NEURAL CONTROL OF PULPAL BLOOD FLOW

L Olgart

Department of Physiology and Pharmacology, Division of Pharmacology, Karolinska Institute!, S171 77 Stockholm, Sweden

ABSTRACT: Blood flow of mammalian dental pulp is under both remote and local control. There is evidence for the existence
of parasympathetic nerves in the pulp, but functionally the cholinergic influence is weak, and the physiological significance of
this autonomic system seems to be low. The evidence for sympathetic vasoconstrictor nerves in the pulp is robust, and there
is convincing support for the contention that these nerves play a physiological role, operating via release of noradrenaline and
neuropeptide Y. However, there is no significant functional evidence in support of sympathetic beta-adrenoceptor-mediated
vasodilation in the pulp. The local control of blood flow involves a subset of intradental sensory nerves. By virtue of their neuropeptide content, these afferent fibers cause vasodilation and inhibit sympathetic vasoconstriction in response to painful
stimulation of the tooth. Such locally governed control may serve to meet immediate demands of the pulp tissue. A locally
triggered reflex activation of sympathetic nerves in the pulp may modulate this control and limit its magnitude. Thus, there are
competitive interactions between local and remote vascular controls which may be put out of balance in the injured and
inflamed dental pulp.
Key words. Blood flow, autonomic nerves, sensory nerves, dental pulp.

Introduction
emodynamic regulation in the dental pulp has several important functions. It serves to provide optimal nutrition to pulpal cells, supports the removal of
metabolites and waste products from the tissue, and
acts to maintain a blood pressure within the vascular
tree of the pulp in harmony with the pulpal tissue pressure. The remote neural control of pre- and post-capillary muscle sphincters in the pulp may not be the most
important regulatory system. There are also local factors,
including certain nerves, which serve to balance the
exchange between blood and tissue during resting conditions or to alter an inappropriate remote signal. Local
factors may also serve to satisfy specific demands
brought about by external stimuli. The physiology of
blood-tissue interactions has previously been extensively reviewed (Heyeraas, 1985, 1990). Therefore, the aim of
this article is critically to evaluate hypotheses about
mechanisms that regulate pulpal blood flow.

Parasympathetic System
Vasodilation as mediated by parasympathetic nerves is
part of a reflexogenic reaction in many organs, e.g., nasal
mucosa, salivary glands, skeletal muscles, and skin. For
example, the reflex-evoked cholinergic transmission
leading to salivary secretion also triggers vasodilation in

7 ( 2 ) 1 5 9 - 1 7 1 (1996)

the gland to support the secretory process.

In the salivary glands, as well as in the nasal mucosa
of several species, secretion is mediated mainly by
acetylcholine (Ach), whereas blood flow, to a great
extent, is mediated by vasoactive intestinal peptide (VIP)
(Lundberg et al, 1981b,c). In these tissues, both mediators are found in parasympathetic fibers associated with
blood vessels (Lundberg et al, 1981a). The possible existence of parasympathetic vasodilation in the dental pulp
has been debated for several decades (Weiss et al, 1972;
Edwall et al, 1973; Tonder, 1976; Cauvin and Kirkendol,
1980; Okabe et al, 1989), and there is still some controversy in this matter. Previous histochemical studies
reported the presence of acetylcholine esterase, responsible for the degradation of Ach in mammalian pulps
(Pohto and Antila, 1968a, 1972; cf. Avery and Chiego,
1990). When applied locally on dog pulps, Ach triggers a
rise in pulpal blood flow (Okabe et al, 1989; Liu et al,
1990). Ach receptors have also been encountered in
porcine dental pulp (Sano et al, 1989). The existence of
specific receptors and agonist effects is not unequivocal
proof of a parasympathetic nervous influence on the
pulp. Nor is the presence of choline esterase evidence
for the presence of cholinergic nerves (Lehman and
Fibiger, 1979). The presence of the Ach-synthesizing
enzyme choline acetyl transferase (ChAT) is a more reli-

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159

70 -.
60 -

I|

Tooth stimulation (n=5)

IAN stimulation (n=4)

Lingual nerve stimulation (n=6)

50

CONTROL

ATROPINE

CHLORISONDAMINE

Figure 1. Blood flow changes in lower canine teeth evoked by

nerve stimulation in three groups of cats. Lingual nerve stimulation (10 V, 2 ms, 30 Hz) in inferior alveolar nerve-denervated animals (10 days before) (n = 6), 3 inferior alveolar nerve
stimulation (10 V, 2 ms, 5 impulses, 2 Hz) (n = 4), bipolar
electrical stimulation (100 IJLA, 5 ms, 5 impulses, 2 Hz) of the
canine tooth (n = 5). Duplicate stimulations were performed in
each animal of all groups before (control) and after administration of atropine (0.5 mg/kg) and after chlorisondamine (30
m
9,/kg). Blood flow was monitored by laser-Doppler flowmetry
(LDF). The anticholinergic drugs influenced only vasodilation
evoked by lingual nerve stimulation.

