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NEURAL CONTROL OF PULPAL BLOOD FLOW
L OlgartDepartment 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 existenceof
parasympathetic nerves in the pulp, but functionally the
cholinergic influence is weak, and the physiological significance
ofthis autonomic system seems to be low. The evidence for
sympathetic vasoconstrictor nerves in the pulp is robust, and
thereis convincing support for the contention that these nerves
play a physiological role, operating via release of noradrenaline
andneuropeptide Y. However, there is no significant functional
evidence in support of sympathetic
beta-adrenoceptor-mediatedvasodilation in the pulp. The local
control of blood flow involves a subset of intradental sensory
nerves. By virtue of their neu-ropeptide content, these afferent
fibers cause vasodilation and inhibit sympathetic vasoconstriction
in response to painfulstimulation of the tooth. Such locally
governed control may serve to meet immediate demands of the pulp
tissue. A locallytriggered reflex activation of sympathetic nerves
in the pulp may modulate this control and limit its magnitude.
Thus, there arecompetitive interactions between local and remote
vascular controls which may be put out of balance in the injured
andinflamed dental pulp.
Key words. Blood flow, autonomic nerves, sensory nerves, dental
pulp.
Introduction
H emodynamic regulation in the dental pulp has sev-eral
important functions. It serves to provide opti-mal nutrition to
pulpal cells, supports the removal ofmetabolites and waste products
from the tissue, andacts to maintain a blood pressure within the
vasculartree of the pulp in harmony with the pulpal tissue
pres-sure. The remote neural control of pre- and post-capil-lary
muscle sphincters in the pulp may not be the mostimportant
regulatory system. There are also local factors,including certain
nerves, which serve to balance theexchange between blood and tissue
during resting con-ditions or to alter an inappropriate remote
signal. Localfactors may also serve to satisfy specific
demandsbrought about by external stimuli. The physiology
ofblood-tissue interactions has previously been extensive-ly
reviewed (Heyeraas, 1985, 1990). Therefore, the aim ofthis article
is critically to evaluate hypotheses aboutmechanisms that regulate
pulpal blood flow.
Parasympathetic SystemVasodilation as mediated by
parasympathetic nerves ispart of a reflexogenic reaction in many
organs, e.g., nasalmucosa, salivary glands, skeletal muscles, and
skin. Forexample, the reflex-evoked cholinergic transmissionleading
to salivary secretion also triggers vasodilation in
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 byacetylcholine
(Ach), whereas blood flow, to a greatextent, is mediated by
vasoactive intestinal peptide (VIP)(Lundberg et al, 1981b,c). In
these tissues, both media-tors are found in parasympathetic fibers
associated withblood vessels (Lundberg et al, 1981a). The possible
exis-tence of parasympathetic vasodilation in the dental pulphas
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 contro-versy in this matter. Previous
histochemical studiesreported the presence of acetylcholine
esterase, respon-sible 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 arise in pulpal
blood flow (Okabe et al, 1989; Liu et al,1990). Ach receptors have
also been encountered inporcine dental pulp (Sano et al, 1989). The
existence ofspecific receptors and agonist effects is not
unequivocalproof of a parasympathetic nervous influence on thepulp.
Nor is the presence of choline esterase evidencefor the presence of
cholinergic nerves (Lehman andFibiger, 1979). The presence of the
Ach-synthesizingenzyme choline acetyl transferase (ChAT) is a more
reli-
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70 -.
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50
I| Tooth stimulation (n=5)^ IAN stimulation (n=4) i Lingual
nerve stimulation (n=6)
CONTROL ATROPINE CHLORISONDAMINE
Figure 1. Blood flow changes in lower canine teeth evoked
bynerve stimulation in three groups of cats. Lingual nerve
stim-ulation (10 V, 2 ms, 30 Hz) in inferior alveolar
nerve-denervat-ed animals (10 days before) (n = 6), 3 inferior
alveolar nervestimulation (10 V, 2 ms, 5 impulses, 2 Hz) (n = 4),
bipolarelectrical stimulation (100 IJLA, 5 ms, 5 impulses, 2 Hz) of
thecanine tooth (n = 5). Duplicate stimulations were performed
ineach animal of all groups before (control) and after
administra-tion of atropine (0.5 mg/kg) and after chlorisondamine
(30m9,/kg). Blood flow was monitored by laser-Doppler
flowmetry(LDF). The anticholinergic drugs influenced only
vasodilationevoked by lingual nerve stimulation.
able indicator of cholinergic nerves, but studies to local-ize
this enzyme have not been carried out on the pulp.The other
mediator (VIP), which co-exists with Ach inpost-ganglionic neurons,
is released upon parasympa-thetic stimulation and is a candidate
for mediation of thenon-cholinergic (atropine-resistant)
vasodilationobserved in, e.g., the cat nasal mucosa and
salivaryglands (Lundberg et al, 1981b,c). In oro-facial
tissues,VIP-immunoreactivity (IR) can thus be used as a markerfor
parasympathetic post-ganglionic neurons. VlP-con-taining nerve
fibers have been found in the dental pulpof several species,
including man (Uddman et al, 1980;Akai and Wakisaka, 1990; Casasco
et al, 1990; Luthman etal, 1992), and intra-arterial injection of
synthetic VIP inthe picomolar range causes vasodilation in the cat
pulp(Olgart et al, 1988). An interesting finding is that
theadjacent gingiva is sensitive to even lower doses of
VIP.Denervation experiments clearly demonstrate that theVIP in the
pulp of cats does not originate from sensory orsympathetic nerves
(Akai and Wakisaka, 1990; Olgart,1990). However, the functional
evidence for parasympa-thetic regulation of blood flow in the pulp
is still the sub-ject of controversy. Different results and
opinions may bepartly due to differences in experimental design,
tech-niques, and species differences.
