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Endogenous vasopressin and baroreflex mechanisms
317
Bra& Research Reviews, ll(1986) 317-334 Elsevier BRR 90055
Endogenous vasopressin and barareflex mechanisms
Ke.y Iyu&: Vasopressin; Baroreflex; Ventroiateral meduibt; Nucleus tractus sahtarius; Paraventricular nucleus; Rat; Rabbit; Cat; Dog
CONTENTS “.. ,.,. . . . . . . _.. . .. ~.. . . l.. . 1II... . .. . .. . . . . . . .. . . .. .. . I _.. . ,. Id
318
....I.. *. .. . .. . . . .. .. . . . . . . .. . ss.~..,..,..........,.,., Io1........... s,...... 4,..,......,, 2, Influenceofb~~reflexstimulionv~~~re~inrelease 2.1. Anatomical identification of ascending projections from specific brain regions to the supraoptic and paraveflt~icuiar nuclei . .~,.....~,..................‘.....,...........*...........1........=..........,...............~.....,.~....,...,.*......~..............~....~. 2.2. Functional assessment of the influence, on vasopressin release, of ascending projections from specific brain regions to _.I.I ,..................,..._... 1.,......,....... f._..,.. _._..,.t..I.......I fl_j~l.._....,l..~._..I tbes~praopticandparaven~i~uIa~nu~Iei ........................................................................................................ 22.1. ~a~da~ven~rolate~~medu~la 2.2.1.1. Rabbits ........................................................................................................................ 2.2.1.2. Rats ............................................................................................................................. 2.2.1.3. Cats ............................................................................................................................. 22.2. Rostra1 ventrotateral medulla ........................................................................................................ 2.2.2.1. Rabbits ........................................................................................................................ 2.2.2.2. Rats ............................................................................................................................. _~............................ 2.2.2.3. Cats ............................................................................................... 2.2.3. Dorsomedial medulla .................................................................................................................. 2.2.3.1. Rabbits ........................................................................................................................ 2.2.3.2, Rats ............................................................................................................................. 2.2.3.X Cats ............................................................................................................................. 2.2,4. FastigialnueIeus .........................................................................................................................
319
1. Uu&-te of brtiste3n-t areas involved in modulating baroreceptor reflexes
3f9 319 313 319 321 322 323 323 323 323 323 323 323 325 325
3. Znfiuence ofendog~no~vaso~~essin on baroreflex mechanisms . . . ..~.....~~.......~..~~..~~~“....~~...~.........~~...~.~........~~~.~~~~~ Xl. Anatomize ident~fj~at~on of descending projections from the supraoptic and paraventricular nuclei to specific brain regions . .(.,... . , . ,., . . .. . . ,. , . . ...“. . .. . . . . . . , .. . .. . . . ., , . . . . . . . . . . . . . . . . . . .. . .. . .. . . . . ,. .. . . . . ., . . . . . . ...“.............................,., 3.2. Functional assessment of the influence on baroreflex mechanisms of distending projections from the supraoptic and para~entri~u~~~ nuclei to specific brain regions . . . . . . ..*....................~..~.*..**........*...................~............~‘.....*.*.. 3.2.1. Rabbits .................... ................................................................................................................. 3.2.2. Rats ........................................................................................................................................ 32.3. Cats ........................................................................................................................................ 3.2.4. Dogs .......................................................................................................................................
327 327 327 329 330
4. Summary
331
................................................................................................................................................
A~knowiedgements References
........................................................................................................................................
...................................................................................................................................................
Co~~e~~o~~e~c~; SM. Gardiner, department ham, NGT 2UH, U.K.
326 326
331 331
of Physjolo~y, Medical School, Queen’s Medical Centre, Clifton Boulevard, Not&g
31X 1. OUTLINE
OF BRAINSTEM
MODULATING
AREAS
BARORECEPTOR
INVOLVED
IN
REFLEXES
tained,
but abolished
cardic responses
the vasodepressor
to unilateral
4”,41. These findings
indicate
that the rostrai area of the VLM is important
in relay-
vagus nerve stimulation The
complexities
of the
volved in baroreceptor
neuronal
reflexes
viewed23*s7. In the present
article,
evant circuits which may influence, Baroreceptor
in-
have been well rea necessarily
plistic outline will be given, highlighting by, vasopressin
circuitry
sim-
only the rel-
or be influenced
(AVP) release. afferent
cranial nerves enter the medulla
at the level of the
obex and run in the solitary tract to terminate nucleus of the solitary tract (NTS). Efferent, vagal, preganglionic
neurones
ing baroreflex inhibitory
are situated
in the cardiac,
in the me-
dulla (in the dorsal motor nucleus of the vagus (DMX) and the nucleus ambiguus). The relative distribution of the total population of cardiac vagal neurones between these nuclei is species-dependent23, but both receive projections from the NT@“. Efferent, sympathetic, preganglionic neurones are located in the intermediolateral cell coIumns (ILC) of the spinal cord. There is no evidence for a direct connection between the NTS and the ILC (the major noradrenergic innervation of the spinal cord derives from pontine neurones with cell bodies in the A, grouph2). However, within the ventrolateral medulla (VLM) there are areas that receive projections from the NTS and which influence sympathetic preganglionic activity in the spinal cord. There are two areas within the VLM that have important effects on cadiovascular control (see review in refs. 24,76). A rostra1 site coincides, in the rat, with the location of adrenaline neurones of the C, group46. Bilateral lesions in this area have been shown to reduce heart rate and lower blood pressure (BP) to levels similar to those seen in animals with spinal cord transection25,4”‘41. The possibility that baroreceptor information may be relayed through the region has been studied. Since bilateral lesions of the C, area caused such a profound hypotension (see above), it was necessary to design the experiments in such a way that normal levels of arterial BP could be maintained prior to baroreflex testing. This was possible since vagal afferents innervate the NTS bilaterally whereas NTS projections to the C, area are unilateral. Thus lesions placed in the NTS contralateral to the side of testing and in the ipsilateral C1 area resulted in normal levels of BP being main-
information.
amino
acid (GABA),
Since application
acid transmitter
y-amino
excitatory
of the butyric
which causes hyperpolarization
bodies, had similar effects to lesioning application
fibres in the IXth and Xth
and brady-
carotid sinus stretch or
of bicuculiine
(a GABA
antagonist)
effects 26.7’. it was suggested outflow,
tonic, inhibitory,
GABAergic
There is anatomical
and normally
evidence
had
that the C,
area was involved in the tonic maintenance thetic vasomotor
of cell
the area’” and
of sympareceived
a
input from the NTS. for a projection
from
the C, area to the ILC1,‘“,78,79. but the transmitter(s~ involved in modulating sympathetic efferent outflow are unidentified. A more caudally situated area in the VLM which is involved in cardiovascular control coincides with the location of noradrenergic neurones of the A, group ” . Neurones from this region do not project diredy to the spinal cord. Lesions region did not have such a marked effect as on baroreflex responses to carotid sinus
appear to in the Ar C, lesions stretch’“.
There was, however, a transient (up to 4 h) reduction in the gain of the BP-heart period response to baroreceptor activation, and a persistent reduction in the gain of the BP-vascular resistance response to hypotensive stimuli following A, lesionsW. The cardiovascular responses to this manoeuvre are dealt with more fully in section 2.21. Electrical stimulation of the A, area caused a fall in BP which was due to withdrawal of sympathetic vasomotor tone”; application of L-glutamate (the excitatory amino acid transmitter) had a similar effect”. Thus, activity in the A, area can clearly influence sympathetic vasomotor tone, but these indirect pathways to the spinal cord have yet to be traced anatomically. There is evidence for a projection from the A, region towards the NTS”, but whether or not there are also projections to other medullary areas remains to be determined. It is feasible that the A1 region may project to the Cr area (the regions being directly juxtaposed or even mixed), and thereby inhibit sympathetic vasomotor outflow. Indeed, there is growing evidence for interactions between the Al and the C, areas”“““.
319 2. INFLUENCE
OF BAROREFLEX
STIMULI ON VASO-
of the median eminence the brainstem
PRESSIN RELEASE
though this differential 2.1. Anatomical identification of ascending projections from specific brain regions to the supraoptic and
be important,
paraventricular nuclei
magno-
siderable
In addition there
to descending are
projections
also ascending
from the
catecholaminergic
distribution
it is relevant
and parvocellular
of terminals
processes
divisions
primarily
innervate
dendritic
cated in the region of the caudal NTS and DMX) to
vasopressin
is exclusively
the paraventricular
not to cell bodiesg3.
praoptic nucleus
nucleus (PVN)“,
cell group (lopossibly the SU-
between
the
periventricu-
lar region of the PVN in the rat, the noradrenergic terminals
neurones,
from the A, noradrenaline
may
of the PVN82,83.
within the parvocellular,
non-vasopressinergic
projections
centres in
to note that there is con-
overlap of dendritic
Furthermore, NTS,
and to autonomic
and spinal cord (see section 3.1). Al-
neurones
and
processes any
input
to dendrites
on to and
(SON)96 (but see ref. 77), the parathe locus coeruleus17,80 (but see
2.2. Functional assessment of the influence, on vaso-
also refs. 61, 77) and the bed nucleus of the stria terminalis”. Interestingly, the two latter nuclei have recently been shown to contain vasopressinergic cell bodies9’. Ascending projections from the A, region terminate in the locus coeruleus17*80, the PVN and SONgl. Nerve terminals containing PNMT (phenylethanolamine-N-methyltransferase) and so, by inference, adrenaline, have been identified in the locus coeruleus, the DMX, NTS and PVN46. It has been suggested that the C, area may project to the parvocellular division of the PVN93, but firm evidence is lacking. The locus coeruleus (which coincides with the location of the A6 group of noradrenergic neurones22) also sends projections to the PVN.