able indicator of cholinergic nerves, but studies to localize this enzyme have not been carried out on the pulp.
The other mediator (VIP), which co-exists with Ach in
post-ganglionic neurons, is released upon parasympathetic stimulation and is a candidate for mediation of the
non-cholinergic
(atropine-resistant)
vasodilation
observed in, e.g., the cat nasal mucosa and salivary
glands (Lundberg et al, 1981b,c). In oro-facial tissues,
VIP-immunoreactivity (IR) can thus be used as a marker
for parasympathetic post-ganglionic neurons. VlP-containing nerve fibers have been found in the dental pulp
of several species, including man (Uddman et al, 1980;
Akai and Wakisaka, 1990; Casasco et al, 1990; Luthman et
al, 1992), and intra-arterial injection of synthetic VIP in
the picomolar range causes vasodilation in the cat pulp
(Olgart et al, 1988). An interesting finding is that the
adjacent gingiva is sensitive to even lower doses of VIP.
Denervation experiments clearly demonstrate that the
VIP in the pulp of cats does not originate from sensory or
sympathetic nerves (Akai and Wakisaka, 1990; Olgart,
1990). However, the functional evidence for parasympathetic regulation of blood flow in the pulp is still the subject of controversy. Different results and opinions may be
partly due to differences in experimental design, techniques, and species differences.
In a preliminary study, long-lasting electrical stimulation of the lingual nerve in cats led to depletion of the

160

stores of VIP-IR in tooth pulps of ipsilateral lower canine

teeth (Gazelius and Olgart, 1989). This would suggest a
parasympathetic influence on pulpal blood flow. The lingual nerve carries parasympathetic fibers to the submandibular and lingual glands and to the tongue. An
additional finding was that a brief (30 Hz) electrical stimulation of this nerve occasionally induced a weak vasodilation in the ipsilateral lower canine pulp, provided that
nerve branches supplying adjacent tissues were cut.
Interestingly, in cats subjected to unilateral inferior alveolar nerve (IAN) neurotomy one week prior to the experiment, predictable and enhanced vasodilator responses
were obtained. The Ach antagonist atropine reduced this
response by 46%, thus leaving a remaining atropineresistant response. Chlorisondamine (an autonomic
ganglion blocker) completely blocked the remaining
response (Fig. 1). Since these experiments were carried
out under non-physiological conditions {i.e., in the
absence of sensory and sympathetic supply), complete
interpretation must await further experiments. In contrast, Sasano and collaborators recently reported experiments done on the cat which suggest that there is no
parasympathetic control of pulpal blood flow, although
such a control was shown to exist in the adjacent gingiva (Sasano et al,. 1995a, b). Electrical stimulation of facial
and glossopharyngeal nerve roots, known to carry
parasympathetic fibers, elicited hexamethonium-sensitive blood flow increases in the ipsilateral lip, but not in
the adjacent canine pulp. These results corroborate earlier histochemical studies showing the existence of
markers for parasympathetic nerves in the gingiva and lip
of the cat (Izumi and Karita, 1991, 1993; Kaji etal, 1988,
1991). The weakness or absence of signs of parasympathetic pulpal vasodilation obtained in animal experiments could possibly be due to vigorous parasympathetic vasodilation in neighboring innervated tissues which
would then "steal" perfusion pressure from the pulp
(Tonder, 1976). Experiments designed to trigger a physiological reflex activation of the autonomic nerves would
perhaps circumvent this experimental problem. Such
studies were recently carried out in conscious humans
(Aars et al, 1992, 1993; Kemppainen et al, 1994). In the
1993 study by Aars et al, the isometric hand-grip test
(used as a stress stimulus) induced a moderate rise in
pulpal blood flow which could be blocked by atropine
(Fig. 2). It is noteworthy that, after cholinergic blockade,
the identical stress stimulus resulted in a reversed effect,
i.e., vaso-constriction, suggesting that the two antagonistic autonomic systems were simultaneously activated.
It is thus possible that a concomitant vasoconstrictor
influence in adjacent tissues prevented "stealing of
blood" from the pulp, thus allowing a cholinergic vasodilation to occur in these human experiments.
Interesting information suggesting possible interaction between cholinergic and adrenergic nerves in the

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7(2):159-171 (1996)

human pulp was recently reported (Parker et al, 1995).

Adrenergic terminals in the pulp appear to be equipped
with receptors of both the muscarinic and the nicotinic
type. Agonist activation of these receptors was shown to
reduce the release of noradrenaline from activated sympathetic nerves in human dental pulp in vitro. It therefore
seems possible that cholinergic neurons in the pulp
exert a modulatory influence on sympathetic functions.
These intriguing findings call for further investigation.
In summary, all prerequisites (receptors, chemical
mediators, and nerves) for a parasympathetic control of
pulpal blood flow are present. This remote regulation
appears to have only a weak influence on pulpal blood
flow, which may explain the divergent experimental
results. The physiological significance of an existing
parasympathetic vascular control in the pulp is probably
low.