In a preliminary study, long-lasting electrical stimu-lation of
the lingual nerve in cats led to depletion of the
stores of VIP-IR in tooth pulps of ipsilateral lower canineteeth
(Gazelius and Olgart, 1989). This would suggest aparasympathetic
influence on pulpal blood flow. The lin-gual nerve carries
parasympathetic fibers to the sub-mandibular and lingual glands and
to the tongue. Anadditional finding was that a brief (30 Hz)
electrical stim-ulation of this nerve occasionally induced a weak
vasodi-lation in the ipsilateral lower canine pulp, provided
thatnerve branches supplying adjacent tissues were
cut.Interestingly, in cats subjected to unilateral inferior
alve-olar nerve (IAN) neurotomy one week prior to the experi-ment,
predictable and enhanced vasodilator responseswere obtained. The
Ach antagonist atropine reduced thisresponse by 46%, thus leaving a
remaining atropine-resistant response. Chlorisondamine (an
autonomicganglion blocker) completely blocked the remainingresponse
(Fig. 1). Since these experiments were carriedout under
non-physiological conditions {i.e., in theabsence of sensory and
sympathetic supply), completeinterpretation must await further
experiments. In con-trast, Sasano and collaborators recently
reported experi-ments done on the cat which suggest that there is
noparasympathetic control of pulpal blood flow, althoughsuch a
control was shown to exist in the adjacent gingi-va (Sasano et al,.
1995a, b). Electrical stimulation of facialand glossopharyngeal
nerve roots, known to carryparasympathetic fibers, elicited
hexamethonium-sensi-tive blood flow increases in the ipsilateral
lip, but not inthe adjacent canine pulp. These results corroborate
ear-lier histochemical studies showing the existence ofmarkers for
parasympathetic nerves in the gingiva and lipof the cat (Izumi and
Karita, 1991, 1993; Kaji etal, 1988,1991). The weakness or absence
of signs of parasympa-thetic pulpal vasodilation obtained in animal
experi-ments could possibly be due to vigorous parasympathet-ic
vasodilation in neighboring innervated tissues whichwould then
"steal" perfusion pressure from the pulp(Tonder, 1976). Experiments
designed to trigger a physio-logical reflex activation of the
autonomic nerves wouldperhaps circumvent this experimental problem.
Suchstudies were recently carried out in conscious humans(Aars et
al, 1992, 1993; Kemppainen et al, 1994). In the1993 study by Aars
et al, the isometric hand-grip test(used as a stress stimulus)
induced a moderate rise inpulpal 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
antago-nistic autonomic systems were simultaneously activated.It is
thus possible that a concomitant vasoconstrictorinfluence in
adjacent tissues prevented "stealing ofblood" from the pulp, thus
allowing a cholinergic vasodi-lation to occur in these human
experiments.
Interesting information suggesting possible interac-tion between
cholinergic and adrenergic nerves in the
160 Crit Rev Oral Biol Ued 7(2):159-171 (1996)
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human pulp was recently reported (Parker et al, 1995).Adrenergic
terminals in the pulp appear to be equippedwith receptors of both
the muscarinic and the nicotinictype. Agonist activation of these
receptors was shown toreduce the release of noradrenaline from
activated sym-pathetic nerves in human dental pulp in vitro. It
thereforeseems possible that cholinergic neurons in the pulpexert a
modulatory influence on sympathetic functions.These intriguing
findings call for further investigation.
In summary, all prerequisites (receptors, chemicalmediators, and
nerves) for a parasympathetic control ofpulpal blood flow are
present. This remote regulationappears to have only a weak
influence on pulpal bloodflow, which may explain the divergent
experimentalresults. The physiological significance of an
existingparasympathetic vascular control in the pulp is
probablylow.
Sympathetic SystemThe sympathetic system is involved in many
vital func-tions, not all related to hemodynamic regulation. Amajor
role of the sympathetic system is the maintenanceof blood pressure.
An appropriate stimulus triggers anincrease in sympathetic
activity, which results in anincrease in blood pressure. This
effect is generated byvasoconstriction of arterioles in most
tissues, and bydirect effects on the heart. Sympathetic
vaso-constric-tion in the pulps and jaws is insignificant for
circulatoryhomeostasis, since these tissues represent a
relativelysmall blood volume. The sympathetic vasomotor controlof
the pulp may have local importance.