pressin release, of ascending projections, from specific brain regions to the supraoptic and paraventricular
brachial
nucleu$l,
Of the 3 noradrenergic cell groups mentioned above (A,, AZ, A6) which project to the PVN, the A1 provides the greatest input (68% of the total) with the contribution from A2 being much smaller (26%) and that from A6 even less (6%)“. A similar distribution of inputs is seen in the SONgl but, since that nucleus contains fewer terminals, the inputs from A2 and A6 are minimal. The majority of the noradrenergic axons which innervate the PVN from A1 and A2 run within the ventral noradrenergic bundle (VNAB) in the ventral tegmental tract, whilst the dorsal noradrenergic bundle (DNAB) carries the projection from A6. At midbrain level, however, axons from A, in the VNAB may join the DNABgl. The A, projections terminate in the magnocellular division of the PVN and in the SONgl; it is from these areas that axons project to the posterior pituitary (see section 3.1). The A2 and A, projections terminate in the parvocellular division of the PVNsl; it is from this area that axons project to the zona externa
nuclei The majority of information cited above was obtained from histological studies. Clearly the anatomical substrate exists whereby ascending projections from A,, A, (NTS/DMX), A6 (locus coeruleus) and possibly C, might transmit cardiovascular information to the PVN and/or SON and so modulate AVP release. In addition, there may be non-monoaminergic projections from regions near the At (caudal VLM) and AZ (NTS/DMX) which influence AVP release. Below are detailed the relevant functional studies concerned with this topic. 2.2.1. Caudal ventrolateral medulla (A,) 2.2.1.1. Rabbits. In the first report on the effects of lesioning the A, area in rabbitst3, lesions were placed, bilaterally, at 3 levels (at the level of the obex, 1 mm caudal and 2 mm caudal). The lesions were placed under halothane anaesthesia and cardiovascular variables were monitored whilst the animals regained consciousness. It was shown that following the lesions, hypertension developed; there was an increase in distal aortic vascular resistance, and heart rate slowed. The bradycardia reached a peak sooner than the hypertension (30 min and 40 min postlesion, respectively) suggesting that it was not solely a baroreflex response to the rise in BP. Within 2 h after the lesioning, BP and heart rates had returned to control levels, but distal aortic vascular resistance remained high. In surviving animals, BP and heart rates were still apparently normal two weeks later, but vascular
320
resistance
in the distal aorta was 70% higher than the
of similar magnitude
to that seen in animals with the
control value. For this to be the case. either regional
spinal cord intact. Plasma AVP levels rose (twice as
haemodynamic changes must have occurred to offset the elevated resistance in the distal aorta. or stroke
high as in the intact
volume
tion of a vasopressin
(and hence cardiac output)
reduced.
In an accompanying
that the vascular by a-adrenoceptor
resistance
paper”” it was shown changes
antagonism
amine and it was suggested neurones
inhibit
vasomotor
response
were abolished
with phenoxybenz-
that lesions placed in the
A, area destroyed sympathetic
must have been
that normally
to the intervention
acted to
tone. The heart rate was further
analyzed
and it was proposed that there were two components - one dependent on, and one independent of, baroreceptors”.
In addition
to the bradycardia
there was
a temporary reduction in the cardiac reflex responses to rises and falls in mean arterial pressure. It was proposed that the lesions had destroyed two populations of neurones (the identity of which is obscure) that had opposing actions on heart rate. The bradycardia was thought to be due to the destruction of neurones that normally acted independently of arterial baroreceptors, to inhibit cardiac slowing. The reduced baroreflex sensitivity was thought to be due to destruction of neurones that normally participate in baroreflexes to facilitate cardiac slowing in response to increases in pressure’. This does not. however, explain the fact that the tachycardic response to falls in pressure was also blunted. the heart rate responses
Thus it would appear that to A, lesioning
require
fur-
ther investigation (see below). The possible involvement of AVP in the cardiovascular responses to lesions of the A, area was investigated by the same group in a later study”. This, now well-cited paper, showed that A, lesioning, or administration of kainic acid into the A, area (to cause depolarization blockade), increased plasma AVP levels 6-fold. Further experiments were done to determine whether or not AVP in the plasma was responsible for the hypertension (although it had been shown earlier that phenoxybenzamine abolished the hyperwhereas this drug enhances sensitivity to tension”. AVP’“). In the first experiment, urethane-anaesthetized animals were spinally transected, to remove any sympathetic vasomotor efferent influence. ‘Normal’ BP was maintained by i.v. infusion of noradrenaline, and then kainic acid was applied to the A, area. Under those conditions there was a pressor response
animals)
sponse was completely
and the pressor
abolished
(V,) receptor
by i.v. administraantagonist,
are, however. problems with the interpretation these data indicate the elevation in plasma ‘causes the hypertension”’
rc-
There that AVP
which follows destruction
of the A, area. Since the animals were spinally transected,
normal
baroreflex
buffering
mechanisms
which might serve to offset a pressor action of AVP” would
have been
adrenaline
absent.
Furthermore.
since nor-
and AVP may act synergistically”.
the in-
fused noradrenaline may have enhanced the pressor action of AVP. The fact that plasma AVP rose twice as high in the animals with spinal cord transection presumably indicates that the operation had interfered with neural pathways that normally operate to reduce plasma AVP levels when BP rises. In a further experiment”, rabbits were briefly anaesthetized with halothane whilst lesions were placed in the A, area and the animals were then allowed to recover. Once the hypertension had developed (mean BP increased by 42 mm Hg). administration of a V, antagonist caused a 19 mm Hg reduction in mean BP. The results of that study” were taken to support the hypothesis”‘.75 that noradrenergic neurones from the A, area ‘tonically inhibit activity of AVP-secreting neuroendocrine cells’. But very recently, one of the authors has retracted that statement on the basis of new evidencelJ. In urethaneanaesthetized rabbits. ‘blockade’ of the A, area by application of tetrodotoxin increased BP (and increased heart rate) but was without effect on plasma AVP levels. Blessing and Willoughby” suggested that in the earlier experiments (see above) the electrolytic lesions had caused excitation rather than inhibition of activity in fibres ascending from A, to PVN. The new proposal, i.e. that fibres from the A, exert an excitatory, rather than an inhibitory, influence on AVP release. is consistent with the observation that the GABA-antagonist, bicuculline, administered into the A, region (i.e. a manoeuvre assumed to be comparable to A, stimulation) elevated plasma AVP8*. In support of the new proposal. Blessing and Willoughby’4” very recently showed that high doses of L-glutamate (lo-100 nmol) injected into the A, region increased plasma AVP levels, even when the
321 concomitant fall in BP was prevented. A lower dose of L-glut~ate (1 nmol) did not affect plasma AVP although it did lower BPL4”.The latter observation was also reported by Sved et al.89. However, these authors drew attention to the possibility that high doses of L-glutamate may diffuse into the rostra1 VLM and exert an effect at that site@. Finally, it still remains to be explained why in the earlier study”, administration of kainic acid into the A, region (in a schedule designed to cause blockade, not excitation) caused plasma AVP levels to rise. If, as is now suggested, efectrolytic lesioning caused excitation of a pathway ascending to the PVN, the question arises whether or not it also caused excitation of a pathway which influenced sympathetic vasomotor outflow, i.e. activated a pressor mechanism rather than inhibited tonically active depressor neurones. This would seem unlikely, however, since tetrodotoxin had similar effects on BP to electrolytic lesioning, Thus it appears that the latter intervention can have differential effects on populations of neurones within the A, area, causing excitation of those projecting to the hypothalamus and inhibition of those influencing sympathetic vasomotor tone. Indeed, a very recent paper from these authors89 provides some evidence to support this possibility. In that study, surprisingly, lesioning of the A, region caused a rise in plasma AVP levels, but failed to alter BP, whereas administration of muscimol (a GABA-agonist) elevated BP in the absence of a change in plasma AVP levels. Furthermore, bicuculline (a GABA-antagonist) caused a rise in plasma AVP, even when the associated fall in BP was prevented, and L-glutamate caused BP to fall without changing plasma AVP (see above). The conclusion from that study was that AVP and BP responses to manipulation of the caudal VLM do not always parallel each other, and that BP responses were largely a function of sympathetic outflow. However, the suggested reason for the failure of the lesioning experiments to cause hypertension was, nonetheless, that the associated AVP response was less than seen previously’2. It remains to clarify why different procedures designed to ‘block’ the A, region appeared to have different effects on heart rate. Thus, electrolytic lesions resulted in bradycardia accompanying the hypertension13**, whereas blockade with tetrodotoxin14or inhibition with GABA” resulted in a tachycar-
dia together with hypertension. In addition to the possibility of differential effects of lesioning on populations of neurones (discussed above), another consideration is that in the experiments using tetrodotoxin or GABA, the animals were anaesthetized, whereas in the experiments which involved lesioning measurements were made in the conscious state. The bradycardia which occurred in the conscious animals was shown to have a ‘baroreceptor-dependent’ component and a ‘baroreceptor-independent’ component, and AVP was suggested as a possible mediator of the latter*. In the experiments where tetrodotoxin was given into the A, region of anaesthetized animals, it is feasible that the anaesthetic had impaired baroreceptor reflexes. Hence, the rise in BP, which occurred without a change in plasma AVP, would not have been accompanied by either component of the bradycardia which occurred in the conscious lesioned animals; an underlying tachycardic response to the procedure may therefore have been unmasked. To summarize, it appears that a number of questions need to be answered before any conclusive statements can be made regarding the influence of the A, region on AVP release and cardiovascular control in rabbits. For example: (1) why are the changes in BP and heart rate which follow A, lesioning transient? (2) are there both excitatory and inhibitory influences from the A, region on AVP release? (3) what are the transmitters involved? (4) are central vasopressinergic mechanisms influenced by the A, region? (5) does AVP, released either centrally or peripherally, contribute to the alterations in baroreflex sensitivity which follow A, lesioning? (6) does lesioning or stimulating the A, region modify the changes in plasma AVP levels which follow baroreceptor unloading? Since the first draft of this review was written, we have been given a pre-print of a paper which directly addresses our last question. In that study, Blessing and Willoughby’4b showed that injection of the GABA-agonist, muscimol, into the Ai region in rabbits, completely abolished the rises in plasma AVP caused by either haemorrhage or constriction of the inferior vena cava. 2.2.1.2. Rats. It has been shown that lesioning the Ai region in rats caused a transient hypertension and
322 bradycardia6’. Plasma AVP levels were elevated, but appeared not to contribute indispensably to the hypertension since an equally large rise in BP occurred following A, lesioning ic AVP (Brattleboro
in rats which lack hypothalamrats) as in normal (Wistar-Kyo-
to; WKY) rats. Interestingly, the hypertension periment
persisted
(180 min)
in the Brattleboro for the duration
whereas
peaked 70 min after lesioning possible,
therefore,
hypertension different
of the ex-
in the WKY
rats it
and then waned6’. It is
that the underlying
cause of the
differed in the two strains. Indeed,
report”
in a
it was shown that adrenalectomy
two days prior to the lesioning sive response
rats,
in Brattleboro
reduced the hypertenrats, but not in the con-
trol rats. That study showed the BP response to A, lesioning in rats could be completely prevented by combined adrenalectomy and sympathectomy (with 6-OHDA) but under those conditions, the heart rate response was unaffected. It was suggested that the BP response was largely due to sympathetic efferent activity whereas AVP might be important in mediating the bradycardia, since the change in heart rate in the Brattleboro rats (31% reduction) was less than in the WKY rats (50% reduction). But inspection of the data from the first report” reveals that the absolute changes in heart rate in the two strains (WKY -136 beats/mitt; Brattleboro -132 beatsimin) were almost identical; the difference (in percentage terms) was due to the Brattleboro rats having a resting tachycardia. The rise in plasma AVP which occurred following A, lesioning in the WKY rats was cautiously interpreted as reflecting either the removal of a tonic inhibitory influence on AVP release, or stimulation of AVP-containing cells in the hypothalamus”. From the available electrophysiological evidence it appears that the latter suggestion may be the more likely. Day et al. 27 showed that stimulation of the A, region in rats caused excitation in 42% of PVN neurons tested (the others were unresponsive). Eight of the ceils were identified as being ‘vasopressinergic’ (on the basis of phasic firing patterns and inhibition by baroreceptor activation) and of the 8, 7 were excited by A, stimulation. ‘Oxytocinergic’ cells were also identified (being continuously active and unaffected by baroreceptor activation) and none of those was influenced by A, stimulation*‘. A similar phenomenon was observed in studies on cells in the SON**. It was shown that treatment with 6-OHDA (centrally) abol-
ished the responses tion, indicating noradrenaline.