140

120

100
*-

80

10

140

Sympathetic System
The sympathetic system is involved in many vital functions, not all related to hemodynamic regulation. A
major role of the sympathetic system is the maintenance
of blood pressure. An appropriate stimulus triggers an
increase in sympathetic activity, which results in an
increase in blood pressure. This effect is generated by
vasoconstriction of arterioles in most tissues, and by
direct effects on the heart. Sympathetic vaso-constriction in the pulps and jaws is insignificant for circulatory
homeostasis, since these tissues represent a relatively
small blood volume. The sympathetic vasomotor control
of the pulp may have local importance.
There is overwhelming evidence that the pulpal
microcirculation is under the control of sympathetic
nerves. Taylor (1950), using vital microscopy, showed
that stimulation of the transsected cervical sympathetic
trunk caused a reduction of blood flow in rat incisor pulp.
This finding was later confirmed by Pohto and Scheinin
(1962), who also observed that an adrenaline solution
applied at the apical foramen of the rat incisor caused a
reduction of blood flow in the coronal pulp. Thus, constriction of vessels in and in the vicinity of the pulp caused
similar effects. The evidence that a-adrenoceptors exist
in pulpal vessels was based, in part, on the finding that
local application of noradrenaline (NA) on the exposed
pulp produced vaso-constriction (Ogilvie et al, 1966;
Ogilvie, 1967). Using histochemical and biochemical
techniques, many researchers have provided conclusive
evidence for adrenergic vasomotor innervation in the
dental pulp of several species, including man (Anneroth
and Norberg, 1968; Pohto and Antila, 1968b; Kukletova et
al, 1968; Larsson and Linde, 1971; Parker et al, 1986;
Kerezoudis et al, 1992; Luthman et al, 1992). The postganglionic fibers originate from the cervical sympathetic
ganglion, and after joining the trigeminal nerve at its
ganglion, most of them follow the course of the sensory

7(2): 1 59-1 71 (1996)

10

Time (min)
Figure 2. Experiment in human upper incisors showing the influence of atropine on changes in pulpal blood flow (upper panel)
and mean arterial pressure (lower panel) evoked by isometric
hand grip (IHG) followed by arterial occlusion of the upper arm
(OCCL). Results are expressed as percentage of baseline and
median values with 25-75 percentiles. Solid line is control
responses without atropine, and dashed line is after administration of atropine (0.015 mg/kg). * P < 0.05 compared with
baseline; ^r P < 0.05 compared with control (n = 7). Blood flow
was measured with laser-Doppler flowmetry (LDF). (Modified
with permission from Aars et al., 1993.)

nerves to the teeth and adjacent tissues in the cat and rat
(Matthews and Robinson, 1980; Marfurt et al, 1986;
Kerezoudis et al, 1995). In the rat, a small but significant
proportion of the sympathetic nerves follow another
route to the teeth, possibly traveling via the vessels
(Kerezoudis etal, 1995).
Detailed functional studies have shown that sympathetic vasoconstriction in the cat and dog pulp is mediated mainly by vascular receptors of the a,-type (Edwall
and Kindlova, 1971). These receptors are located postjunctionally, e.g., on the vascular smooth muscle cells.
Adrenoceptors of the a 2 -type are located both preand post-junctionally. Activation of pre-junctional
a 2 -adrenoceptors by NA results in a reduced aj-evoked
vasoconstriction, due to an auto-inhibitory control of NA
release from the sympathetic nerve endings. Post-junctional activation of a 2 -receptors usually results in a weak

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161

4 Hz

16 Hz

4Hz

16 Hz

-20 -

-40 -

-60 -

-80

T T

Figure 3. Effects of a 2 -, a^adrenergic blockers on pulpal blood

flow (LDF) responses in rat incisor pulp upon sympathetic nerve
stimulation (4 V, 1 ms, 4 and 16 Hz, 1 min). Responses before
and ^ after administration of the a2-adrenoceptor antagonist
idazoxan (0.5 mg/kg) and i the apadrenoceptor antagonist
prazosin (50 ixg/kg). Numbers in columns are numbers of animals; values are means SEM; * * * P < 0.001 as compared
with control responses.

vasoconstriction. Pulpal vessels in the dog, like periodontal vessels in the cat, are equipped with both a,and a2-adrenoceptors (Edwall et al, and Gazelius, 1988;
Kim et al, 1989; Ibricevic et al, 1991). The influence of
vasoconstrictor a2-receptors on blood flow in the dog
and the cat was shown to be smaller than that of
a,-receptors. Evidently, there are species differences,
since in the rat incisor the a2-adrenergic blocker idazoxan was shown not to influence sympathetic vasoconstriction (Fig. 3) (Kerezoudis etal, 1993a). The a-adrenoceptors seem to be distributed at both the arterioles and
the venules in the rat dental pulp (Kim et al, 1989). This
may mean that the remote sympathetic control can
selectively regulate the pre- and post-capillary sphincters in the pulp in order to adjust pressure in the intermediate capillary sections, as required by the tissue.
However, such selective regulation of regional flow has
not been demonstrated. There is no detailed description
about the distribution of adrenergic receptors in the
human teeth.
The influence of sympathetic activity on pulpal circulation in resting conditions seems to be low in both
animals and man. In anesthetized animals in a supine
position, cutting the sympathetic nerve or administering
an a-adrenoceptor antagonist does not alter blood flow
162