There is overwhelming evidence that the pulpalmicrocirculation
is under the control of sympatheticnerves. Taylor (1950), using
vital microscopy, showedthat stimulation of the transsected
cervical sympathetictrunk 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
solutionapplied at the apical foramen of the rat incisor caused
areduction of blood flow in the coronal pulp. Thus, con-striction
of vessels in and in the vicinity of the pulp causedsimilar
effects. The evidence that a-adrenoceptors existin pulpal vessels
was based, in part, on the finding thatlocal application of
noradrenaline (NA) on the exposedpulp produced vaso-constriction
(Ogilvie et al, 1966;Ogilvie, 1967). Using histochemical and
biochemicaltechniques, many researchers have provided
conclusiveevidence for adrenergic vasomotor innervation in
thedental pulp of several species, including man (Annerothand
Norberg, 1968; Pohto and Antila, 1968b; Kukletova etal, 1968;
Larsson and Linde, 1971; Parker et al, 1986;Kerezoudis et al, 1992;
Luthman et al, 1992). The post-ganglionic fibers originate from the
cervical sympatheticganglion, and after joining the trigeminal
nerve at itsganglion, most of them follow the course of the
sensory
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10
140
4 6Time (min)
10
Figure 2. Experiment in human upper incisors showing the
influ-ence of atropine on changes in pulpal blood flow (upper
panel)and mean arterial pressure (lower panel) evoked by
isometrichand grip (IHG) followed by arterial occlusion of the
upper arm(OCCL). Results are expressed as percentage of baseline
andmedian values with 25-75 percentiles. Solid line is
controlresponses without atropine, and dashed line is after
administra-tion of atropine (0.015 mg/kg). * P < 0.05 compared
withbaseline; ^r P < 0.05 compared with control (n = 7). Blood
flowwas measured with laser-Doppler flowmetry (LDF). (Modifiedwith
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 significantproportion of the
sympathetic nerves follow anotherroute to the teeth, possibly
traveling via the vessels(Kerezoudis etal, 1995).
Detailed functional studies have shown that sympa-thetic
vasoconstriction in the cat and dog pulp is medi-ated mainly by
vascular receptors of the a,-type (Edwalland Kindlova, 1971). These
receptors are located post-junctionally, e.g., on the vascular
smooth muscle cells.Adrenoceptors of the a2-type are located both
pre-and post-junctionally. Activation of
pre-junctionala2-adrenoceptors by NA results in a reduced
aj-evokedvasoconstriction, due to an auto-inhibitory control of
NArelease from the sympathetic nerve endings. Post-junc-tional
activation of a2-receptors usually results in a weak
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4 Hz 16 Hz 4Hz 16 Hz
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T TT
fFigure 3. Effects of a2-, a^adrenergic blockers on pulpal
bloodflow (LDF) responses in rat incisor pulp upon sympathetic
nervestimulation (4 V, 1 ms, 4 and 16 Hz, 1 min). Responses
beforeand ^ after administration of the a2-adrenoceptor
antagonistidazoxan (0.5 mg/kg) and i the apadrenoceptor
antagonistprazosin (50 ixg/kg). Numbers in columns are numbers of
ani-mals; values are means SEM; * * * P < 0.001 as comparedwith
control responses.
vasoconstriction. Pulpal vessels in the dog, like peri-odontal
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 ofvasoconstrictor a2-receptors on blood flow
in the dogand the cat was shown to be smaller than that
ofa,-receptors. Evidently, there are species differences,since in
the rat incisor the a2-adrenergic blocker idazox-an was shown not
to influence sympathetic vasocon-striction (Fig. 3) (Kerezoudis
etal, 1993a). The a-adreno-ceptors seem to be distributed at both
the arterioles andthe venules in the rat dental pulp (Kim et al,
1989). Thismay mean that the remote sympathetic control
canselectively regulate the pre- and post-capillary sphinc-ters in
the pulp in order to adjust pressure in the inter-mediate capillary
sections, as required by the tissue.However, such selective
regulation of regional flow hasnot been demonstrated. There is no
detailed descriptionabout the distribution of adrenergic receptors
in thehuman teeth.
