centrally to stimulate vagal output (47).
Recent data have suggested that activation of central
SHT,, receptors can also produce vasoconstriction,
tachycardia and increased renal sympathetic nerve
activity. This phenomenon can be well demonstrated
with the intracerebroventricular administration of a 5-
HT,, agonist, such as 8-hydroxy-2-(di-n-propyl-
amino)tetraline (8-OH DPAT), suggesting that 5-HT,,
receptors in the forebrain mediate sympathoexcitatory
responses, whereas similar receptors in the hindbrain
mediate sympatholytic responses (47). Interestingly,
trials using flesinoxan, a 5-HTlAreceptor agonist, as
an antihypertensive medication revealed a decrease in
blood pressure with single-dose administration. Un-
fortunately, patients appeared to develop tolerance
after repeated use. Further studies have confirmed a
200 FRISHMAN GREWALL
significant reduction in mean arterial pressure during
infusion of flesinoxan, but no favourable long-term
effects (48). Nevertheless, there is evidence that
urapidil, commonly known as an a,-adrenoceptor
antagonist, may actually lower blood pressure via its
5-HT,, agonist properties (47).In fact, recent studies
indicate that it is an effective antihypertensive agent in
the treatment of elderly patients with hypertension,
and it also has a potentially favourable lipid profile
(49). Additionally, studies using A-74283, a centrally
acting 5-HT,, agonist, showed a potent hypotensive
effect in spontaneously hypertensive rats via systemic
vasodilation (50).
Whereas some investigators have demonstrated that
the sympathoexcitatory effects of 5-HT, agonists may
also be mediated via 5-HT, receptors in the rostra1
ventrolateral medulla (47), recent data have suggested
that the 5-HT, receptor in the forebrain also contrib-
utes, although these receptors, unlike those in the
hindbrain, do not cause increased renal sympathetic
nervous activity (51).
Considerable evidence suggests that 5-HT3 recep-
tors do not contribute to central regulation of blood
pressure (47), although they are found in the carotid
body where they increase carotid sinus nerve discharge
(52), as well as on vagal afferent terminals in the
epicardium where they mediate the sympatho-
inhibitory Bezold-Jarisch reflex (53, 54).
Serotonin receptor antagonists as
proposed therapy
There has been recent interest in the use of serotonin
receptor antagonists as a therapy for various cardio-
vascular diseases, including hypertension. Ketanserin
(Fig 1 ), a highly selective 5-HT, serotonergic antagon-
ist, has been perhaps the most widely studied of these
drugs. Its vasoactive actions are complex and may
include additional a-adrenergic blocking properties.
Ketanserin: mechanisms of pharmacological
action
Blockade of 5-HT, semtonergic receptot: The majority
of ketanserin’s pharmacological activities are at-
tributed to the blockade of the 5-HT, serotonin
receptor. Many studies have documented the blood
pressure-lowering action of ketanserin through its
interference with serotonin vasoconstrictive actions.
The drug causes a decrease in peripheral vascular
resistance (17, 56). It attenuates the pressor response
that serotonin exerts on blood vessels (17, 38,56-58).
These studies have been carried out by using rats (56)
and dogs (17), as well as in human mesenteric (57),
peripheral (58), pulmonary and cardiac vessels (38,
0 The Finnish Medical Society Duodecim, Ann Med 2000; 32: 195-209
59). Ketanserin also inhibited the amplification effects
of serotonin on norepinephrine, histamine, angiotensin
I1 and PGFZain the rabbit femoral artery (17). There
is also evidence suggesting an irreversible component
to the actions of ketanserin (19, 57).
In addition to the serotonin receptors found on
endothelium and smooth muscle cells, serotonin
receptors are also located on the platelets themselves.
Ketanserin inhibits serotonin interactions also at this
level, and indirect evidence indicates that it may also
antagonize the positive feedback of serotonin on its
own release (16).