of SON neurones
that the transmitter
Kubo et al.“‘obtained
to A, stimulainvolved
may be
further evidence for an exci-
tatory influence, on AVP release, of neurones in the caudal VLM in rats. In their study, however, the area of interest
was defined
as being just ‘below’ the A,
area (the precise coordinates tion of L-glutamate cord transection
Injec-
into that region in rats with spinal
caused a rise in BP which was abol-
ished by peripheral nist. Application
were not given).
administration
of a V, antago-
of kainic acid into those sites which
had evoked pressor
responses
blocked
the response
to L-glutamate but had no persistent effect on ‘resting’ BP; this indicates that the excitatory input to AVP secreting neurones was not tonically active. Kubo et al.s4 also found evidence for a possible involvement of the glutamate-sensitive area in the cauda1 VLM in relaying influences on AVP release from the NTS (see section 2.2.3.2.). In addition to a possible excitatory pathway ascending from the caudal VLM to the PVN and SON, recent data have been interpreted as showing a tonically active, inhibitory, noradrenergic, projection from the A, region to the PVN’06. Knife cuts were placed in the dorsal medulla to transect afferent and efferent projections to and from the DMXiNTS region at the level of the obex. This operation produced a rise in BP, heart rate and plasma AVP levels and there was evidence of a decrease in the activity in ascending catecholaminergic projections from the A, area to the PVN. On the basis of those findings, the authors proposed a scheme in which the experimental procedure had interrupted a tonic inhibitory noradrenergic influence on AVP release, but clearly the knife cuts would have lesioned many different pathways, making the interpretation of the study difficult 2.2.1.3. Cats. Feldberg and Rocha E Silva’4.“5 delineated two areas in the VLM of the cat that were involved in cardiovascular control mechanisms; the more caudally situated area corresponded with the region of the A, cell bodies. Application of the amino acids, GABA or glycine, to that area did not affect resting BP or plasma AVP levels and did not influence the pressor response to bilateral occlusion of the carotid arteries, but did inhibit the rise in plasma AVP levels which normally accompanied the latter
323 manoeuvre3s. It was concluded that some barorecep tor afferents reaching the ventral surface of the medulla synapsed at this caudal site (situated at the transition between the medulla and spinal cord) and, through mediation of a synaptic transmitter that was an inhibitory amino acid, caused suppression of AVP release. Bilateral carotid occlusion, by ‘unloading’ the arterial baroreceptors, thus caused a removal of the ‘amino acid brake’ and hence permitted AVP release3’. Although this study could be criticized on methodology (bioassay of AVP, large baseline variability, pentobarbitone anaesthesia), it is almost the only work (but see also ref. 14b) which has assessed the effects of interfering with regions in the caudal VLM on AVP release in response to baroreceptor unloading. 2.2.2. Rostra1 ventrolateral medulla (C,) As mentioned in a previous section (l), the rostra1 area of the VLM is generally thought to be a pressor area that relays baroreceptor afferent information from the brainstem to the spinal cord. Although there is some evidence that projections ascend from the rostra1 VLM to the PVNy3, there is little information on the influence of this region on pituitary AVP release. Indeed, since it appears that the projections from C, to PVN may terminate in the parvocellular division of the nucleusy3, which does not contain cells projecting to the posterior pituitarys6, then there is no reason for supposing that this pathway might be involved in affecting release of AVP into plasma. Adrenergic terminals have, however, been localized in the magnocellular division of the PVN46. 2.2.2.1. Rabbits. To our knowledge there have been no studies in rabbits of the influence of the rostral VLM on AVP release. 2.2.2.2. Rats. The rostra1 VLM area in the rat coincides with the location of the adrenaline-containing cell bodies of the C1 area46. Stimulation of that region in chloralose-anaesthetized animals79 was shown to elicit an increase in BP, a variable heart rate response (mostly tachycardia), and an increase in plasma levels of noradrenaline, adrenaline, dopamine and AVP (Zfold). The rise in AVP was greater (5 fold) when the increase in BP was largely prevented by sectioning the spinal cord; under those conditions the small rise in BP that occurred was abolished by peripheral administration of a V, antagonist79. The
greater increase in plasma AVP levels in the spinally transected animals indicates that interference with the C, area in the intact rats had not abolished a baroreceptor-mediated inhibitory effect on AVP release. The pathways involved in the effects of Ci stimulation on AVP release are unknown. Since adrenalinecontaining neurons in this area do not project to the magnocellular division of the PVN (see above) it is likely that any adrenergic pathway is an indirect one; alternatively, the pathway may be non-catecholaminergic. It is not known whether or not lesioning the C, area influences AVP responses to baroreceptor unloading in rats. 2.2.2.3. Cats. In addition to the caudal site in the VLM (described above), Feldberg and his colleagues3’ identified a more rostra1 area that may be analogous to the site described above in rats. They showed that application of GABA or glycine to the rostra1 VLM in the cat reduced resting BP and the pressor response to bilateral occlusion of the carotid arteries, but did not influence the rise in plasma AVP that followed the manoeuvre. They concluded that some baroreceptor afferents reaching the ventral surface of the medulla synapsed at this rostra1 site and, through the mediation of an inhibitory aminoacid transmitter, caused suppression of sympathetic tone, without affecting AVP release. (Incidentally, it is interesting that the pressor response to bilateral carotid occlusion was reduced when plasma AVP levels were unaffected, since this is contrary to other reports showing a major contribution from AVP to the pressor response elicited by occlusion of the carotid arteriess3.) To summarize the available evidence, it appears that the rostra1 VLM is involved in the baroreflex modulation of sympathetic tone (affecting AVP release minimally, or not at all) whilst the caudal VLM is involved in modulating AVP release into plasma; whether or not the latter area has both excitatory and inhibitory influences remains to be determined. 2.2.3. ~orsomed~a~ medulla 2.2.3.1. Rabbits. To our knowledge there have been no studies directly concerned with the influence of the NTS region on AVP release in rabbits. 2.2.3.2. Rats.. Several years ago it was shown that electrolytic lesions placed bilaterally in the intermediate third of the NTS in halothane-anaesthetized
324 rats
resulted
started
in
fulminating
hypertension
once the administration
been terminated”*. with a reduction
The hypertension
adrenalectomy
(i.e. normalized
ied”.
with
that the
of an inhibitory
ence from the NTS on sympathetic More recently,
combined
the hypertension
BP) and so it was concluded
rise in BP was due to removal
hypertension
but no change in
with 6-OHDA abolished
had
was associated
in cardiac output,
heart rate. Treatment bilateral
which
of anaesthetic
efferent
a possible involvement
influ-
outflow.
of AVP in the
caused by NTS lesions has been stud-
It was shown that in chloralose-anaesthetized
rats, lesions in the NTS caused a pressor response,
a
tachycardia, and a rise in plasma AVP levels”. The 3 events, however, were dissociated inasmuch as the pressor response peaked within 10 min of lesioning, the plasma AVP levels peaked 20 min after the lesioning, and heart rate increased progressively throughout the 60-min period of measurement. Ten min after the operation, when plasma AVP levels had risen from 16 to 80 pg/ml, and BP had increased by 56 mm Hg, administration of a V, antagonist lowered BP by 32 mm Hg, whereas it was without effect in rats which had received sham-lesions and were normotensive”. In the same series of experiments it was shown that lesioning the NTS caused equally large increases in BP (49 mm Hg) in rats which had been pretreated with a ganglion blocker, but under those conditions, treatment with the V, antagonist completely reversed the hypertension and, in fact, rendered the animals hypotensive”‘. The complication with those experiments, however, is that following ganglion blockade, BP was ‘normalized’ by the administration of phenylephrine. Sved and his colleagues” also included a series of experiments in conscious animals. (The experimental procedures, however, required the animals to be anaesthetized with halothane twice within a 2-h period). In those animals (as in the earlier description of the phenomenon3*) BP only began to rise in the rats with NTS lesions 1.5 min after termination of the anaesthesia, i.e. at a time when BP had reached its peak in the chloralose-anaesthetized rats. Sixty min later, plasma AVP levels were elevated (245 pgiml), BP had risen by 69 mm Hg, and administration of a V, antagonist caused BP to fall by 41 mm Hg. Thus, in the chloralose-anaesthetized, and in the conscious state, AVP may contribute directly to the
hypertension a subsequent
induced by lesioning study.