The influence of sympathetic activity on pulpal cir-culation in
resting conditions seems to be low in bothanimals and man. In
anesthetized animals in a supineposition, cutting the sympathetic
nerve or administeringan a-adrenoceptor antagonist does not alter
blood flow
(Edwall, 1971; Heyeraas Tonder and Naess, 1978). Inseated
conscious humans, mandibular block anaesthe-sia (mepivacain) does
not change resting pulpal bloodflow, whereas it blocks
stress-induced vasoconstriction(Aars et al, 1992). The low resting
level of sympatheticactivity and a low degree of autoregulation
may, at leastto some extent, explain why pulpal blood flow in
experi-mental animals under general anesthesia is very depen-dent
on alterations in systemic perfusion pressure (Fig.4) (see also
Sasano et al, 1989). The same explanationmay be applied to the
observation that, in conscioushumans resting in a comfortable
chair, pulpal blood flowdecreases if the subject falls asleep. When
these subjectsare abruptly awakened, pulpal blood flow
instantlyincreases as blood pressure and heart rate
increase(Gazelius and Olgart, unpublished). Changes in
bloodpressure may also explain the increase in blood flowobserved
in adolescent human pulps after physical exer-cise and the
successive decrease as systemic circulatoryparameters normalize
(Olgart, 1995). In these examplesfrom human recordings, the
apparent absence of pres-sure autoregulation may, to some extent,
be misleading.It cannot be ruled out that autonomic nerves were
acti-vated, resulting in blood flow alterations
overrulingautoregulation. The delicate question about the
exis-tence of autoregulation in pulpal circulation in con-scious
humans needs further research. At any rate, mostevidence points to
the fact that the level of sympatheticcontrol of blood flow to the
pulp in resting conditions islow. However, in certain threatening
situations, includingphysical and mental stress, which cause a
general activa-tion of the sympathetic system, the neural
vasoconstric-tor control is also activated in the pulp (see Aars et
al,1992, 1993). This has been demonstrated in anesthetizeddogs
(Heyeraas Tonder, 1975; Kim et al, 1980). In the lat-ter study, a
reflex activation of the sympathetic systemcould be induced by
experimental hypotension (hemor-rhage and nitro-prusside infusion)
or by a decrease inoxygen transport (by hemodilution). The
concomitantreduction in pulpal blood flow was related to
sympathet-ic vasoconstriction, since the effect was partly blocked
byan a-adrenoceptor antagonist. However, part of theeffect was also
due to a fall in systemic blood pressure.
The involvement of a p-adrenoceptor-mediatedvasodilator
component in the sympathetic control ofpulpal blood flow has been a
matter of great controversy(Tonder, 1976; Heyeraas Tonder and
Naess, 1978;Gazelius and Olgart, 1980; Kim et al, 1980).
Althoughlocal application of p-adrenoceptor agonists on the
pulpcauses vasodilation, thereby implying the presence ofthese
receptors in the pulp (Okabe et al, 1989; Liu et al,1990), there is
little evidence that they have any signifi-cance in neural control.
The only functional evidence fora sympathetic nerve-induced
vasodilation mediated byP-adrenoceptors in the pulp was obtained by
direct
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tooth stimulation of the incisor in the rat (Kerezoudis etal,
1992). The specific (3-adrenoceptor blocker, timolol,abolished a
small vasodilator response which was visibleafter a-adrenergic
blockade in these experiments.However, in the same series of
experiments, the authorswere unable to evoke vasodilation by
stimulation of thesympathetic nerve trunk. These results imply that
theexisting (3-adrenoceptors in the pulp may not be of
phys-iological/functional importance in the neural control ofblood
flow. The possibility that the (3-receptors react tocirculating
adrenaline has not found support in animalexperiments (Olgart,
unpublished).
Dopamine, which is a precursor of NA, is present insympathetic
nerves in rat incisor pulp and may be usedas a marker for these
nerves in the pulp (Kerezoudis et al,1995). It has agonistic
actions on a- and p-adrenocep-tors, as well as on dopamine
receptors. As shown in arecent study (Kerezoudis et al, 1995),
dopamine does notseem to contribute to neural control of pulpal
vessels,since appropriate dopamine antagonists do not influ-ence
vasoconstriction induced by sympathetic nervestimulation.
The fact that some vasoconstriction remains afterappropriate
a-adrenoceptor blockade, particularly dur-ing high-frequency
stimulation of the sympathetic sup-ply (Heyeraas Tonder and Naess,
1978; Kerezoudis et al,1993a) (see Fig. 3), can be explained by the
presence ofneuropeptide Y (NPY) in sympathetic terminals in thepulp
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 dis-tribution of axons with NPY-IR is
very similar to the dis-tribution of axons with dopamine-
p-hydroxylase, anenzyme involved in catecholamine synthesis
(seeWakisaka, 1990). In addition, following ablation of thesuperior
cervical ganglion, NPY-containing axons disap-pear from the pulp.
Intra-arterial injection of NPY in catscauses a sustained reduction
in pulpal blood flow whichis resistant to a-adrenoceptor blockade
(Edwall et al,1985). Results obtained from various other tissues in
dif-ferent species suggest that the release of NPY
occurspredominantly at higher frequencies of sympatheticnerve
stimulation (Lundberg et al, 1986). Since a physio-logically evoked
activity in post-ganglionic sympatheticfibers shows an irregular
bursting pattern (Wallin, 1981),conditions for a complementary role
of the classic (NA)and novel (NPY) transmitters in pulpal vasomotor
con-trol are at hand. Since NA exerts pre-synaptic inhibitionon NPY
release via a2-adrenoceptors, the use ofnon-specific a-adrenoceptor
blockers may enhance theNPY-evoked component of the
vasoconstriction, thusoffering an additional explanation for the
resistance tosuch an a-blockade.
It may be concluded that there is firm evidence for asympathetic
vascular control in the dental pulp in many
200
CDI
E
a.GQ
100
LLQ
10864-
2-0
minFigure 4. Simultaneous recording of blood pressure
(upperpanel) and pulpal blood flow in the ferret lower canine
tooth(lower panel). Blood flow (LDF perfusion units) measured
withlaser-Doppler flowmetry. Alteration in blood pressure
wasinduced by intravenous injection with pentobarbital (arrows, 2+
2 mg/kg).
species, including man. However, a reduction of bloodflow to the
pulp due to sympathetic activation may also,to various degrees,
depend on the constriction of feedingarterioles upstream, outside
the pulp proper. The media-tors presently known are noradrenaline
and neuropep-tide Y. The system does not seem to be tonically
active inoral tissues, but physical and mental stress may trigger
asympathetic vasoconstriction in the oral tissues, inclu-ding the
pulp.