Researchers now believe that ketanserin, by
blocking the 5-HT,-mediated pressor actions of
serotonin, also unmasks unopposed 5-HT, receptor
activity, leading to vasodilation (10, 17, 60). Un-
opposed stimulation of 5-HT, receptors inhibits the
release of catecholamines stimulated from postsynaptic
adrenergic nerves (10,42).This, in turn, would reduce
a-adrenergic (constrictor) responses. Ketanserin has
even been shown to block serotonin-induced vessel
occlusion in animal models.
More recently, several novel 5-HT, antagonists have
been characterized. MC1-9042, LY 53857 and SR
46349, which are more 5-HT,-specific compounds
with negligible a,-adrenoreceptor blockade, exhibit
potent antithrombotic activity in various animal
models (61-63). These findings further strengthen the
notion that serotonin plays a vital role in platelet
aggregation and thrombus formation and suggests the
potential use of serotonergic antagonists in various
thrombotic diseases.
a-udrenevgic blockade. Not all the pharmacological
effects of ketanserin are explained by serotonin
antagonism alone. Studies have uncovered evidence
both in favour of and against a-adrenergic blocking
actions of ketanserin. The research was performed by
using both acute and chronic administration of
ketanserin in animals and humans. Following or
preceding ketanserin administration, drugs that
interact with a-adrenergic receptors were administered.
The data were subsequently interpreted to see if there
was an interaction between ketanserin and a -
adrenergic antagonist or agonist drugs, which included
the a-agonists methoxamine and phenylephrine and
the a-antagonists prazosin and phentolamine.
Studies using methoxamine seem to support a
partial a-blocking action for ketanserin, while those
using phenylephrine have shown a less definite role
for an a-blocking effect for ketanserin (59, 64-66).
Still other evidence exists for the combination of a,
and SHT, receptor blockade actions being responsible
for the acute antihypertensive action of ketanserin,
while the chronic effects may be related predominately
to the 5-HT, receptor blockade through central and
peripheral effects (67).There is also evidence sup-
 SEROTONINAND
porting a mechanism involving ketanserin-induced
reduction in cardiac preload and increased venous
compliance (68). The contribution of ketanserin’s a-
blocking activity to its hypotensive actions is still
unclear.
In contrast to the role of ketanserin in blocking the
effects of a-agonists, a-adrenergic blockers have been
assessed as to their ability to block the effects of
ketanserin. If ketanserin exerts its primary influence
by blocking a-adrenergic receptor sites, then prior
administration of prazosin, a strong a-antagonist,
should block the actions of ketanserin. When prazosin
was given prior to ketanserin infusion, it effectively
blocked the hypotensive effects of ketanserin (60).
Nelson and co-workers showed similar results when
they performed a corresponding experiment in sheep
(69).
However, evidence against the a-blocking theory
comes from work with phentolamine. When adminis-
tered prior to ketanserin in a perfused dog heart, this
a-antagonist did not interfere with ketanserin-induced
inotropic and chronotropic changes (70).
Some circumstantial evidence supporting the a-
blocking properties of ketanserin comes from studies
of its sister drug, ritanserin. Ritanserin, in vitro, is a
potent 5-HT, antagonist, clearly devoid of any a-
adrenergic blocking activity. However, this molecule
does not have antihypertensive effects in viuo,
although it may prove to be effective in treating other
conditions such as portal hypertension (71). When
administered to the spontaneously hypertensive rat
over 8 weeks, it failed to reduce blood pressure or
affect heart rate at rest or following jet air stress
induction (56). There was also no change in sub-
sequent response to prazosin.
A trial in humans by Hosie and co-workers (72)
was equally disappointing. In this trial, a single oral
dose of ritanserin demonstrated no significant effect
on blood pressure in doses sufficient to induce
measurable alterations in psychological function.
Ketanserin, however, produced significant changes in
blood pressure in these same patients.