(Edwall, 1971; Heyeraas Tonder and Naess, 1978). In

seated conscious humans, mandibular block anaesthesia (mepivacain) does not change resting pulpal blood
flow, whereas it blocks stress-induced vasoconstriction
(Aars et al, 1992). The low resting level of sympathetic
activity and a low degree of autoregulation may, at least
to some extent, explain why pulpal blood flow in experimental animals under general anesthesia is very dependent on alterations in systemic perfusion pressure (Fig.
4) (see also Sasano et al, 1989). The same explanation
may be applied to the observation that, in conscious
humans resting in a comfortable chair, pulpal blood flow
decreases if the subject falls asleep. When these subjects
are abruptly awakened, pulpal blood flow instantly
increases as blood pressure and heart rate increase
(Gazelius and Olgart, unpublished). Changes in blood
pressure may also explain the increase in blood flow
observed in adolescent human pulps after physical exercise and the successive decrease as systemic circulatory
parameters normalize (Olgart, 1995). In these examples
from human recordings, the apparent absence of pressure autoregulation may, to some extent, be misleading.
It cannot be ruled out that autonomic nerves were activated, resulting in blood flow alterations overruling
autoregulation. The delicate question about the existence of autoregulation in pulpal circulation in conscious humans needs further research. At any rate, most
evidence points to the fact that the level of sympathetic
control of blood flow to the pulp in resting conditions is
low. However, in certain threatening situations, including
physical and mental stress, which cause a general activation of the sympathetic system, the neural vasoconstrictor control is also activated in the pulp (see Aars et al,
1992, 1993). This has been demonstrated in anesthetized
dogs (Heyeraas Tonder, 1975; Kim et al, 1980). In the latter study, a reflex activation of the sympathetic system
could be induced by experimental hypotension (hemorrhage and nitro-prusside infusion) or by a decrease in
oxygen transport (by hemodilution). The concomitant
reduction in pulpal blood flow was related to sympathetic vasoconstriction, since the effect was partly blocked by
an a-adrenoceptor antagonist. However, part of the
effect was also due to a fall in systemic blood pressure.
The involvement of a p-adrenoceptor-mediated
vasodilator component in the sympathetic control of
pulpal blood flow has been a matter of great controversy
(Tonder, 1976; Heyeraas Tonder and Naess, 1978;
Gazelius and Olgart, 1980; Kim et al, 1980). Although
local application of p-adrenoceptor agonists on the pulp
causes vasodilation, thereby implying the presence of
these receptors in the pulp (Okabe et al, 1989; Liu et al,
1990), there is little evidence that they have any significance in neural control. The only functional evidence for
a sympathetic nerve-induced vasodilation mediated by
P-adrenoceptors in the pulp was obtained by direct

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7(2):159-171 (1996)

tooth stimulation of the incisor in the rat (Kerezoudis et

al, 1992). The specific (3-adrenoceptor blocker, timolol,
abolished a small vasodilator response which was visible
after a-adrenergic blockade in these experiments.
However, in the same series of experiments, the authors
were unable to evoke vasodilation by stimulation of the
sympathetic nerve trunk. These results imply that the
existing (3-adrenoceptors in the pulp may not be of physiological/functional importance in the neural control of
blood flow. The possibility that the (3-receptors react to
circulating adrenaline has not found support in animal
experiments (Olgart, unpublished).
Dopamine, which is a precursor of NA, is present in
sympathetic nerves in rat incisor pulp and may be used
as a marker for these nerves in the pulp (Kerezoudis et al,
1995). It has agonistic actions on a- and p-adrenoceptors, as well as on dopamine receptors. As shown in a
recent study (Kerezoudis et al, 1995), dopamine does not
seem to contribute to neural control of pulpal vessels,
since appropriate dopamine antagonists do not influence vasoconstriction induced by sympathetic nerve
stimulation.
The fact that some vasoconstriction remains after
appropriate a-adrenoceptor blockade, particularly during high-frequency stimulation of the sympathetic supply (Heyeraas Tonder and Naess, 1978; Kerezoudis et al,
1993a) (see Fig. 3), can be explained by the presence of
neuropeptide Y (NPY) in sympathetic terminals in the
pulp of several species, including man (Uddman et al,
1984; Edwall et al, 1985; Wakisaka, 1990; Casasco et al,
1990; Luthmanetal., 1992; Heyeraas et al, 1993). The distribution of axons with NPY-IR is very similar to the distribution of axons with dopamine- p-hydroxylase, an
enzyme involved in catecholamine synthesis (see
Wakisaka, 1990). In addition, following ablation of the
superior cervical ganglion, NPY-containing axons disappear from the pulp. Intra-arterial injection of NPY in cats
causes a sustained reduction in pulpal blood flow which
is resistant to a-adrenoceptor blockade (Edwall et al,
1985). Results obtained from various other tissues in different species suggest that the release of NPY occurs
predominantly at higher frequencies of sympathetic
nerve stimulation (Lundberg et al, 1986). Since a physiologically evoked activity in post-ganglionic sympathetic
fibers shows an irregular bursting pattern (Wallin, 1981),
conditions for a complementary role of the classic (NA)
and novel (NPY) transmitters in pulpal vasomotor control are at hand. Since NA exerts pre-synaptic inhibition
on NPY release via a 2 -adrenoceptors, the use of
non-specific a-adrenoceptor blockers may enhance the
NPY-evoked component of the vasoconstriction, thus
offering an additional explanation for the resistance to
such an a-blockade.
It may be concluded that there is firm evidence for a
sympathetic vascular control in the dental pulp in many