the NTS in rats. In
Sved”” showed
that treatment
with a ganglion blocker, after the induction of the hypertension, completely reversed the elevation in BP but did not affect the plasma AVP level or the subsequent response to the V, antagonist, i.e. ganglion blockade rendered the animals ‘normotensive’ and addition of the V, antagonist then caused hypotension. In that study, clonidine was shown to markedly reduce the elevated
plasma AVP levels in rats with
NTS lesions and to blunt the subsequent
response
to
the V, antagonistgo. The sites and mechanisms of this effect of clonidine require further investigation. The conclusion
from these recent studies was that
both the sympathetic nervous system and AVP contribute to the hypertension which follows bilateral lesioning of the NTS in rats”‘.“. Quantitation of the relative inputs from the two systems is difficult since combined blockade renders the animals hypotensive. If a ganglion blocker is given prior to the lesioning it appears that the contribution from AVP is enhanced, whereas treatment with a ganglion blocker after the lesions have been placed lowers BP, but does not appear to affect the contribution from AVP to the maintenance of BP. (The possibility that following acute hypotension elicited by ganglion blockade, activity in the renin-angiotensin system may contribute to BP maintenance38 has not been addressed.) The above-mentioned results are consistent with an inhibitory influence of the NTS region on AVP release, as are the results of Kubo et a1.5”. They showed that injection of kainic acid into the NTS (to cause depolarization blockade) evoked a pressor response in pentobarbital-anaesthetized rats with spinal cord transection. The pressor response was abolished by peripheral administration of a V, antagonist and was reduced (but not abolished) by blockade of the glutamate-sensitive cells in the caudal VLM (see section 2.2.1.2.). Kubo et a1.‘4 suggested that blockade of the NTS region had removed a tonic inhibitory influence on AVP release, transmitted partly via the glutamate-sensitive neurons in the caudal VLM. Since the response of plasma AVP to NTS blockade was not abolished by the application of kainic acid to the caudal VLM, it is likely that other inhibitory projections may ascend from the NTS; whether these are direct or indirect remains to be determined. In addition to an inhibitory influence of the NTS
325 region on AVP release, there is evidence for an excitatory influence. Thus, electrical stimulation of the intermediate portion of the NTS and DMX area in halothane-anaesthetized rats with spinal cord transection elicited a rise in BP@ and an elevation in plasma AVP 1eve1s’“; the pressor response was reversed by i.v. administration of a V1 antagonist and did not occur in Brattleboro rats69. (It is interesting to note that these findings are entirely consistent with the much earlier studies done in dogs* in which it was shown that electrical stimulation of the NTS caused antidiuresis and thus, by inference, AVP release.) In electrophysiological studies27 orthodromic responses of PVN neurones to electrical stimulation of the A, (NTS/DMX) region were monitored. Excitatory responses were obtained from 25% of the neurones tested, but these cells were identified as oxytocinergic rather than vasopressinergic. There does not appear to be any firm evidence for a direct pathway, from NTS to PVN, involved in modulating AVP release. To our knowledge, no studies have been directed towards determining the effects of lesioning, blocking or stimulating regions in the NTS on the AVP responses to baroreceptor unloading. The study of Lightman et al.59 provided some information on the possible pathways concerned with transmitting cardiovascular information to the PVN or SON and thereby modulating AVP release in rats. Lesions were placed either in the DNAB (carrying projections from A6 and also, probably, A,; see section 2.1) or in the VNAB (carrying projections from AZ and, to some extent, A,), Interestingly there were no marked effects on basal BP or plasma AVP following the lesions (compared with the cardiovascular changes which follow either A, or A2 lesioning). While this might indicate an absence of any tonic influence from A,, AZ or A, on AVP release, it should be noted that the animals were anaesthetized with sodium pentobarbitone. Since the local application of pentobarbitone or GABA into the A, area has been shown to mimic the effects of lesioning that site76, it is feasible that a tonic influence on AVP release had been interrupted by the anaesthetic. Nevertheless, there were increases in plasma AVP in response to haemorrhage and these were reduced by 50% in rats with VNAB lesions and by 97% in rats with DNAB lesions59. The greater effectiveness of the DNAB lesions might indicate that the projection from A6 is the
most important in modulating AVP release, but it must be emphasized that projections from Ai may join the DNAB and that the A6 probably receives projections from A217,80,although the evidence for this is not unequivocal 61,77.It is feasible, therefore, that DNAB lesioning could have affected ascending projections from all 3 noradrenergic cell groups either directly or indirectly. 2.2.3.3. C&. Electrophysiological studies49*103*‘04 demonstrated two pathways from the NTS to the SON in cats, one with an excitatory influence on the neurosecretory cells (with a long latency) and one with an inhibitory influence (with a shorter latency). The cells were defined as being ‘neurosecretory’ if they lay within the histological boundaries of the SON and had axons which projected to the posterior lobe of the pituitary. Electrophysiological identification of the neurosecretory cells was on the basis of antidromic potentials being evoked by posterior lobe stimulation and the ‘collision’ technique. However, whether the cells were vasopressinergic or oxytocinergic was not established, since the characteristic firing patterns of such cells which is seen in rats is said to be less easily demonstrable in cats.
There is some evidence that the fastigial nucleus (FN), which projects to many of the brainstem regions involved in cardiovascular contro12, may modulate baroreflex responses60. More recent evidence suggests that the FN may also influence AVP release29,30.Electrical stimulation of the FN has been shown to elicit a sympathetically mediated pressor response in several species but in rats, if sympathetic efferent influences are removed (either by spinal cord transection or by chemical sympathectomy combined with adrenalectomy), there is a residual pressor response to FN stimulation which can be shown to be due to AVP29,30.Under conditions of sympathectomy or spinal cord transection, when the initial, large pressor response to FN stimulation was abolished, the rise in AVP levels during stimulation (7-fold) was greater than in the intact animals (3-fold). This might suggest that interference with the FN (by stimulation) had not interrupted the inhibitory influence of a rise in BP on AVP release. However, recent evidence suggests that interference with the FN does affect the release of AVP in response to haemor-
326 rhage”.
In that study”
ly in the FN and 4-6 conscious, arterial
lesions were placed bilateralh later,
when the rats were
BP and AVP responses
haemorrhage
measured.
to a standardized
ing the PVN or SON should be cautious unless the transmitter is identified. A further, potentially important.
(5 ml/300 g over 5 min) were
In the animals with FN lesions, basal plas-
point is that in the caudal region of the PVN
(from where projections to other brain areas arise: see below) some AVP neurones have axons which
ma AVP levels were lower (2 pgiml) than in sham-le-
give rise to short
sioned rats (4 pgiml) and haemorrhage
Thus the possibility
an increase
in plasma
caused less of
AVP levels (up to about
pg/ml) than in the controls
30
(up to 75 pg/ml). Despite
or long collateral
branches”‘-““.
exists that some neurones
may
project to more than one area, and hence elicit effects indirectly.
the lesser AVP response, however, the animals with FN lesions showed no impairment in their BP recov-
The distribution of immunocytochemically fied AVP-and oxytocin-containing cells,
ery following
and/or terminals has recently been reviewed thoroughly 31.85.86.The present brief resume will highlight
haemorrhage,
in contrast
ments in chloralose-anaesthetized recovery
following
significantly
impaired
to experi-
dogsb4 in which BP
haemorrhage
or endotoxin
in animals
was
with lesions in the
FN. The reason for this difference, as the authors suggestedy2, may be due to the recruitment of other compensatory mechanisms in the conscious rats which might have been impaired in the anaesthetized dogs. In no species is it clear which projections from the brainstem to the PVN and SON are involved in mediating the AVP response to baroreceptor unloading. Currently, it appears that there are both inhibitory and excitatory projections which traverse several brain regions, but the identity of transmitters involved and delineation of the major quires further investigation.
pathways
re-
VASOPRESSIN
ON
the vasopressinergic projections tial cardiovascular relevance.
identifibres.
to areas with poten-
From the SON, virtually all AVP- or oxytocin-containing neurones project to the posterior pituitary. Furthermore, all neurones projecting to the posterior pituitary from the SON stain for neurophysin and AVP or oxytocin85.X6. AVP- or oxytocin-staining neurones in the rostra1 and lateral portions (magnocellular division) of the PVN project to the posterior pituitary, but some neurones projecting to the posterior pituitary from those areas do not contain oxytotin or AVP85.86. It is from the caudal portion of the PVN (parvocellular division) that projections to other brain regions derive. Two major descending bundles have been identified using anterograde labelling technique@“. In the lower medulla, fibres have been
nuclei to
shown to traverse the lateral reticular nucleus and nucleus ambiguus (close to the A, region), the posterior part of the NTS. the DMX and area postrema and spinal cord6’. In all the above-mentioned areas, branching fibres, varicosities and terminal boutons
There are some general points to be made under this section. One is that the PVN and SON contain a large number of different types of neurones, each of which may contain a variety of neurotransmitters and/or neuromodulatorsY4. For instance, there are at least 5 different neuronal types projecting from the PVN to the spinal cord in rats; only about 20% of the projections are oxytocinergic or vasopressinergic and there is a preponderance of the former94. Thus, a response elicited by PVN stimulation does not necessarily imply an involvement of AVP in the process, and the interpretation of data obtained by stimulat-
were demonstrated. In the NTSiDMX region, both oxytocinergic and vasopressinergic terminals have been shown-the relative density of the former being much greater than the latterJ1~8”~8h.Using an in vitro system, the synaptic release of the peptides has been studied’“. In the NTS region, oxytocin was released in measurable amounts when the preparation was stimulated with veratridine. There was no measurable release of AVP in the NTS, although AVP was released in the lateral septal region where the density of AVP terminals is much greater”. Using a combination of staining techniques, Sladeks” demonstrated the presence of neurophysinpositive varicosities in juxtaposition to noradren-
3. INFLUENCE
OF ENDOGENOUS
BAROREFLEX
MECHANISMS
3.1. Anatomical
identification
of descending
tions from the supraoptic and paraventricular
projec-
specific brain regions
327 aline-containing perikarya in the A, and A, regions; the incidence of these appositions was higher in the Al region. Thus the anatomical substrate appears to exist for a reciprocal link between ascending aminergic and descending peptidergic neurones. There are also projections from the PVN to the locus coeruleus (A&. In that region it has been shown that AVP and noradrenaline are co-localized in some cell bodies’$ the projections of these neurones and the functional significance of the co-localization are unknown. The locus coeruleus also receives a vasopressinergic projection from the bed nucleus of the stria terminalis31s9’ which in turn receives a projection from A2 (see section 2.1); thus the potential for complex neuronal circuits is vast. 3.2. Functional assessment of the influence on barorejlex mechanisms of descending projections from the supraoptic and paraventricular nuclei to specific brain regions
For the most part, functional studies have involved the administration of AVP or oxytocin into selected brain areas (described above as receiving projections from PVN), and monitoring the cardiovascular changes. These have been reviewed elsewhere6 and will not be dealt with in this article. There have been relatively few studies dealing with the possible role of endogenous AVP in baroreflex mechanisms, and in none of these have the results been unequivocal. 3.2.1. Rabbits. We know of no published studies directly concerned with the influence of endogenous AVP on baroreceptor mechanisms in rabbits, although the data cited in section 2.2.1.1. are germane to this question. 3.2.2. Rats. In contrast to results in cats (see below), PVN stimulation in urethane-anaesthetized rats (of unidentified strain) caused hypotension and bradycardia’. The hypotension was associated with renal and mesenteric vasoconstriction, but a vasodilatation in the hindquarters. Increasing the stimulation frequency from 20 to 40 Hz diminished the bradycardic and depressor effects - the latter, presumably, because the vasoconstrictor responses increased proportionately more than the vasodilator responses’. Following sino-aortic denervation, PVN stimulation at 20 and 40 Hz caused pressor and tachycardic effects that increased with stimulation frequency. At both frequencies of stimuIation the vaso-
constrictor responses were enhanced, whereas the hindlimb vasodilator response was attenuated with stimulation at 40 Hz. These results are not easily reconciled with the proposition that PVN stimulation attenuates baroreflexes, and provide no evidence that the effects observed were due to activation of central vasopressinergic mechanisms, although preliminary data were cited as showing that PVN stimulation in Brattleboro rats evoked little or no cardiovascular response’. More recently, Porter and Brody7r found that electrical stimulation of the PVN in urethane-anaesthetized Sprague-Dawley rats produced increases rather than decreases’ in blood pressure. However, like Berecek et al.’ they found the blood pressure effects were accompanied by increases in mesenteric and renal resistance but vasodilatation in the hindquarters. The latter response was inhibited by interruption of the PVN-dorsal medullary pathway, whereas interference with the PVN-ventrolateral medullary pathway blocked the vasoconstrictor and pressor responses to PVN stimulation. Ganglion blockade caused marked attenuation of the responses to PVN stimulation, while adrenalectomy preferentially diminished the hindquarters vasodilatation. Surprisingly, peripheral administration of a Vi-receptor antagonist had no effect on the responses to PVN stimulation, indicating that release of AVP from the pituitary was not involved. However, Porter and Brady” did not determine whether or not the central pathways concerned in the cardiovascular responses were vasopressinergic. Lawrence et al.“5 also found that PVN stimulation in urethane-anaesthetized Sprague-Dawley rats caused a tachycardia and a pressor response. Following stimulation, BP returned towards baseline, but there was a profound bradycardia. During the poststimulus period there was a secondary slow rise in BP. Vagotomy or atropine abolished the bradycardia and tended to enhance the tachycardia. Surprisingly, under these conditions, the pressor response was unaffected, although abolition of the tachycardia (with propranolol) diminished it. Intravenous administration of an antagonist of Vi-receptors caused a substantial fall in resting BP and heart rate (consistent with activation of AVP-mediated mechanisms in urethane-anaesthetized rats4). Under these conditions, the poststimulus, pressor response was delayed - an observation that is difficult
32x
to interpret. sponses
particularly
since all cardiovascular
to PVN stimulation
were abolished
ganglion blocker, chlorisondamine. tral administration that
thalamic.