Strong support proving that a-antagonism is not
essential for ketanserin to bring down blood pressure
comes from studying individuals with autonomic
nervous system failure. In these patients, a-blockade
(through drugs such as prazosin) has no effect on
blood pressure. Yet, ketanserin can produce hypo-
tensive actions in these patients (60).
Merely demonstrating that ketanserin manifests a-
blocking activity does not prove the primary pharma-
cological mechanism of a-receptor blocking of the
drug. As pointed out earlier, serotonin, through the 5-
HT, receptor, enhances a-activity (9).Thus, ketanserin
will show a-adrenergic attenuation through seroton-
ergic mechanisms, whether or not it directly blocks a-
receptors.
0 The Finnish Medical Society Duodecirn, Ann Med 2000; 32: 195-209
THE HEART 201
Much more research must be carried out to clarify
the relative contributions of serotonin and adrenergic
blockade in order to define clearly the mechanism of
action of ketanserin.
Central nervous system actions. As previously
discussed, serotonin may play a role in central nervous
system blood pressure regulation. The absence of
reflex tachycardia with ketanserin strongly points to
an additional pharmacological action beyond that of
pure peripheral vasodilation (73, 74). The adverse
reaction profile of ketanserin indicates that it does
penetrate the blood-brain barrier (5, 75). Further-
more, Reimann and co-workers (75) have shown
ketanserin to cause EEG slowing similar to that caused
by clonidine (a central a,-agonist). How ketanserin
affects central receptors in blood pressure regulation
and whether conventional doses of ketanserin produce
sufficient central nervous system concentrations to
produce a blood pressure-lowering effect remain to be
determined.
Studies involving infusion of ketanserin into cat
vertebral and femoral arteries suggest a central 5-HT,
receptor component to hypertension regulation (76).
However, pretreatment with atropine attenuated the
hypotensive activity of ketanserin. This is consistent
with the observation that central serotonergic path-
ways project to the nucleus of the solitary tract to
inhibit vagal outflow.
Curiously, ritanserin infusion did not produce
significant changes in blood pressure, despite its
known lipophilic nature and probable central nervous
system penetration. Ritanserin, unlike ketanserin, does
not displace [3H]-spiperone (which labels 5-HT,
receptors) from brainstem 5-HT, receptors in the rat,
and shows somewhat different binding specificities
than ketanserin, perhaps suggesting subtypes of 5-HT,
receptors (1 7).
Another explanation for the discrepancy between
ketanserin and ritanserin may relate to the former
drug’s a-blocking properties. Ketanserin may block
central a,-receptors (17), a property not shared by
ritanserin to any significant extent. Studies by McCall
and Harris (74) in cats treated with prazosin and
ketanserin strongly suggest that ketanserin mediates
its central effects via a-receptors. Finally, in human
brain tissue, [3H]-ketanserin demonstrates significant
binding to central a,-receptors in concentrations
obtained by current treatment regimens (77).
The hypothesis that the absence of reflex tachy-
cardia indicates a central effect of ketanserin has itself
been called into question. Berdeaux and co-workers
(78) studied the effect of ketanserin on the baro-
receptor reflex in normal individuals. They found that
ketanserin, even in doses capable of lowering blood
pressure in normotensive individuals, had no effect on
baroreceptor sensitivity to either hypotension induced
202 FRISHMANGREWALL
by nitroglycerin or to hypertension induced by phenyl-
ephrine. It was the opinion of the authors that the
absence of reflex tachycardia after ketanserin adminis-
tration resulted from its specificity for peripheral a,-
receptors without significant a,-blocking activity
similar to that of prazosin.
In summary, ketanserin probably displays some
central nervous system actions as it does not produce
reflex tachycardia in accordance with its hypotensive
effects. The mechanism of this central action may be
mediated either via a-adrenergic or serotonergic
receptors.