7 ( 2 ) : 159-171 ( 1 9 9 6 )

200

CD

E 100
a.
GQ

10
8
LL

420
min

Figure 4. Simultaneous recording of blood pressure (upper

panel) and pulpal blood flow in the ferret lower canine tooth
(lower panel). Blood flow (LDF perfusion units) measured with
laser-Doppler flowmetry. Alteration in blood pressure was
induced by intravenous injection with pentobarbital (arrows, 2
+ 2 mg/kg).

species, including man. However, a reduction of blood

flow to the pulp due to sympathetic activation may also,
to various degrees, depend on the constriction of feeding
arterioles upstream, outside the pulp proper. The mediators presently known are noradrenaline and neuropeptide Y. The system does not seem to be tonically active in
oral tissues, but physical and mental stress may trigger a
sympathetic vasoconstriction in the oral tissues, including the pulp.
SYMPATHETIC MODULATION OF

LOCAL PAIN TRANSMISSION?

Sympathetic vasoconstriction in the cat dental pulp has

been shown strongly to modulate the excitability of
intradental sensory nerves (Edwall and Scott, 1971).
Thus, sensory terminals of the A-type readily lose their
normal sensitivity during pulpal ischemia (Olgart and

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163

ARTERIAL
PRESSURE
mm Hg

100

DISAPPEARANCE
RATE
k 102min'

TIME ( 4 0 s e c )
SIGNAL

Local Modulation

2001

INHIBITION OF SYMPATHETIC VASCULAR CONTROL

6.

4 hours

Figure 5. Influence of deep cavity preparation on sympathetic vasoconstrictor response in the pulp of the cat; initial response (1) and
after 4 hours (2). 1 , 2 sympathetic stimulation with 6 Hz. Pulpal
blood flow was measured with the iodide disappearance technique.
(From Forssell-Ahlberg and Edwall, 1977, with permission.)

Gazelius, 1977). A heat stimulus, which excites these

nerves under normal conditions, was shown to be without such an effect during a period of sympathetic activation. In animals, a reduction in pain sensation as a part
of the "fight and flight" reaction may appear valuable, but
for the human dental pulp, such an effect would not generally be considered useful. Extrapolated to human
teeth, fluctuations in pulpal pain intensity may be
explained, for example, by stress-induced sympathetic
vasoconstriction. Perhaps this is one reason why some
patients with pulpal symptoms find that the pain disappears on the way to the dentist. On the other hand,
increased activity in sympathetic nerves and release of
NA may result in the opposite effect, namely, direct excitation of certain sensory nerve endings. As recently
shown in experimentally induced chronic inflammation
in rat cutaneous tissue, a2-adrenoceptor-mediated sympathetic activity excites certain nociceptors (Sato et al,
1993). Therefore, a-adrenoceptors present on sensory
nerve endings may stimulate pain transmission when
activated by NA and may hypothetically contribute to
fluctuations in pain symptoms from inflamed pulps.
One critically important aspect of autonomic vasomotor regulation, and other possible functions of autonomic nerves, is that both the sympathetic and parasympathetic systems operate at the general or segmental
levels and tend to ignore the needs of an individual tissue such as the pulp. However, as we shall see, reflex
activation of sympathetic nerves to the pulp may play a
role in modulating locally triggered vascular reactions.
Furthermore, local mechanisms in the pulp may modulate the effects of the remote control.

164

Sympathetic vasoconstriction in the pulp is susceptible

to inhibition following local insults directed to the tissue. In the cat, particularly in mature teeth, deep cavity
preparation and heating or cooling of the tooth may
abolish the vasoconstrictor response to sympathetic
activation for several hours after application of the local
stimulus (Fig. 5) (Edwall, 1971; Forssell-Ahlberg and
Edwall, 1977). Nearby intra-arterial infusions of acetylcholine, histamine, bradykinin, and substance P also
counteract an ongoing sympathetic vasoconstriction
(Edwall eta!., 1973; Gazelius et al, 1977). This effect of the
vasodilator substances may somehow be related to a
local inhibition of sympathetic influence, since some of
these agents may be released under physiological conditions and in conjunction with early signs of pulp inflammation. This view is supported by observations showing
that pre-capillary sphincters become refractory to vasoconstrictor stimuli in the initial stages of inflammation
(Zweifach, 1971, 1973). It is therefore possible that
vasoactive mediators released locally in the pulp override the effects of an existing sympathetic influence. The
removal of the flow- and pressure-limiting control may
explain why the pulsating pain from pulpitis becomes
worse when a patient bends over. In such a case, pulp tissue pressure may increase uncontrolled by sympathetic
neural influence, thus activating sensitized pain receptors in the pulp.
An active sympathetic control is not necessarily a
prerequisite for local blood flow regulation. Also, in the
absence of neural vasoconstriction, basal myogenic tone
in the healthy pulp permits a pronounced vasodilation to
take place in the pulp via an increased metabolism and
local release of vasoactive substances (Edwall etal, 1973;
Heyeraas Tonder, 1980).
NON-ADRENERGIC, NON-CHOLINERGIC
VASODILATOR NERVES