to PVN
Lawrence
thus no evidence
Results with cen-
of the AVP antagonist
the responses
affected.
stimulation
et al.” concluded for an involvement
vasopressinergic
re-
by the
might be taken
as an indication
indicated
absence of hypothalamic
were
reflex
un-
that there was of extrahypo-
projections
reduction in BP was attributable to the effects ot AV3V stimulation on heart rate and inotropy. and
in the
re-
effects
(but
Evans heterozygotes
strictor deficiency
indicating
partially
that there were few (3 out of 26) pregangli-
onic vagal motor neurones by PVN stimulation’(’
orthodromically
activated
and that there was no correla-
tion between inputs from the PVN and carotid sinus afferents to neurones in the NTS in rat?‘. However,
L.ongresponses the abili-
AVP”. The vasocon-
in Brattleboro
in peripheral
corrected
However,
in spite of possessing
hypothalamic
sponses to PVN stimulation. These results are consistent with evidence from electrophysiological studies
abnormalities
see below).
also showed abnormal
to AV3V stimulation, ty to synthesize
that the congenital
AVP augments cardiac baro-
rats was not due to
mechanisms,
by peripheral
but was
administration
of
AVP, although central administration of AVP was more effective in this regardx. But in neither case did AVP treatment
influence
the diminished
hindquarter
of endogenous AVP in baroreflex mechanisms has involved comparative studies of Brattleboro rats and
vasodilator response to AV3V stimulation. Peripheral administration of a V,-receptor antagonist to Long-Evans rats resulted in the responses to AV3V stimulation resembling those seen in Brattleboro rats’. Conversely. following sino-aortic denervation. the responses to AV3V stimulation in Brattleboro rats were not dissimilar to those seen in Long-Evans rats’. Nelson et al.“’ found that PVN stimulation caused frequency-dependent increases in heart rate and blood pressure in anaesthetized Long-Evans and Brattleboro rats. However, the latter strain were less sensitive to, and had a higher threshold for, PVN stimulation. As in the experiments described above,
animals of the parent strain (Long-Evans rats). Electrical stimulation of the brain region anteroventral to the third ventricle (AV3V) in urethane-anaesthetized, Long-Evans rats caused a fall in BP and heart rate, accompanied by renal and mesenteric vasoconstriction, and vasodilatation in the hindquarters ” . Although the authors claimed these effects were frequency-dependent, the traces presented show that the depressor and bradycardiac effects were frequency-independent in some animals. The vasoconstrictor responses increased proportionally more than the vasodilator responses at the higher stimulation frequencies; an explanation of the dissociation between changes in pressure and vascular resistance was not offered, although the contrast with the responses to PVN stimulation is striking’. AV3V stimulation in Brattleboro rats caused greater depressor and bradycardic effects than seen in LongEvans rats and these differences were accompanied by much less marked changes in regional vascular resistance in the former animals. Presumably, then, the
pretreatment of Brattleboro rats with exogenous AVP (either peripherally or centrally) improved their pressor responsiveness. (In no publication demonstrating the normalization of impaired cardiovascular regulation in Brattleboro rats by administration of exogenous AVP have the authors proferred an explanation for this finding. It seems most unlikely that administration of large doses of exogenous AVP could exert subtle neurotransmitter or neuromodulatory influences.) Collectively. these results point to a variety of factors other than AVP being involved in the different responses to brain stimulation seen in Long-Evans and Brattleboro rats. Electrical stimulation of the brain may have non-specific effects. and the results are frequently complicated by the use of anaesthetics that, themselves, may influence vasopressinergic mechanisms in normal animals. Such problems may be avoided by the use of ‘physiological’ stimuli in conscious animals. While there is evidence for differences in cardiac baroreflex sensitivities in conscious Long-Evans and
Lawrence et al.” failed to demonstrate that administration of the AVP antagonist into the lateral ventricle would have reliably antagonized the effects of endogenous AVP in specific brain areas. Indeed, a more recent publication from this group showed that administration of a V, antagonist into the NTS reduced the pressor and tachycardic responses to PVN stimulation”. The authors did not comment upon their disparate conclusions in these two studies. Another approach to the investigation of the role
329 Brattleboro rats37,47,we have elsewhere3 cautioned against a simplistic interpretation of such findings47. At present there is no unequivocal support for the assertion that the deficiency of hypothalamic and extrahypothalamic AVP in Brattleboro rats is associated with straightforward abnormalities of cardiovascular regulation. Hatzinikolaou et al.45found that i.v. infusion of hypertonic saline elicited AVP release into the plasma, and caused activation of the sympathoadrenal system in conscious, nephrectomized Wistar rats. The resulting hypertension was due to differential vasoconstriction in peripheral vascular beds, accompanied by a reduction in cardiac output and a bradycardia45.The vasoconst~ction and cardiac output effects were antagonized by i.v. administration of a Vi-receptor antagonist, but there was still a marked bradycardia under those conditions. Charocopos et al.19 suggested that these effects might have been due to AVP interacting with baroreflex mechanisms, and it is possible that the failure of the AVP antagonist to abolish the bradycardia was due to a central effect of AVP at a site not accessible to the antagonist (see above). However, there is conflicting evidence that osmotic stimuli activate extrahypothalamic descending vasopressinergic pathways57.105. Since blockade of a- and B-adrenoceptors augmented the contribution of AVP to the hypertension resulting from administration of hypertonic saline, Hatzinikolaou et al.45 suggested that an intact adrenergic system somehow offsets the effect of AVP. But it seems more likely that these results reflect an enhanced recruitment of AVP-mediated mechanisms following adrenoceptor antagonism when the action of the renin-angiotensin system was absent3g.101.The overlapping, interactive nature of the influences of the sympathoadrenal axis, the renin-angiotensin system and AVP on cardiovascular regulation make it difficult to demonstrate an obvious involvement of AVP in the maintenance of BP when the other systems are intact3%38.‘01. Although this is usually the case when BP is normal or elevated, there are also hypotensive conditions in which AVP does not exert an overt pressor effect5$98.It has been argued that this is due to AVP interacting with baroreflex mechanisms to offset its own pressor influence9*, but the physiological purpose of such an effect is obscure unless it is to do with regulation of regional blood flow
rather than control of systemic perfusion pressure. In conscious rats with DOCA-saline hypertension, Rascher et al.74 found elevated circulating levels of AVP. The administration of a V,-receptor antagonist reduced total peripheral resistance but mean arterial BP was maintained because there was a concurrent increase in cardiac output. Animals undergoing sinoaortic denervation prior to the induction of DOCA-saline hypertension showed a marked hypotensive response to the Vi-receptor antagonist because total peripheral resistance fell with no associated change in cardiac output. While these results might indicate a specific interaction between endogenous AVP and baroreflex mechanisms, it is noteworthy that the sinoaortic-dene~ated and sham-operated animals showed similar elevations in plasma AVP, but there were no consistent differences in resting cardiac output or total peripheral resistance in the two groups (if anything, the latter variable was Iower in sinoaortic-denervated than in sham-operated animals). Thus these observations are not entirely consistent with an interaction between endogenous AVP and the reflex control of cardiac output or vascular resistance. 3.23. Cats. Ciriello and Calaresu” investigated the cardiovascular effects of hypothalamic stimulation in chloralose-anaesthetized cats. Electrical stimulation of certain areas caused tachycardia in spinalized animals, while stimulation of other areas caused tachycardia in bilaterally vagotomized cats. In the latter, pressor responses were also seen, but not always with stimulation that caused tachycardia. Generally, those areas that caused pressor and tachycardisc responses due to sympathetic effects corresponded to ‘paraventricular tracts’ descending to the ILC, whereas those areas responsible for increases in heart rate due to vagal withdrawal corresponded to the ventrolateral PVN projecting to medullary vagal neurones2’. Ciriello and Calaresu*’ also found sites in the PVN-SON region that, when activated, caused attenuation of the bradycardia elicited by ipsi- or contra-lateral carotid sinus nerve stimulation. In no experiment did activation of the PVN-SON region influence the cardiac response to stimulation of the aortic nerve. (No comments were made about the influence of hypothalamic stimulation on the responses of BP to activation of afferent nerves.) Between one and 3 h after bilateral PVN-SON lesions (in 9 ani-
330
mals) there was a significant increase in the bradycardie response to carotid sinus nerve stimulation, but no change in the response
to stimulation
of the aortic
ulating endogenous
nerve. There is no evidence that the effects observed by Ciriello and Calaresu’” were due to stimulation of
giotensin
vasopressinergic
chycardic
neurones.
is no evidence that neurons
Furthermore,
region other than the posterior 3.1), it is likely that the responses stimulation
pituitary obtained
were due to activation
from the PVN2”. The intriguing hypothalamic
stimulation
since there
in the SON project to any (see section with SON
of fibres arising
differential
effects of
on carotid sinus and aortic
nerve reflexes remain to be investigated. 3.2.4.