Haemodynamic effects (Table 3). Ketanserin has been
shown to lower blood pressure in both acute and
chronic treatment studies. Following intravenous in-
fusion of ketanserin, both systolic and diastolic
pressures promptly fall (59, 65, 66, 79). With chronic
use over months, no tolerance to the blood pressure-
lowering effect is observed (80).Vasodilation appears
to be the mechanism by which ketanserin lowers blood
pressure (55, 59, 60, 64, 65, 79-81) in both short-
term and long-term studies.
As a vasodilator, ketanserin increases regional blood
flow to the kidney, gastrointestinal tract, heart, brain,
bones and skin (60). Coronary blood flow does not
appear to be influenced by ketanserin therapy (59,
82). As a consequence of its vasodilator action,
ketanserin is associated with modest retention of fluid
and weight gain (approximately 1 kg) (60, 83, 84).
The greatest weight gains are seen with the more
dramatic hypotensive responses (85). Because of a
Table 3. Haemodynamic and metabolic actions of ketanserin
treatment in hypertensive patients.
Acute
Function therapy
Haemodynamic
Systemic blood pressure 1 1
Peripheral vascular resistance J1
Heart rate t*
Cardiac output 7t+*
Stroke volume t+
Pulmonary artery pressure Jt+
Pulmonary wedge pressure Jt+
Myocardial contractility tt+*
Venous capacitance 7 t
Metabolic
Plasma renin activity tt+
Plasma catecholamines t*
Plasma aldosterone t+1
Urinary Na+excretion t t+
1'= increase: 1= decrease: t+ = no apparent change;
*Reflex responses to acute vasodilation with ketanserin.
(Reproduced from (5)with permission.)
haemodilution effect, ketanserin is often found to
cause small reductions in blood hematocrit (86).
Similar to observations made with other vaso-
dilators, ketanserin can cause an increase in heart rate
with acute intravenous administration (42, 79). How-
ever, this increase in heart rate is transient and is not
seen with long-term ketanserin treatment (60, 83, 87).
Furthermore, more recent studies do not show this
reflex tachycardia even with intravenous adminis-
tration (38, 59, 60, 88, 89).
Ketanserin appears to have no effect on cardiac
output and its physiological rise with exercise (60).
Stroke volume is apparently not affected (38). Right
atrial pressure may fall modestly with acute ketanserin
usage, possibly related to venodilator actions (60, 90).
Pulmonary capillary wedge pressure may fall (pro-
bably as a result of reduced afterload) or remain at
pretreatment levels (60, 64, 65, 91, 92).
Ketanserin has no apparent direct effect on
myocardial contractility (59, 81, 93); however, there
may be an inotropic effect due to reflex sympathetic
tone (46, 92, 94, 95). The drug can lower pulmonary
artery pressure acutely (60, 86, 91), but with chronic
treatment no change in the pressure is observed (60,
64).
Essentially, ketanserin behaves as a peripheral
vasodilator with little or no direct effect on the heart.
Electrophysiological actions. One potentially adverse
effect of ketanserin is prolongation of the ECG QTc
interval. Studies of ketanserin in rats have revealed
prolongation of action potentials consistent with class
I11 antiarrhythmic activity (93). Further studies in-
volving rabbits have noted that ketanserin behaves
acutely as both a Class I and mild Class I11 anti-
arrhythmic drug, but with chronic use it displays
primarily Class I11 actions, demonstrating pro-
longation of repolarization and an increase in action
Chronic potential duration (96). It delays conduction and
therapy prolongs refractiveness by both time and voltage-
dependent mechanisms. The study concluded that
ketanserin has potential for both suppression and
aggravation of cardiac arrhythmias. Studies with
1
t+ canine myocardium also demonstrated QTc pro-
t+ longation and Class 111 antiarrhythmic effects, as well
t+ as torsade de pointes during epicardial aconitine
t+ administration (97). However, they concluded that
t+
t+
ketanserin alone was unlikely t o cause torsade de
pointes, as it did not increase arrhythmogenicity in the
absence of other factors such as hypokalaemia.
t+ Early clinical trials revealed a minor degree of QTc
t+ prolongation
- that was not believed to be clinically
t+ significant, as there was no evidence of other ECG
changes (98). Decreases in atrioventricular nodal
conduction time, sinus node recovery time and the
atrial refractory period, consistent with a reflex
increase in catecholamines, were also seen (99).