A certain population of afferent (sensory) nerves in the

pulp of animals and man seems to exert vasodilator
effects in the pulp. The fibers belong to a morphologically and functionally diverse subset of sensory nerves sharing the trait of being susceptible to the stimulatory and
sensory blocking actions of capsaicin, the pungent ingredient in hot peppers (Szolcsanyi, 1984; Holzer, 1991; see
Olgart, 1996). These nerves are excited by a variety of
noxious stimuli, and they are peptidergic, small- and
medium-sized neurons associated with unmyelinated
(C) or thin-myelinated (A-delta) fibers (Janig and Lisney,
1989; Matthews and Vongsavan, 1994; Olgart, 1996).
These nerves contain vasoactive neurokinins (substance
P [SP] and neurokinin A [NKA]) and calcitonin

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7(2):159-171 (1996)

gene-related peptide (CGRP) (Olgart et al, 1977a; Akai

and Wakisaka, 1990; Luthman et al, 1992). Both SP and
CGRP are potent vasodilators in the pulp, whereas NKA
has a much smaller effect on pulpal blood flow (Gazelius
et al, 1987; Olgart, 1990). Upon activation of such nerves
in the pulp, SP is released (Olgart et al, 1977b; Brodin et
al, 1981a). After exerting its effects, SP is rapidly degraded by enzymes in the pulp tissue (Gazelius et al, 1981a).
Similar observations of release and degradation have
been made for the other neuropeptides in a number of
tissues.
Activation of sensory nerves in the pulp, either by
brief antidromic electrical stimulation of the inferior
alveolar nerve or by direct stimulation on the tooth
crown, induces a long-lasting blood flow increase in the
pulp (Heyeraas Tonder and Naess, 1978; Gazelius and
Olgart, 1980; Kerezoudis et al, 1993b). The mechanism of
this reaction in rat incisor pulp was recently shown to
involve both SP and CGRP (Kerezoudis et al, 1994a,b).
Specific antagonists were used to show that the initial
component of the response was mediated by SP, whereas the continued long-lasting rise in blood flow was
dependent on CGRP. Stimulation of the supplying nerves
or direct stimulation of the tooth crown, for several minutes, also increased vascular permeability in the pulp, as
shown by the Evans blue extravasation technique
(Kerezoudis et al, 1993c). This delayed reaction was
shown to be mediated by SP and prostaglandins. In the
neighboring gingiva, histamine is also involved.
Interestingly, only a few or single pulses are necessary to
evoke a large vasodilator response in the pulp, and it is
noteworthy that stimulation of adjacent tissues, including the lip, gingiva, and neighboring teeth, also results
in pulpal vasodilation in the canine tooth on the ipsilateral side (Olgart, 1996; Sasano et al, 1995a). An additional intriguing finding is that vasodilation is also evoked in
adjacent soft tissues by painful stimulation of human
teeth (Kemppainen et al, 1994; Kuriwada et al, 1995).
Taken together, these results indicate branching of sensory axons and suggest that there is an axon
reflex-mediated spread of vascular reactions occurring
beyond the site or tissue stimulated. This arrangement
implies that a painful stimulus directed at the tooth may
result in counteraction of an increased vascular tone,
regardless of whether the vasoconstriction is taking
place inside the pulp or in the feeding arterioles outside
the pulp.
Other stimuli of clinical relevance, like drilling and
probing of exposed dentin, application of ultrasound,
and percussion of teeth, also cause vasodilation in the
pulp, which is mediated by intradental sensory nerves
(Fig. 6) (Olgart et al, 1991; Matthews and Vongsavan,
1994). In addition, brief extensive load, causing elastic
deformation of dentin in cat teeth, evokes bursts of
impulses in intradental nerves and vasodilation in the

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100

lOG

Figure 6. Influence of grinding ( 3 x 1 s) of dentin on pulpal

blood flow in control and inferior alveolar nerve denervated
lower canine teeth of the cat. (A) At enamel-dentin junction; (B)
in inner half of dentin. Deep preparation in denervated teeth (B,
lower panel) probably caused a direct inhibition of the myogenic tone of pulpal vessels.

pulp (Olgart et al, 1988). Thus, stimuli known to cause

pain in human teeth by hydrodynamic mechanisms initiate neurogenic vascular responses in the pulp. Such an
axon reflex-mediated vasodilation is regarded as an
appropriate defense reaction which enhances the transport of nutrients and metabolites in the tissue. A further
consequence related to the sudden increase in blood
flow and volume in the encapsulated pulp tissue is an
enhanced outward dentinal fluid flow, presumably due
to the concomitant increase in local tissue pressure
(Matthews and Vongsavan, 1994). The outward dentinal
fluid flow may also play a part in local defense by protecting the pulp from invasive threats. In this context, it
is noteworthy that sympathetic vasoconstriction alters
the movement of dentinal fluid flow to an inward direction under exposed dentin surfaces of the cat (Matthews
and Vongsavan, 1994). Such a condition would be less
favorable, since it may promote transport of external irritants to the pulp. The finding that sympathetic vasoconstriction can be counteracted and reversed to a vasodilation by the local nerve-induced vasodilator mechanisms
(Kerezoudis et al, 1993a) draws attention to a valuable
interaction which may support pulpal health in certain
situations.
Indirect evidence suggests that the sensory neuropeptides can also be released without obvious stimu-