Dogs.
Several
studies
have examined
the
possibility that ‘physiological’ release of endogenous AVP influences cardiovascular regulation in dogs. Montani et a1.68found that there was a significant increase in circulating AVP in conscious dogs following the intra-carotid injection of 2.52 M saline. This effect was unaccompanied by any change in mean arterial BP because the significant increase in total peripheral resistance that occurred was associated with a reduction in cardiac output. (It is notable that the latter was independent of any change in heart rate.) The increase in total peripheral resistance following hypertonic saline administration into the carotid artery was about the same as that seen with i.v. infusion of exogenous AVP at a rate of 40 pg.kg-t.min-‘. However, the latter manoeuvre caused an increase in plasma AVP that was about half that seen with saline administration. One possible interpretation of these results is that the increase in total peripheral resistance due to the direct vasoconstrictor effects of endogenous AVP was more effectively buffered than that due to exogenous AVP because osmotic stimulation also activated descending extrahypothalamic vasopressinergic pathways that augmented the baroreflex mediated withdrawal of peripheral vasoconstrictor tone. However, barodenervation had no significant effect on the change in total peripheral resistance seen with osmotic stimulatio@. Furthermore, there is no evidence that osmotic stimuli have any effect on AVP levels in extrahypothalamic regions of the central nervous system, at least in rats’05. Attempts to demonstrate, directly, an involvement of endogenous AVP in the regional vascular adjustments following water deprivation were unsuccessful”. Recent studies utilizing other procedures for stim-
AVP release have not provided
clear-cut evidence of an interaction tide with baroreflex mechanisms. II injected
anaesthetized
into
dogs elicited
responses”. magna
AVP at a central
the vertebral modest
artery
pressor
These responses
uated by prior administration the cisterna
of this neuropepFor example, an-
were atten-
of a VI-antagonist
(indicating
in
and ta-
an involvement
into of
level), but this effect was not seen
when the antagonist tery or i.v. Michelini
was given into the vertebral et a1.“5 suggested
ar-
that endoge-
nous AVP may have been acting centrally
to inhibit
baroreflexes and that, following administration of the AVP antagonist, the disinhibited baroreflex mechanisms would have been more likely to prevent
the
sympathetic activation due to angiotensin II stimulating the area postrema. However. it is notable that in none of the experiments were pressor effects accompanied by a bradycardia, i.e. there was no evidence that cardiac baroreflexes were functiona16’. The extent to which endogenous AVP contributes to the pressor responses resulting from administration of hypertonic saline is in debate’“.4’,‘s. As elsewhere, the use of anaesthetics in some studies adds to the confusion. However, it is of interest that recent experiments showed that a V,-antagonist administered i.v. converted the response to intraventricular hypertonic saline from a decrease into an increase in renal sympathetic nerve activity”‘. This effect was not seen when the AVP antagonist was given into the ventricular system. Although the site of this interaction has yet to be determined, the above effects occurred in association with a diminution in the pressor responses and an increase in the tachycardia associated with administration of hypertonic saline into the ventricular system. Thus the findings are not consistent with a straightforward involvement of endogenous AVP in baroreflex mechanisms. Recent studies in conscious dogs’” produced results that indicated endogenous AVP may exert an inhibitory influence on the activation of sympathetic efferent activity following hypertension due to interruption of vagal afferent activity. Teleologically such an interaction would seem to be undesirable in hypotensive states unless it resulted in a fine-tuning of the control of regional blood flows in the face of diminished perfusion pressure, as mentioned above. In summary, in no species under any condition is
332 there unequivocal evidence of a defined interaction between endogenous AVP and baroreflex mechanisms. However, various bits of evidence are suggestive of such an interaction and it now remains to do the appropriate experiments. 4. SUMMARY
This article reviews the anatomical and functional evidence for ascending pathways from specific brain regions ta the PVN and SQI\I which could influence AVP release. The majority of evidence favours the main projection being from a region in the caudal VtM which ivlay coincide with the noradrenergic neurons of the AI ceelfgroup However, the transmitter(s) involved have yet to be identified, and whether the pathway is excitatory and/or inhibitory remains to be fully resolved. Anatomical and functional evidence is reviewed
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t’ordescending projections from the SON and PVN to specific brain regions involved in cardiovascular coatrol, and their possible involvement in baroreflex rn~~an~~s is discussed. However, there is Me unequivocaI evidence that AVP is the main neurotra~s~ mitter utilized by descending projections from PVH to NTS and DMX. While, in some situations, circulating endogenous AVP exerts cardiovascular effects, details of its putative influences on baroreflex rnec~~~~~ are facking,
ACKNOWLEDGEMENTS
Work from the author% ~a~rat~~~ was sup~~e~ by grants from the British Heart Foundation. We are grateful to colleagues who sent us reprints and/or preprints of their work, and are indebted to Rosemary Alefounder for her expert typing of this review,
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Bra& Research Reviews, ll(1986) 317-334 Elsevier BRR 90055
Endogenous vasopressin and barareflex mechanisms
Ke.y Iyu&: Vasopressin; Baroreflex; Ventroiateral meduibt; Nucleus tractus sahtarius; Paraventricular nucleus; Rat; Rabbit; Cat; Dog
CONTENTS “.. ,.,. . . . . . . _.. . .. ~.. . . l.. . 1II... . .. . .. . . . . . . .. . . .. .. . I _.. . ,. Id
318
....I.. *. .. . .. . . . .. .. . . . . . . .. . ss.~..,..,..........,.,., Io1........... s,...... 4,..,......,, 2, Influenceofb~~reflexstimulionv~~~re~inrelease 2.1. Anatomical identification of ascending projections from specific brain regions to the supraoptic and paraveflt~icuiar nuclei . .~,.....~,..................‘.....,...........*...........1........=..........,...............~.....,.~....,...,.*......~..............~....~. 2.2. Functional assessment of the influence, on vasopressin release, of ascending projections from specific brain regions to _.I.I ,..................,..._... 1.,......,....... f._..,.. _._..,.t..I.......I fl_j~l.._....,l..~._..I tbes~praopticandparaven~i~uIa~nu~Iei ........................................................................................................ 22.1. ~a~da~ven~rolate~~medu~la 2.2.1.1. Rabbits ........................................................................................................................ 2.2.1.2. Rats ............................................................................................................................. 2.2.1.3. Cats ............................................................................................................................. 22.2. Rostra1 ventrotateral medulla ........................................................................................................ 2.2.2.1. Rabbits ........................................................................................................................ 2.2.2.2. Rats ............................................................................................................................. _~............................ 2.2.2.3. Cats ............................................................................................... 2.2.3. Dorsomedial medulla .................................................................................................................. 2.2.3.1. Rabbits ........................................................................................................................ 2.2.3.2, Rats ............................................................................................................................. 2.2.3.X Cats ............................................................................................................................. 2.2,4. FastigialnueIeus .........................................................................................................................
319
1. Uu&-te of brtiste3n-t areas involved in modulating baroreceptor reflexes
3f9 319 313 319 321 322 323 323 323 323 323 323 323 325 325
3. Znfiuence ofendog~no~vaso~~essin on baroreflex mechanisms . . . ..~.....~~.......~..~~..~~~“....~~...~.........~~...~.~........~~~.~~~~~ Xl. Anatomize ident~fj~at~on of descending projections from the supraoptic and paraventricular nuclei to specific brain regions . .(.,... . , . ,., . . .. . . ,. , . . ...“. . .. . . . . . . , .. . .. . . . ., , . . . . . . . . . . . . . . . . . . .. . .. . .. . . . . ,. .. . . . . ., . . . . . . ...“.............................,., 3.2. Functional assessment of the influence on baroreflex mechanisms of distending projections from the supraoptic and para~entri~u~~~ nuclei to specific brain regions . . . . . . ..*....................~..~.*..**........*...................~............~‘.....*.*.. 3.2.1. Rabbits .................... ................................................................................................................. 3.2.2. Rats ........................................................................................................................................ 32.3. Cats ........................................................................................................................................ 3.2.4. Dogs .......................................................................................................................................
327 327 327 329 330
4. Summary
331
................................................................................................................................................
A~knowiedgements References
........................................................................................................................................
...................................................................................................................................................
Co~~e~~o~~e~c~; SM. Gardiner, department ham, NGT 2UH, U.K.