0 The Finnish Medical Society Duodecim, Ann Med 2000; 32: 195-209
 SEROTONIN
AND
Holter monitoring of patients after 1 month of
ketanserin treatment failed to reveal a correlation
between the amount of QTc prolongation and an
increase or decrease in ventricular arrhythmias. Pro-
longed QTc interval carries a risk of subsequent
torsade de pointes. Thus far, studies have not shown
increased arrhythmia-related deaths from ketanserin.
Evidence from the Prevention of Atherosclerotic Com-
plications (PACK) trial ( 100) implicates ketanserin-
induced QTc prolongation as a factor in patient
mortality. This study prospectively followed a cohort
of patients with intermittent claudication. The study
was designed to examine the possibility that ketanserin
protects against vascular morbidity. However, the
group receiving ketanserin experienced a significant
mortality excess which correlated with QTc pro-
longation. When the data were analyzed more closely,
it became apparent that the mortality was highest in
the group receiving nonpotassium-sparing diuretics. In
summary, the adverse arrhythmogenicity of ketanserin,
while probably not significant when the drug is used
as monotherapy, may potentially manifest itself when
the drug is combined with diuretics. Hypokalaemia is
known to predispose to torsade de pointes. Although
there was no documentation of torsade de pointes, the
possibility that ketanserin combined with hypo-
kalaemia leads to torsade, and sudden death, cannot
be overlooked.
Haemorheologic and antiplatelet properties of
ketanserin
Blood viscosity. Ketanserin may increase organ
perfusion because of favourable rheological effects.
Several investigators have demonstrated reduced blood
viscosity with the drug (101, 102). The drug may
increase red blood cell deformability (91), an opposite
effect from serotonin, allowing for better flow through
constricted blood vessels. Much of these favourable
haemorheologic effects could also be explained
through fluid retention and haemodilution (103).
Platelets. Ketanserin affects platelet aggregation in
response to a variety of mediators with both acute and
chronic treatment. It generally inhibits aggregation,
but not all studies show the same effect.
Several researchers have demonstrated a decrease
in serotonin-induced platelet aggregation after both
acute and chronic ketanserin treatment in patients
with either peripheral vascular disease or recent MI
(7, 86, 101, 103-105). A hypersensitive platelet
response to serotonin aggregation after the seventh
day on ketanserin has been described; this effect was
corrected by the administration of an additional dose
of ketanserin (105). This hypersensitivity suggests an
up-regulation of serotonin platelet receptors.
Epinephrine (4) and collagen-induced (86, 105)
0 The Finnish Medical Society Duodecim, Ann Med 2000; 32: 195-209
THE HEART 203
platelet aggregability are also reduced with ketanserin
treatment.
Gleerup and co-workers (106) have suggested that
a pretreatment assay of ex vivo platelet aggregation
secondary to serotonin can predict the antihyper-
tensive response to ketanserin. In their study of 12
patients with uncomplicated hypertension, the area
under the curve of ex vivo platelet aggregation
secondary to serotonin plotted before commencement
of ketanserin therapy was directly related to the
subsequent fall in diastolic blood pressure observed
during treatment with ketanserin.
Metabolic actions of ketanserin
The effects of ketanserin on the renin-angiotensin-
aldosterone axis, sodium metabolism and catechol-
amine release are summarized in Table 3; however,
much more work needs t o be performed to clarify the
role of serotonin, and thus, of ketanserin on these
systems.
Pharmacokinetics of ketanserin
Ketanserin lends itself to a simple once daily oral
dosing regimen. It is completely absorbed by the
gastrointestinal tract and is predominantly metab-
olized by the liver.