SYMPATHETIC MODULATION OFLOCAL PAIN TRANSMISSION?
Sympathetic vasoconstriction in the cat dental pulp hasbeen
shown strongly to modulate the excitability ofintradental sensory
nerves (Edwall and Scott, 1971).Thus, sensory terminals of the
A-type readily lose theirnormal sensitivity during pulpal ischemia
(Olgart and
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ARTERIALPRESSUREmm Hg
2001
100 J
DISAPPEARANCE 6 .
RATEk 102min'
TIME (40sec)SIGNAL 4 hours
Figure 5. Influence of deep cavity preparation on sympathetic
vaso-constrictor response in the pulp of the cat; initial response
(1) andafter 4 hours (2). 1, 2 sympathetic stimulation with 6 Hz.
Pulpalblood flow was measured with the iodide disappearance
technique.(From Forssell-Ahlberg and Edwall, 1977, with
permission.)
Gazelius, 1977). A heat stimulus, which excites thesenerves
under normal conditions, was shown to be with-out such an effect
during a period of sympathetic activa-tion. In animals, a reduction
in pain sensation as a partof the "fight and flight" reaction may
appear valuable, butfor the human dental pulp, such an effect would
not gen-erally be considered useful. Extrapolated to humanteeth,
fluctuations in pulpal pain intensity may beexplained, for example,
by stress-induced sympatheticvasoconstriction. Perhaps this is one
reason why somepatients with pulpal symptoms find that the pain
disap-pears on the way to the dentist. On the other hand,increased
activity in sympathetic nerves and release ofNA may result in the
opposite effect, namely, direct exci-tation of certain sensory
nerve endings. As recentlyshown in experimentally induced chronic
inflammationin rat cutaneous tissue, a2-adrenoceptor-mediated
sym-pathetic activity excites certain nociceptors (Sato et
al,1993). Therefore, a-adrenoceptors present on sensorynerve
endings may stimulate pain transmission whenactivated by NA and may
hypothetically contribute tofluctuations in pain symptoms from
inflamed pulps.
One critically important aspect of autonomic vaso-motor
regulation, and other possible functions of auto-nomic nerves, is
that both the sympathetic and parasym-pathetic systems operate at
the general or segmentallevels and tend to ignore the needs of an
individual tis-sue such as the pulp. However, as we shall see,
reflexactivation of sympathetic nerves to the pulp may play arole
in modulating locally triggered vascular reactions.Furthermore,
local mechanisms in the pulp may modu-late the effects of the
remote control.
Local Modulation
INHIBITION OF SYMPATHETIC VASCULAR CONTROL
Sympathetic vasoconstriction in the pulp is susceptibleto
inhibition following local insults directed to the tis-sue. In the
cat, particularly in mature teeth, deep cavitypreparation and
heating or cooling of the tooth mayabolish the vasoconstrictor
response to sympatheticactivation for several hours after
application of the localstimulus (Fig. 5) (Edwall, 1971;
Forssell-Ahlberg andEdwall, 1977). Nearby intra-arterial infusions
of acetyl-choline, histamine, bradykinin, and substance P
alsocounteract an ongoing sympathetic vasoconstriction(Edwall
eta!., 1973; Gazelius et al, 1977). This effect of thevasodilator
substances may somehow be related to alocal inhibition of
sympathetic influence, since some ofthese agents may be released
under physiological condi-tions and in conjunction with early signs
of pulp inflam-mation. This view is supported by observations
showingthat pre-capillary sphincters become refractory to
vaso-constrictor stimuli in the initial stages of
inflammation(Zweifach, 1971, 1973). It is therefore possible
thatvasoactive mediators released locally in the pulp over-ride the
effects of an existing sympathetic influence. Theremoval of the
flow- and pressure-limiting control mayexplain why the pulsating
pain from pulpitis becomesworse when a patient bends over. In such
a case, pulp tis-sue pressure may increase uncontrolled by
sympatheticneural influence, thus activating sensitized pain
recep-tors in the pulp.
An active sympathetic control is not necessarily aprerequisite
for local blood flow regulation. Also, in theabsence of neural
vasoconstriction, basal myogenic tonein the healthy pulp permits a
pronounced vasodilation totake place in the pulp via an increased
metabolism andlocal release of vasoactive substances (Edwall etal,
1973;Heyeraas Tonder, 1980).