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165

Activation

Sympathetic
Nerve
Figure 7. Schematic drawing showing proposed bidirectional
interactions between remote (sympathetic) control and local
(sensory) control of pulpal blood flow. Sympathetic vasoconstriction (a) is counteracted by local activation of sensory nerves
and release of vasodilator neuropeptides (CGRP and SP) (b).
Reflex activation (c) of sympathetic nerves and local release of
NA attenuates the release of CGRP and SP (d).

lation of the tooth (Olgart and Gazelius, 1988). This

assumption was based on findings in the cat, showing
that neurotomy-induced depletion of the peptide stores
in the pulp parallels enhanced vasodilator responses to
injections with SP (Olgart et al, 1993). Interpreted as a
phenomenon of receptor supersensitivity, this finding
implies that the tachykinins, by a slow release, exert a
continuous influence on their receptors on pulpal vessels in the normal unstimulated pulp. Such a "spill-over"
of the neuropeptides, in all probability, is not associated
with any impulse propagation centrally. The chemosensitive nature of the peptidergic nerves may lead to endogenous activation by inflammatory mediators released in
the pulp. This aspect became obvious when it was found
that pulpal vasodilation in response to local application
of bradykinin occurred, to a great extent, via activation of
sensory nerves (Olgart et al, 1991). Thus, afferent nerves
in the pulp may, to various degrees, participate in
hemoregulation depending on the status of the pulp.
This view is interesting in relation to the phenomenon of
sprouting of sensory nerve terminals, and up-regulation
of the neuropeptides, observed in acute stages of pulp
inflammation (Byers and Taylor, 1990). Under such conditions, it would be expected that afferent nerves participate in the inflammatory process by an increased release
of the neuropeptides.

Sympathetic modulation of
local vascular reactions
Rat incisor teeth provide a special feature in that both
sympathetic vasoconstriction and sensory nerveinduced vasodilation may be studied in response to

166

direct electrical stimulation of the tooth crown

(Kerezoudis et al, 1992). In this model, interactions
between local and remote neurogenic control of blood
flow can be analyzed in some detail. After short trains of
electrical pulses on the tooth, a transient vasoconstriction followed by a long-lasting vasodilation is seen. After
a-adrenoceptor blockade and following acute cutting of
the sympathetic supply, the vasodilator component of
the response is significantly enhanced (Kerezoudis et al,
1993d). This implies that, when triggered, the local neurogenic control is under a sympathetic influence. The
findings also suggest that an inhibitory sensory-sympathetic reflex may be evoked by a nociceptive tooth stimulation, thus limiting the locally induced vasodilation.
Since previous in vitro experiments have shown that NA
inhibits stimulus-evoked CGRP release in bovine pulp
tissue (Engelstad et al, 1992), it appears that NA released
from sympathetic terminals exerts an inhibitory action
on sensory neuropeptide release in the pulp. The mechanism of this action of NA is probably via activation of
pre-synaptic a-adrenoceptors on the sensory nerve terminals, thus attenuating the release of the vasodilator
agents. The delayed increase in vascular permeability initiated by SP is similarly controlled by NA released from
sympathetic terminals (Kerezoudis et al, 1993a).
In summary, there is evidence to suggest the existence of mutual and competitive interactions between
the remote and local neural mechanisms controlling pulpal blood flow. A locally triggered neurogenic vasodilation may override sympathetic vasoconstriction to support local demands, and a stimulus-induced sympathetic nerve activity may limit such local control (Fig. 7).
Under physiological conditions, these counteracting
mechanisms may keep necessary control of blood flow in
balance. However, in a state of acute inflammation, when
the sympathetic function is impaired (see above), and
when there is sprouting of afferent CGRP-containing
fibers in the pulp tissue (Byers and Taylor, 1990), the
local mechanisms will apparently dominate. In such
compromised pulps, other flow-limiting factors, such as
endothelium-derived endothelins (see below) and an
increased tissue pressure, may be of importance for
recovery (Heyeraas Tonder, 1980).

OTHER MECHANISMS MODULATING

PULPAL BLOOD FLOW

There are several less-well-investigated options for

blood flow regulation in the pulp. One example is the
observation that endothelins (ET) are present in the
human dental pulp (Casasco et al, 1991). Particularly,
one subtype (ET-1) in this group of endothelium-derived
peptides exerts powerful and prolonged vasoconstrictive
effects when injected into peripheral vessels, including