326 326
331 331
of Physjolo~y, Medical School, Queen’s Medical Centre, Clifton Boulevard, Not&g
31X 1. OUTLINE
OF BRAINSTEM
MODULATING
AREAS
BARORECEPTOR
INVOLVED
IN
REFLEXES
tained,
but abolished
cardic responses
the vasodepressor
to unilateral
4”,41. These findings
indicate
that the rostrai area of the VLM is important
in relay-
vagus nerve stimulation The
complexities
of the
volved in baroreceptor
neuronal
reflexes
viewed23*s7. In the present
article,
evant circuits which may influence, Baroreceptor
in-
have been well rea necessarily
plistic outline will be given, highlighting by, vasopressin
circuitry
sim-
only the rel-
or be influenced
(AVP) release. afferent
cranial nerves enter the medulla
at the level of the
obex and run in the solitary tract to terminate nucleus of the solitary tract (NTS). Efferent, vagal, preganglionic
neurones
ing baroreflex inhibitory
are situated
in the cardiac,
in the me-
dulla (in the dorsal motor nucleus of the vagus (DMX) and the nucleus ambiguus). The relative distribution of the total population of cardiac vagal neurones between these nuclei is species-dependent23, but both receive projections from the NT@“. Efferent, sympathetic, preganglionic neurones are located in the intermediolateral cell coIumns (ILC) of the spinal cord. There is no evidence for a direct connection between the NTS and the ILC (the major noradrenergic innervation of the spinal cord derives from pontine neurones with cell bodies in the A, grouph2). However, within the ventrolateral medulla (VLM) there are areas that receive projections from the NTS and which influence sympathetic preganglionic activity in the spinal cord. There are two areas within the VLM that have important effects on cadiovascular control (see review in refs. 24,76). A rostra1 site coincides, in the rat, with the location of adrenaline neurones of the C, group46. Bilateral lesions in this area have been shown to reduce heart rate and lower blood pressure (BP) to levels similar to those seen in animals with spinal cord transection25,4”‘41. The possibility that baroreceptor information may be relayed through the region has been studied. Since bilateral lesions of the C, area caused such a profound hypotension (see above), it was necessary to design the experiments in such a way that normal levels of arterial BP could be maintained prior to baroreflex testing. This was possible since vagal afferents innervate the NTS bilaterally whereas NTS projections to the C, area are unilateral. Thus lesions placed in the NTS contralateral to the side of testing and in the ipsilateral C1 area resulted in normal levels of BP being main-
information.
amino
acid (GABA),
Since application
acid transmitter
y-amino
excitatory
of the butyric
which causes hyperpolarization
bodies, had similar effects to lesioning application
fibres in the IXth and Xth
and brady-
carotid sinus stretch or
of bicuculiine
(a GABA
antagonist)
effects 26.7’. it was suggested outflow,
tonic, inhibitory,
GABAergic
There is anatomical
and normally
evidence
had
that the C,
area was involved in the tonic maintenance thetic vasomotor
of cell
the area’” and
of sympareceived
a
input from the NTS. for a projection
from
the C, area to the ILC1,‘“,78,79. but the transmitter(s~ involved in modulating sympathetic efferent outflow are unidentified. A more caudally situated area in the VLM which is involved in cardiovascular control coincides with the location of noradrenergic neurones of the A, group ” . Neurones from this region do not project diredy to the spinal cord. Lesions region did not have such a marked effect as on baroreflex responses to carotid sinus
appear to in the Ar C, lesions stretch’“.
There was, however, a transient (up to 4 h) reduction in the gain of the BP-heart period response to baroreceptor activation, and a persistent reduction in the gain of the BP-vascular resistance response to hypotensive stimuli following A, lesionsW. The cardiovascular responses to this manoeuvre are dealt with more fully in section 2.21. Electrical stimulation of the A, area caused a fall in BP which was due to withdrawal of sympathetic vasomotor tone”; application of L-glutamate (the excitatory amino acid transmitter) had a similar effect”. Thus, activity in the A, area can clearly influence sympathetic vasomotor tone, but these indirect pathways to the spinal cord have yet to be traced anatomically. There is evidence for a projection from the A, region towards the NTS”, but whether or not there are also projections to other medullary areas remains to be determined. It is feasible that the A1 region may project to the Cr area (the regions being directly juxtaposed or even mixed), and thereby inhibit sympathetic vasomotor outflow. Indeed, there is growing evidence for interactions between the Al and the C, areas”“““.
319 2. INFLUENCE
OF BAROREFLEX
STIMULI ON VASO-
of the median eminence the brainstem
PRESSIN RELEASE
though this differential 2.1. Anatomical identification of ascending projections from specific brain regions to the supraoptic and
be important,
paraventricular nuclei
magno-
siderable
In addition there
to descending are
projections
also ascending
from the
catecholaminergic
distribution
it is relevant
and parvocellular
of terminals
processes
divisions
primarily
innervate
dendritic
cated in the region of the caudal NTS and DMX) to
vasopressin
is exclusively
the paraventricular
not to cell bodiesg3.
praoptic nucleus
nucleus (PVN)“,
cell group (lopossibly the SU-
between
the
periventricu-
lar region of the PVN in the rat, the noradrenergic terminals
neurones,
from the A, noradrenaline
may
of the PVN82,83.
within the parvocellular,
non-vasopressinergic
projections
centres in
to note that there is con-
overlap of dendritic
Furthermore, NTS,
and to autonomic
and spinal cord (see section 3.1). Al-
neurones
and
processes any
input
to dendrites
on to and
(SON)96 (but see ref. 77), the parathe locus coeruleus17,80 (but see
2.2. Functional assessment of the influence, on vaso-
also refs. 61, 77) and the bed nucleus of the stria terminalis”. Interestingly, the two latter nuclei have recently been shown to contain vasopressinergic cell bodies9’. Ascending projections from the A, region terminate in the locus coeruleus17*80, the PVN and SONgl. Nerve terminals containing PNMT (phenylethanolamine-N-methyltransferase) and so, by inference, adrenaline, have been identified in the locus coeruleus, the DMX, NTS and PVN46. It has been suggested that the C, area may project to the parvocellular division of the PVN93, but firm evidence is lacking. The locus coeruleus (which coincides with the location of the A6 group of noradrenergic neurones22) also sends projections to the PVN.
pressin release, of ascending projections, from specific brain regions to the supraoptic and paraventricular
brachial
nucleu$l,
Of the 3 noradrenergic cell groups mentioned above (A,, AZ, A6) which project to the PVN, the A1 provides the greatest input (68% of the total) with the contribution from A2 being much smaller (26%) and that from A6 even less (6%)“. A similar distribution of inputs is seen in the SONgl but, since that nucleus contains fewer terminals, the inputs from A2 and A6 are minimal. The majority of the noradrenergic axons which innervate the PVN from A1 and A2 run within the ventral noradrenergic bundle (VNAB) in the ventral tegmental tract, whilst the dorsal noradrenergic bundle (DNAB) carries the projection from A6. At midbrain level, however, axons from A, in the VNAB may join the DNABgl. The A, projections terminate in the magnocellular division of the PVN and in the SONgl; it is from these areas that axons project to the posterior pituitary (see section 3.1). The A2 and A, projections terminate in the parvocellular division of the PVNsl; it is from this area that axons project to the zona externa
nuclei The majority of information cited above was obtained from histological studies. Clearly the anatomical substrate exists whereby ascending projections from A,, A, (NTS/DMX), A6 (locus coeruleus) and possibly C, might transmit cardiovascular information to the PVN and/or SON and so modulate AVP release. In addition, there may be non-monoaminergic projections from regions near the At (caudal VLM) and AZ (NTS/DMX) which influence AVP release. Below are detailed the relevant functional studies concerned with this topic. 2.2.1. Caudal ventrolateral medulla (A,) 2.2.1.1. Rabbits. In the first report on the effects of lesioning the A, area in rabbitst3, lesions were placed, bilaterally, at 3 levels (at the level of the obex, 1 mm caudal and 2 mm caudal). The lesions were placed under halothane anaesthesia and cardiovascular variables were monitored whilst the animals regained consciousness. It was shown that following the lesions, hypertension developed; there was an increase in distal aortic vascular resistance, and heart rate slowed. The bradycardia reached a peak sooner than the hypertension (30 min and 40 min postlesion, respectively) suggesting that it was not solely a baroreflex response to the rise in BP. Within 2 h after the lesioning, BP and heart rates had returned to control levels, but distal aortic vascular resistance remained high. In surviving animals, BP and heart rates were still apparently normal two weeks later, but vascular
320
resistance
in the distal aorta was 70% higher than the
of similar magnitude
to that seen in animals with the
control value. For this to be the case. either regional
spinal cord intact. Plasma AVP levels rose (twice as
haemodynamic changes must have occurred to offset the elevated resistance in the distal aorta. or stroke
high as in the intact
volume
tion of a vasopressin
(and hence cardiac output)
reduced.
In an accompanying
that the vascular by a-adrenoceptor
resistance
paper”” it was shown changes
antagonism
amine and it was suggested neurones
inhibit
vasomotor
response
were abolished
with phenoxybenz-
that lesions placed in the
A, area destroyed sympathetic
must have been
that normally
to the intervention
acted to
tone. The heart rate was further
analyzed
and it was proposed that there were two components - one dependent on, and one independent of, baroreceptors”.
In addition
to the bradycardia
there was
a temporary reduction in the cardiac reflex responses to rises and falls in mean arterial pressure. It was proposed that the lesions had destroyed two populations of neurones (the identity of which is obscure) that had opposing actions on heart rate. The bradycardia was thought to be due to the destruction of neurones that normally acted independently of arterial baroreceptors, to inhibit cardiac slowing. The reduced baroreflex sensitivity was thought to be due to destruction of neurones that normally participate in baroreflexes to facilitate cardiac slowing in response to increases in pressure’. This does not. however, explain the fact that the tachycardic response to falls in pressure was also blunted. the heart rate responses
Thus it would appear that to A, lesioning
require
fur-
ther investigation (see below). The possible involvement of AVP in the cardiovascular responses to lesions of the A, area was investigated by the same group in a later study”. This, now well-cited paper, showed that A, lesioning, or administration of kainic acid into the A, area (to cause depolarization blockade), increased plasma AVP levels 6-fold. Further experiments were done to determine whether or not AVP in the plasma was responsible for the hypertension (although it had been shown earlier that phenoxybenzamine abolished the hyperwhereas this drug enhances sensitivity to tension”. AVP’“). In the first experiment, urethane-anaesthetized animals were spinally transected, to remove any sympathetic vasomotor efferent influence. ‘Normal’ BP was maintained by i.v. infusion of noradrenaline, and then kainic acid was applied to the A, area. Under those conditions there was a pressor response
animals)
sponse was completely
and the pressor
abolished
(V,) receptor
by i.v. administraantagonist,
are, however. problems with the interpretation these data indicate the elevation in plasma ‘causes the hypertension”’
rc-
There that AVP
which follows destruction
of the A, area. Since the animals were spinally transected,
normal
baroreflex
buffering
mechanisms
which might serve to offset a pressor action of AVP” would
have been
adrenaline
absent.