NON-ADRENERGIC, NON-CHOLINERGICVASODILATOR NERVES
A certain population of afferent (sensory) nerves in thepulp of
animals and man seems to exert vasodilatoreffects in the pulp. The
fibers belong to a morphological-ly and functionally diverse subset
of sensory nerves shar-ing the trait of being susceptible to the
stimulatory andsensory blocking actions of capsaicin, the pungent
ingre-dient in hot peppers (Szolcsanyi, 1984; Holzer, 1991;
seeOlgart, 1996). These nerves are excited by a variety ofnoxious
stimuli, and they are peptidergic, small- andmedium-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 (substanceP [SP]
and neurokinin A [NKA]) and calcitonin
164 Crit Rev Oral Biol Ued 7(2):159-171 (1996)
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gene-related peptide (CGRP) (Olgart et al, 1977a; Akaiand
Wakisaka, 1990; Luthman et al, 1992). Both SP andCGRP are potent
vasodilators in the pulp, whereas NKAhas a much smaller effect on
pulpal blood flow (Gazeliuset al, 1987; Olgart, 1990). Upon
activation of such nervesin the pulp, SP is released (Olgart et al,
1977b; Brodin etal, 1981a). After exerting its effects, SP is
rapidly degrad-ed by enzymes in the pulp tissue (Gazelius et al,
1981a).Similar observations of release and degradation havebeen
made for the other neuropeptides in a number oftissues.
Activation of sensory nerves in the pulp, either bybrief
antidromic electrical stimulation of the inferioralveolar nerve or
by direct stimulation on the toothcrown, induces a long-lasting
blood flow increase in thepulp (Heyeraas Tonder and Naess, 1978;
Gazelius andOlgart, 1980; Kerezoudis et al, 1993b). The mechanism
ofthis reaction in rat incisor pulp was recently shown toinvolve
both SP and CGRP (Kerezoudis et al, 1994a,b).Specific antagonists
were used to show that the initialcomponent of the response was
mediated by SP, where-as the continued long-lasting rise in blood
flow wasdependent on CGRP. Stimulation of the supplying nervesor
direct stimulation of the tooth crown, for several min-utes, also
increased vascular permeability in the pulp, asshown by the Evans
blue extravasation technique(Kerezoudis et al, 1993c). This delayed
reaction wasshown to be mediated by SP and prostaglandins. In
theneighboring gingiva, histamine is also involved.Interestingly,
only a few or single pulses are necessary toevoke a large
vasodilator response in the pulp, and it isnoteworthy that
stimulation of adjacent tissues, inclu-ding the lip, gingiva, and
neighboring teeth, also resultsin pulpal vasodilation in the canine
tooth on the ipsilat-eral side (Olgart, 1996; Sasano et al, 1995a).
An addition-al intriguing finding is that vasodilation is also
evoked inadjacent soft tissues by painful stimulation of humanteeth
(Kemppainen et al, 1994; Kuriwada et al, 1995).Taken together,
these results indicate branching of sen-sory axons and suggest that
there is an axonreflex-mediated spread of vascular reactions
occurringbeyond the site or tissue stimulated. This
arrangementimplies that a painful stimulus directed at the tooth
mayresult in counteraction of an increased vascular tone,regardless
of whether the vasoconstriction is takingplace inside the pulp or
in the feeding arterioles outsidethe pulp.
Other stimuli of clinical relevance, like drilling andprobing of
exposed dentin, application of ultrasound,and percussion of teeth,
also cause vasodilation in thepulp, which is mediated by
intradental sensory nerves(Fig. 6) (Olgart et al, 1991; Matthews
and Vongsavan,1994). In addition, brief extensive load, causing
elasticdeformation of dentin in cat teeth, evokes bursts ofimpulses
in intradental nerves and vasodilation in the
100
lOG
Figure 6. Influence of grinding ( 3 x 1 s) of dentin on
pulpalblood flow in control and inferior alveolar nerve
denervatedlower 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 myo-genic tone of pulpal vessels.
pulp (Olgart et al, 1988). Thus, stimuli known to causepain in
human teeth by hydrodynamic mechanisms initi-ate neurogenic
vascular responses in the pulp. Such anaxon reflex-mediated
vasodilation is regarded as anappropriate defense reaction which
enhances the trans-port of nutrients and metabolites in the tissue.
A furtherconsequence related to the sudden increase in bloodflow
and volume in the encapsulated pulp tissue is anenhanced outward
dentinal fluid flow, presumably dueto the concomitant increase in
local tissue pressure(Matthews and Vongsavan, 1994). The outward
dentinalfluid flow may also play a part in local defense by
pro-tecting the pulp from invasive threats. In this context, itis
noteworthy that sympathetic vasoconstriction altersthe movement of
dentinal fluid flow to an inward direc-tion under exposed dentin
surfaces of the cat (Matthewsand Vongsavan, 1994). Such a condition
would be lessfavorable, since it may promote transport of external
irri-tants to the pulp. The finding that sympathetic
vasocon-striction can be counteracted and reversed to a
vasodila-tion by the local nerve-induced vasodilator
mechanisms(Kerezoudis et al, 1993a) draws attention to a
valuableinteraction which may support pulpal health in
certainsituations.