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7(2): 159-171 (1996)

those of the dental pulp (Gilbert et al, 1992). Recently, it

has been suggested that ET-1 contributes to basal vascular tone, as shown in porcine pulmonary vessels
(Weitzberg et al, 1994) and in the brachial artery of conscious humans (Haynes and Webb, 1994). Local infusion
of novel, specific ET-selective receptor antagonists
caused vasodilation, implying that endogenous generation of ET-1 maintains vascular tone through activation
of ET receptors. These intriguing findings will extend our
understanding of regional blood flow regulation.
Another example of a possible mechanism modulating pulpal blood flow is the observation that somatostatin-positive nerves, probably of trigeminal origin, are
present in the pulp (Luthman et al, 1992). Injection of
pharmacologically relevant doses of this peptide in the
cat reduces the stimulus-induced release of SP (Gazelius
et al, 1981b). Parallel to this finding, somatostatin attenuates afferent nerve-induced vasodilation in the cat pulp
(Brodin et al, 1981b). Thus, if released, this neuropeptide
could play a modulatory role on local vasodilator mechanisms. However, there is as yet only limited evidence for
a functional role of somatostatin in the pulp (Olgart,
1996).
Enkephalins, present in certain pulpal cells of the
dog (Kudo et al, 1981), have been shown to reduce both
SP release and vasodilation induced by stimulation of
pulpal afferent nerves in the cat (Brodin et al, 1981b,
1983). However, such peripheral actions of these opioids
appear to be of significance primarily in tissue inflammation (Stein, 1993).
Nitric oxide (NO), which is a molecule with powerful
vasodilator capacity, is, in all probability, enzymatically
produced in certain cells in the odontoblast layer and in
vascular endothelium (Kerezoudis et al, 1993e). Under
basal blood flow conditions, NO appears to play a role in
modulating the local myogenic tone of pulpal vessels
(Kerezoudis et al, 1993b). Thus, a basal formation of NO
appears to be maintained as a consequence of the continuous enzyme activation of the endothelium, e.g., by
shear stress. Support for a role of NO in regulation of
vascular tone was obtained in studies on rat incisors and
cat canine teeth which showed that treatment with an
inhibitor of NO-synthase caused vasoconstriction
(Kerezoudis et al, 1993b; Lohinai et al, 1995). Since the
vascular endothelium continously generates both a
vasoconstrictor substance (ET) and a vasodilator agent
(NO), there are prerequisites for modulation of pulp circulation without influence of nerves. An interesting preliminary finding that we obtained in experimentally
inflamed rat pulps is that NO-synthase activity is dramatically increased in pulpal cells and endothelium as
compared with normal pulps. This is yet another example demonstrating that, in developing pulpitis, conditions for regulation of pulpal microcirculation are continuously altered and therefore are extremely difficult to

7(2):15<M71 (1996)

predict. Thus, early pulpitis is an important target for

continued studies, because, at an early stage of inflammation, there are unexplored treatment possibilities.
Therefore, we urgently need more research on how vascular reactions can be controlled and perhaps manipulated in the compromised dental pulp.

Conclusion
The remote (autonomic) neural control of pulpal blood
flow is not tonically active but is typically activated by
stress stimuli and by painful stimuli directed at almost
any part of the body. Thus, the documented effects of
sympathetic and parasympathetic nerves on pulpal
blood flow are mostly incidental and reflect a more widely spread of centrally mediated reflexes that affect much
of the body. There is no evidence for pulpal blood flow
being selectively adjusted by sympathetic or parasympathetic nerve activity to meet specific requirements of the
tissue.
Local neural control, on the other hand, operates on
a local scale. When triggered by a local stimulus (usually a painful one), a subset of intradental sensory fibers
mediates relaxation of pulpal vessels by counteracting a
myogenic or sympathetic vasoconstrictor tone. Many
other non-neural mechanisms, including endotheliumderived vasoactive principles and local tissue pressure,
also contribute to maintaining an optimal blood circulation in the normal pulp.
In the compromised pulp, the remote vasoconstrictor control is attenuated, and the delicate interplay
between local mechanisms may be put out of balance.
Blood circulation in such a pulp becomes very dependent on alterations in systemic perfusion and tissue
pressures, and this may contribute to further progress of
pulp inflammation.

Future Directions
The present knowledge about regulation of pulpal blood
flow is based mainly on results obtained in anesthetized
animals. We need critically to confirm and extend this
knowledge by studying the pulp in conscious humans.
Methods are available, such as non-invasive laserDoppler flowmetry for blood flow recording, and electrophysiological techniques for recording of nerve functions. Novel biochemical techniques should also be
applied on pulps of extracted human teeth and teeth in
situ for the tracing of alterations in the expression of
mediators of neurovascular reactions. Perhaps some of
these functional and biochemical parameters obtained
in humans will show the existence of even more complex
interactions among the many regulatory systems in the
pulp than we thought.
Circulatory control should also be further studied in
pulps with early signs of inflammation in both animals
and man. Such studies have been hampered by difficul-

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167

ties in attempts to induce inflammation in a predictable

manner. Indeed, the ultimate goal of functional studies
of the pulp is to improve diagnostic and clinical procedures in order to improve our understanding of how to
avoid insults and how to cure pulpal inflammation.
A further track to follow is continuous cooperation,
world-wide, between and among groups of scientists
using different approaches and technology in their
research, but sharing the same goal.

Acknowledgments
This review is based upon valuable collaboration with many colleagues
and students, to whom I am greatly indebted. This work was supported
by Swedish MRC Grant 00816 and Karolinska Institutet.

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