Therapeutic experiences with ketanserin
in hypertension
Ketanserin has been studied extensively as an anti-
hypertensive agent in clinical trials (4, 81, 84, 102,
107-109). For the most part, the drug has been shown
to be effective in reducing diastolic blood pressure
with less impressive efficacy in the treatment of systolic
blood pressure (81, 110). Intravenous ketanserin has
been shown to effect a decrease in blood pressure with
no associated increase in heart rate (42). The
mechanism of action for the effects of ketanserin is
theorized to be the lowering of peripheral vascular
resistance (79, 11 1).
In most placebo-controlled oral treatment studies
with ketanserin, a beneficial effect was observed when
ketanserin was used as monotherapy (60, 86) or in
combination with P-blockers or diuretics (84, 112,
113).Studies also provide evidence that ketanserin has
its greatest antihypertensive efficacy in the elderly, in
whom serotonin stimulation of the 5-HT, serotonergic
receptors may be more important than in younger
patients (4,42, 114-117). The degree of changes seen
in both systolic and diastolic blood pressures appears
to be directly related to the patient’s level of pre-
treatment blood pressure and age (118).
204 FRISHMANGREWALL
The comparison of the effects of ketanserin and p-
blockers in hypertensive patients show a mixed
picture. Studies tend to support a comparable diastolic
blood pressure-lowering effect with the two drugs;
however, greater effects on systolic blood pressure and
heart rate reduction were achieved with p-blockers.
In comparison to a-blockers, such as prazosin,
ketanserin shows a comparable blood pressure-
lowering effect. Similarly, separate studies comparing
ketanserin to hydrochlorothiazide (HCTZ) and to
the angiotensin-converting enzyme (ACE) inhibitor,
enalapril, showed ketanserin to be equally effective as
these drugs in the treatment of hypertension over 3-
month periods (114, 119). In comparison to nifedipine,
ketanserin monotherapy was not as efficacious in
normalizing blood pressure (89% normalized on
nifedipine versus 71% on ketanserin) (120). When
compared with methyldopa, ketanserin was found to
be more effective in normalizing the blood pressure of
hypertensive patients (75%versus 49%) (121).
Several studies have shown ketanserin to be useful,
and perhaps more effective in combination with either
p-blockers, ACE inhibitors, or diuretics. The diuretic-
ketanserin combination seems to be uniquely suited to
elderly patients. Additionally, ketanserin monotherapy
has been associated with an increase in weight, which,
according to some studies, negatively correlates with
efficacy. Hence, the addition. of a diuretic to ketanserin
may counteract this. Finally, the addition of a diuretic
may allow for once-daily dosage as opposed to the
more conventional twice to thrice-daily regimen.
However, as noted above, the diuretic-ketanserin
combination may have adverse electrophysiological
effects that may be of concern.
Most of the studies involving ketanserin have
examined its effects as an antihypertensive agent for
up to 3 months only. However, a few studies have
lasted for over 1 year, and, in general, report continued
antihypertensive efficacy of ketanserin after initial
responses (122, 123). Ketanserin is advantageous as
an antihypertensive agent because of its long duration
of action, once-daily dosing regimen and added
antiplatelet effects (124).
The use of ketanserin as an antihypertensive agent
for severe hypertension has also been studied. While
the results of the studies are controversial, it seems
that ketanserin should be a suitable agent for severe
hypertension in either the intramuscular or intra-
venous route, depending on symptom severity.