Indirect evidence suggests that the sensory neu-ropeptides can
also be released without obvious stimu-
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Activation
SympatheticNerve
Figure 7. Schematic drawing showing proposed
bidirectionalinteractions between remote (sympathetic) control and
local(sensory) control of pulpal blood flow. Sympathetic
vasocon-striction (a) is counteracted by local activation of
sensory nervesand release of vasodilator neuropeptides (CGRP and
SP) (b).Reflex activation (c) of sympathetic nerves and local
release ofNA attenuates the release of CGRP and SP (d).
lation of the tooth (Olgart and Gazelius, 1988). Thisassumption
was based on findings in the cat, showingthat neurotomy-induced
depletion of the peptide storesin the pulp parallels enhanced
vasodilator responses toinjections with SP (Olgart et al, 1993).
Interpreted as aphenomenon of receptor supersensitivity, this
findingimplies that the tachykinins, by a slow release, exert
acontinuous influence on their receptors on pulpal ves-sels in the
normal unstimulated pulp. Such a "spill-over"of the neuropeptides,
in all probability, is not associatedwith any impulse propagation
centrally. The chemosensi-tive nature of the peptidergic nerves may
lead to endoge-nous activation by inflammatory mediators released
inthe pulp. This aspect became obvious when it was foundthat pulpal
vasodilation in response to local applicationof bradykinin
occurred, to a great extent, via activation ofsensory nerves
(Olgart et al, 1991). Thus, afferent nervesin the pulp may, to
various degrees, participate inhemoregulation depending on the
status of the pulp.This view is interesting in relation to the
phenomenon ofsprouting of sensory nerve terminals, and
up-regulationof the neuropeptides, observed in acute stages of
pulpinflammation (Byers and Taylor, 1990). Under such con-ditions,
it would be expected that afferent nerves partici-pate in the
inflammatory process by an increased releaseof the
neuropeptides.
Sympathetic modulation oflocal vascular reactions
Rat incisor teeth provide a special feature in that
bothsympathetic vasoconstriction and sensory nerve-induced
vasodilation may be studied in response to
direct electrical stimulation of the tooth crown(Kerezoudis et
al, 1992). In this model, interactionsbetween local and remote
neurogenic control of bloodflow can be analyzed in some detail.
After short trains ofelectrical pulses on the tooth, a transient
vasoconstric-tion followed by a long-lasting vasodilation is seen.
Aftera-adrenoceptor blockade and following acute cutting ofthe
sympathetic supply, the vasodilator component ofthe response is
significantly enhanced (Kerezoudis et al,1993d). This implies that,
when triggered, the local neu-rogenic control is under a
sympathetic influence. Thefindings also suggest that an inhibitory
sensory-sympa-thetic reflex may be evoked by a nociceptive tooth
stim-ulation, thus limiting the locally induced vasodilation.Since
previous in vitro experiments have shown that NAinhibits
stimulus-evoked CGRP release in bovine pulptissue (Engelstad et al,
1992), it appears that NA releasedfrom sympathetic terminals exerts
an inhibitory actionon sensory neuropeptide release in the pulp.
The mech-anism of this action of NA is probably via activation
ofpre-synaptic a-adrenoceptors on the sensory nerve ter-minals,
thus attenuating the release of the vasodilatoragents. The delayed
increase in vascular permeability ini-tiated by SP is similarly
controlled by NA released fromsympathetic terminals (Kerezoudis et
al, 1993a).
In summary, there is evidence to suggest the exis-tence of
mutual and competitive interactions betweenthe remote and local
neural mechanisms controlling pul-pal blood flow. A locally
triggered neurogenic vasodila-tion may override sympathetic
vasoconstriction to sup-port local demands, and a stimulus-induced
sympathet-ic nerve activity may limit such local control (Fig.
7).Under physiological conditions, these counteractingmechanisms
may keep necessary control of blood flow inbalance. However, in a
state of acute inflammation, whenthe sympathetic function is
impaired (see above), andwhen there is sprouting of afferent
CGRP-containingfibers in the pulp tissue (Byers and Taylor, 1990),
thelocal mechanisms will apparently dominate. In suchcompromised
pulps, other flow-limiting factors, such asendothelium-derived
endothelins (see below) and anincreased tissue pressure, may be of
importance forrecovery (Heyeraas Tonder, 1980).
OTHER MECHANISMS MODULATINGPULPAL BLOOD FLOW
There are several less-well-investigated options forblood flow
regulation in the pulp. One example is theobservation that
endothelins (ET) are present in thehuman dental pulp (Casasco et
al, 1991). Particularly,one subtype (ET-1) in this group of
endothelium-derivedpeptides exerts powerful and prolonged
vasoconstrictiveeffects when injected into peripheral vessels,
including
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those of the dental pulp (Gilbert et al, 1992). Recently, ithas
been suggested that ET-1 contributes to basal vas-cular tone, as
shown in porcine pulmonary vessels(Weitzberg et al, 1994) and in
the brachial artery of con-scious humans (Haynes and Webb, 1994).
Local infusionof novel, specific ET-selective receptor
antagonistscaused vasodilation, implying that endogenous
genera-tion of ET-1 maintains vascular tone through activationof ET
receptors. These intriguing findings will extend ourunderstanding
of regional blood flow regulation.
Another example of a possible mechanism modulat-ing pulpal blood
flow is the observation that somato-statin-positive nerves,
probably of trigeminal origin, arepresent in the pulp (Luthman et
al, 1992). Injection ofpharmacologically relevant doses of this
peptide in thecat reduces the stimulus-induced release of SP
(Gazeliuset al, 1981b). Parallel to this finding, somatostatin
atten-uates afferent nerve-induced vasodilation in the cat
pulp(Brodin et al, 1981b). Thus, if released, this
neuropeptidecould play a modulatory role on local vasodilator
mech-anisms. However, there is as yet only limited evidence fora
functional role of somatostatin in the pulp (Olgart,1996).
Enkephalins, present in certain pulpal cells of thedog (Kudo et
al, 1981), have been shown to reduce bothSP release and
vasodilation induced by stimulation ofpulpal afferent nerves in the
cat (Brodin et al, 1981b,1983). However, such peripheral actions of
these opioidsappear to be of significance primarily in tissue
inflam-mation (Stein, 1993).
Nitric oxide (NO), which is a molecule with powerfulvasodilator
capacity, is, in all probability, enzymaticallyproduced in certain
cells in the odontoblast layer and invascular endothelium
(Kerezoudis et al, 1993e). Underbasal blood flow conditions, NO
appears to play a role inmodulating the local myogenic tone of
pulpal vessels(Kerezoudis et al, 1993b). Thus, a basal formation of
NOappears to be maintained as a consequence of the con-tinuous
enzyme activation of the endothelium, e.g., byshear stress. Support
for a role of NO in regulation ofvascular tone was obtained in
studies on rat incisors andcat canine teeth which showed that
treatment with aninhibitor of NO-synthase caused
vasoconstriction(Kerezoudis et al, 1993b; Lohinai et al, 1995).
Since thevascular endothelium continously generates both
avasoconstrictor substance (ET) and a vasodilator agent(NO), there
are prerequisites for modulation of pulp cir-culation without
influence of nerves. An interesting pre-liminary finding that we
obtained in experimentallyinflamed rat pulps is that NO-synthase
activity is dra-matically increased in pulpal cells and endothelium
ascompared with normal pulps. This is yet another exam-ple
demonstrating that, in developing pulpitis, condi-tions for
regulation of pulpal microcirculation are con-tinuously altered and
therefore are extremely difficult to
predict. Thus, early pulpitis is an important target
forcontinued studies, because, at an early stage of inflam-mation,
there are unexplored treatment possibilities.Therefore, we urgently
need more research on how vas-cular reactions can be controlled and
perhaps manipu-lated in the compromised dental pulp.
ConclusionThe remote (autonomic) neural control of pulpal
bloodflow is not tonically active but is typically activated
bystress stimuli and by painful stimuli directed at almostany part
of the body. Thus, the documented effects ofsympathetic and
parasympathetic nerves on pulpalblood flow are mostly incidental
and reflect a more wide-ly spread of centrally mediated reflexes
that affect muchof the body. There is no evidence for pulpal blood
flowbeing selectively adjusted by sympathetic or parasympa-thetic
nerve activity to meet specific requirements of thetissue.
Local neural control, on the other hand, operates ona local
scale. When triggered by a local stimulus (usual-ly a painful one),
a subset of intradental sensory fibersmediates relaxation of pulpal
vessels by counteracting amyogenic or sympathetic vasoconstrictor
tone. Manyother non-neural mechanisms, including
endothelium-derived vasoactive principles and local tissue
pressure,also contribute to maintaining an optimal blood
circula-tion in the normal pulp.
In the compromised pulp, the remote vasoconstric-tor control is
attenuated, and the delicate interplaybetween local mechanisms may
be put out of balance.Blood circulation in such a pulp becomes very
depen-dent on alterations in systemic perfusion and
tissuepressures, and this may contribute to further progress ofpulp
inflammation.
Future DirectionsThe present knowledge about regulation of
pulpal bloodflow is based mainly on results obtained in
anesthetizedanimals. We need critically to confirm and extend
thisknowledge by studying the pulp in conscious humans.Methods are
available, such as non-invasive laser-Doppler flowmetry for blood
flow recording, and electro-physiological techniques for recording
of nerve func-tions. Novel biochemical techniques should also
beapplied on pulps of extracted human teeth and teeth insitu for
the tracing of alterations in the expression ofmediators of
neurovascular reactions. Perhaps some ofthese functional and
biochemical parameters obtainedin humans will show the existence of
even more complexinteractions among the many regulatory systems in
thepulp than we thought.
Circulatory control should also be further studied inpulps with
early signs of inflammation in both animalsand man. Such studies
have been hampered by difficul-
7 ( 2 ) : 1 5 < M 7 1 ( 1 9 9 6 ) Crit Rev Oral Biol Med 167
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ties in attempts to induce inflammation in a predictablemanner.
Indeed, the ultimate goal of functional studiesof the pulp is to
improve diagnostic and clinical proce-dures in order to improve our
understanding of how toavoid insults and how to cure pulpal
inflammation.
A further track to follow is continuous cooperation,world-wide,
between and among groups of scientistsusing different approaches
and technology in theirresearch, but sharing the same goal.
AcknowledgmentsThis review is based upon valuable collaboration
with many colleaguesand students, to whom I am greatly indebted.
This work was supportedby Swedish MRC Grant 00816 and Karolinska
Institutet.
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