Intravenous ketanserin has also been used to treat
patients with hyperaldosteronism with good results in
the control of blood pressure (44).The mechanism of
action of ketanserin in this setting is unknown as
aldosterone levels were not lowered. Ketanserin may
not provide any advantage over other antihypertensive
medications in this condition. Recent evidence suggests
that in the mineralocorticoid form of hypertension,
0 The Finnish Medical Society Duodecim, Ann Med 2000; 32: 195-209
the receptor subtype mediating contraction to 5-HT in
the rat mesenteric artery switches from 5-HT,, to a
mixed 5-HT,,IS-HT,, receptor, making ketanserin
ineffective as an antihypertensive agent. This switch to
ketanserin-insensitive 5-HT, receptors is thought to
coincide with or occur just after an initial increase in
blood pressure (125). Subsequent studies have
supported this notion, revealing significant changes in
5-HT receptor signal transduction both at the level of
the receptor and G protein, resulting in an increase in
5-HT,, receptor number and hence vascular respon-
siveness in rats with this form of hypertension (126).
More recent data confirm that 5-HT,, receptor
expression is induced during the development of this
form of hypertension and contributes to the main-
tenance of severe blood pressure elevations (127).
Further investigation is necessary.
Intravenous ketanserin also appears to be a safe
and effective therapy for postpartum pre-eclampsia, at
least in its mild forms. It holds promise as peripartum
therapy, in both intravenous and oral formulations, as
it does not appear to compromise placental flow;
however, further studies are needed to confirm its
safety, particularly in the oral formularion. Recent
studies have suggested that the addition of ketanserin
to aspirin is associated with a decrease in the number
of cases of pre-eclampsia and severe hypertension in
patients with mild to moderate midtrimester hyper-
tension (128).
The use of ketanserin in intraoperative and post-
operative hypertension also requires further study.
Side-effects of ketanserin
The side-effect profile of ketanserin may relate, in part,
to its serotonergic blocking actions. Common side-
effects at high doses of ketanserin include orthostatic
hypotension and fatigue and lead to poor patient
compliance. Other observed side-effects are listed in
Table 4. The side-effect incidence with ketanserin does
appear favourable when examined in comparison with
Table 4. Side-effects reported with ketanserin in clinical
trials.
1. Postural hypotension and dizziness (probably dose related)
2. Sleep disturbances and anxiety (may be related to central
serotonergic activity)
3. Fatigue
4. Sedation
5. Xerostomia (infrequent)
6. Headache (infrequent)
7. Nasal stuffiness (infrequent)
8. Constipation and diarrhoea (rare)
(Reproducedfrom (5)with permission.)
 SEROTONIN
AND THE HEART
placebo or with other antihypertensive medications
(80, 84, 104, 114, 120, 121, 129, 130). Qualitatively,
ketanserin is associated with more sleep disturbances
and anxiety, whereas p-blockers are associated with
more complaints of depression and headache. Both p-
blockers and ketanserin share fatigue as a common
complaint.
Other cardiovascular applications of
serotonin receptor antagonists
Ketanserin, while currently not approved for use for
hypertension in the USA, has also been used in a wide
spectrum of other vascular and cardiac disorders with
varied success (Table 5 ) , as well as in non-
cardiovascular diseases (Table 6 ) .
Other possible pharmacological therapies involving
serotonin have also been considered for cardiovascular
diseases. Cinanserin, another 5-HT, antagonist, is also
being studied for its possible therapeutic applications.
It has been shown to exert profound protective effects
in two canine models of effort-induced ischaemia
(131). Long-term oral naftidrofuryl, another 5-HT2
antagonist, has been shown to be endothelium
protective in cholesterol-fed rabbits through inhibition
of cholesterol-induced neutrophil activation (132).
Further study is necessary.
While it has been established that diets rich in fish
oils are associated with a reduced risk of cardio-
vascular disease, recent data suggest that the mech-
anism for this phenomenon may involve the inhibition
of endothelial cell proliferation induced by serotonin.
5-HT, a known mitogen for vascular endothelial cells,
is often released by aggregating platelets at sites of
vascular injury. However, in cells preincubated with
eicosapentaenoic acid and docosahexaenoic acid
(omega-3 fatty acids), serotonin failed to stimulate the
proliferation of endothelial cells (133, 134). Further
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