Furthermore.
since nor-
and AVP may act synergistically”.
the in-
fused noradrenaline may have enhanced the pressor action of AVP. The fact that plasma AVP rose twice as high in the animals with spinal cord transection presumably indicates that the operation had interfered with neural pathways that normally operate to reduce plasma AVP levels when BP rises. In a further experiment”, rabbits were briefly anaesthetized with halothane whilst lesions were placed in the A, area and the animals were then allowed to recover. Once the hypertension had developed (mean BP increased by 42 mm Hg). administration of a V, antagonist caused a 19 mm Hg reduction in mean BP. The results of that study” were taken to support the hypothesis”‘.75 that noradrenergic neurones from the A, area ‘tonically inhibit activity of AVP-secreting neuroendocrine cells’. But very recently, one of the authors has retracted that statement on the basis of new evidencelJ. In urethaneanaesthetized rabbits. ‘blockade’ of the A, area by application of tetrodotoxin increased BP (and increased heart rate) but was without effect on plasma AVP levels. Blessing and Willoughby” suggested that in the earlier experiments (see above) the electrolytic lesions had caused excitation rather than inhibition of activity in fibres ascending from A, to PVN. The new proposal, i.e. that fibres from the A, exert an excitatory, rather than an inhibitory, influence on AVP release. is consistent with the observation that the GABA-antagonist, bicuculline, administered into the A, region (i.e. a manoeuvre assumed to be comparable to A, stimulation) elevated plasma AVP8*. In support of the new proposal. Blessing and Willoughby’4” very recently showed that high doses of L-glutamate (lo-100 nmol) injected into the A, region increased plasma AVP levels, even when the
321 concomitant fall in BP was prevented. A lower dose of L-glut~ate (1 nmol) did not affect plasma AVP although it did lower BPL4”.The latter observation was also reported by Sved et al.89. However, these authors drew attention to the possibility that high doses of L-glutamate may diffuse into the rostra1 VLM and exert an effect at that site@. Finally, it still remains to be explained why in the earlier study”, administration of kainic acid into the A, region (in a schedule designed to cause blockade, not excitation) caused plasma AVP levels to rise. If, as is now suggested, efectrolytic lesioning caused excitation of a pathway ascending to the PVN, the question arises whether or not it also caused excitation of a pathway which influenced sympathetic vasomotor outflow, i.e. activated a pressor mechanism rather than inhibited tonically active depressor neurones. This would seem unlikely, however, since tetrodotoxin had similar effects on BP to electrolytic lesioning, Thus it appears that the latter intervention can have differential effects on populations of neurones within the A, area, causing excitation of those projecting to the hypothalamus and inhibition of those influencing sympathetic vasomotor tone. Indeed, a very recent paper from these authors89 provides some evidence to support this possibility. In that study, surprisingly, lesioning of the A, region caused a rise in plasma AVP levels, but failed to alter BP, whereas administration of muscimol (a GABA-agonist) elevated BP in the absence of a change in plasma AVP levels. Furthermore, bicuculline (a GABA-antagonist) caused a rise in plasma AVP, even when the associated fall in BP was prevented, and L-glutamate caused BP to fall without changing plasma AVP (see above). The conclusion from that study was that AVP and BP responses to manipulation of the caudal VLM do not always parallel each other, and that BP responses were largely a function of sympathetic outflow. However, the suggested reason for the failure of the lesioning experiments to cause hypertension was, nonetheless, that the associated AVP response was less than seen previously’2. It remains to clarify why different procedures designed to ‘block’ the A, region appeared to have different effects on heart rate. Thus, electrolytic lesions resulted in bradycardia accompanying the hypertension13**, whereas blockade with tetrodotoxin14or inhibition with GABA” resulted in a tachycar-
dia together with hypertension. In addition to the possibility of differential effects of lesioning on populations of neurones (discussed above), another consideration is that in the experiments using tetrodotoxin or GABA, the animals were anaesthetized, whereas in the experiments which involved lesioning measurements were made in the conscious state. The bradycardia which occurred in the conscious animals was shown to have a ‘baroreceptor-dependent’ component and a ‘baroreceptor-independent’ component, and AVP was suggested as a possible mediator of the latter*. In the experiments where tetrodotoxin was given into the A, region of anaesthetized animals, it is feasible that the anaesthetic had impaired baroreceptor reflexes. Hence, the rise in BP, which occurred without a change in plasma AVP, would not have been accompanied by either component of the bradycardia which occurred in the conscious lesioned animals; an underlying tachycardic response to the procedure may therefore have been unmasked. To summarize, it appears that a number of questions need to be answered before any conclusive statements can be made regarding the influence of the A, region on AVP release and cardiovascular control in rabbits. For example: (1) why are the changes in BP and heart rate which follow A, lesioning transient? (2) are there both excitatory and inhibitory influences from the A, region on AVP release? (3) what are the transmitters involved? (4) are central vasopressinergic mechanisms influenced by the A, region? (5) does AVP, released either centrally or peripherally, contribute to the alterations in baroreflex sensitivity which follow A, lesioning? (6) does lesioning or stimulating the A, region modify the changes in plasma AVP levels which follow baroreceptor unloading? Since the first draft of this review was written, we have been given a pre-print of a paper which directly addresses our last question. In that study, Blessing and Willoughby’4b showed that injection of the GABA-agonist, muscimol, into the Ai region in rabbits, completely abolished the rises in plasma AVP caused by either haemorrhage or constriction of the inferior vena cava. 2.2.1.2. Rats. It has been shown that lesioning the Ai region in rats caused a transient hypertension and
322 bradycardia6’. Plasma AVP levels were elevated, but appeared not to contribute indispensably to the hypertension since an equally large rise in BP occurred following A, lesioning ic AVP (Brattleboro
in rats which lack hypothalamrats) as in normal (Wistar-Kyo-
to; WKY) rats. Interestingly, the hypertension periment
persisted
(180 min)
in the Brattleboro for the duration
whereas
peaked 70 min after lesioning possible,
therefore,
hypertension different
of the ex-
in the WKY
rats it
and then waned6’. It is
that the underlying
cause of the
differed in the two strains. Indeed,
report”
in a
it was shown that adrenalectomy
two days prior to the lesioning sive response
rats,
in Brattleboro
reduced the hypertenrats, but not in the con-
trol rats. That study showed the BP response to A, lesioning in rats could be completely prevented by combined adrenalectomy and sympathectomy (with 6-OHDA) but under those conditions, the heart rate response was unaffected. It was suggested that the BP response was largely due to sympathetic efferent activity whereas AVP might be important in mediating the bradycardia, since the change in heart rate in the Brattleboro rats (31% reduction) was less than in the WKY rats (50% reduction). But inspection of the data from the first report” reveals that the absolute changes in heart rate in the two strains (WKY -136 beats/mitt; Brattleboro -132 beatsimin) were almost identical; the difference (in percentage terms) was due to the Brattleboro rats having a resting tachycardia. The rise in plasma AVP which occurred following A, lesioning in the WKY rats was cautiously interpreted as reflecting either the removal of a tonic inhibitory influence on AVP release, or stimulation of AVP-containing cells in the hypothalamus”. From the available electrophysiological evidence it appears that the latter suggestion may be the more likely. Day et al. 27 showed that stimulation of the A, region in rats caused excitation in 42% of PVN neurons tested (the others were unresponsive). Eight of the ceils were identified as being ‘vasopressinergic’ (on the basis of phasic firing patterns and inhibition by baroreceptor activation) and of the 8, 7 were excited by A, stimulation. ‘Oxytocinergic’ cells were also identified (being continuously active and unaffected by baroreceptor activation) and none of those was influenced by A, stimulation*‘. A similar phenomenon was observed in studies on cells in the SON**. It was shown that treatment with 6-OHDA (centrally) abol-
ished the responses tion, indicating noradrenaline.
of SON neurones
that the transmitter
Kubo et al.“‘obtained
to A, stimulainvolved
may be
further evidence for an exci-
tatory influence, on AVP release, of neurones in the caudal VLM in rats. In their study, however, the area of interest
was defined
as being just ‘below’ the A,
area (the precise coordinates tion of L-glutamate cord transection
Injec-
into that region in rats with spinal
caused a rise in BP which was abol-
ished by peripheral nist. Application
were not given).
administration
of a V, antago-
of kainic acid into those sites which
had evoked pressor
responses
blocked
the response
to L-glutamate but had no persistent effect on ‘resting’ BP; this indicates that the excitatory input to AVP secreting neurones was not tonically active. Kubo et al.s4 also found evidence for a possible involvement of the glutamate-sensitive area in the cauda1 VLM in relaying influences on AVP release from the NTS (see section 2.2.3.2.). In addition to a possible excitatory pathway ascending from the caudal VLM to the PVN and SON, recent data have been interpreted as showing a tonically active, inhibitory, noradrenergic, projection from the A, region to the PVN’06. Knife cuts were placed in the dorsal medulla to transect afferent and efferent projections to and from the DMXiNTS region at the level of the obex. This operation produced a rise in BP, heart rate and plasma AVP levels and there was evidence of a decrease in the activity in ascending catecholaminergic projections from the A, area to the PVN. On the basis of those findings, the authors proposed a scheme in which the experimental procedure had interrupted a tonic inhibitory noradrenergic influence on AVP release, but clearly the knife cuts would have lesioned many different pathways, making the interpretation of the study difficult 2.2.1.3. Cats. Feldberg and Rocha E Silva’4.“5 delineated two areas in the VLM of the cat that were involved in cardiovascular control mechanisms; the more caudally situated area corresponded with the region of the A, cell bodies. Application of the amino acids, GABA or glycine, to that area did not affect resting BP or plasma AVP levels and did not influence the pressor response to bilateral occlusion of the carotid arteries, but did inhibit the rise in plasma AVP levels which normally accompanied the latter
323 manoeuvre3s. It was concluded that some barorecep tor afferents reaching the ventral surface of the medulla synapsed at this caudal site (situated at the transition between the medulla and spinal cord) and, through mediation of a synaptic transmitter that was an inhibitory amino acid, caused suppression of AVP release. Bilateral carotid occlusion, by ‘unloading’ the arterial baroreceptors, thus caused a removal of the ‘amino acid brake’ and hence permitted AVP release3’. Although this study could be criticized on methodology (bioassay of AVP, large baseline variability, pentobarbitone anaesthesia), it is almost the only work (but see also ref. 14b) which has assessed the effects of interfering with regions in the caudal VLM on AVP release in response to baroreceptor unloading. 2.2.2. Rostra1 ventrolateral medulla (C,) As mentioned in a previous section (l), the rostra1 area of the VLM is generally thought to be a pressor area that relays baroreceptor afferent information from the brainstem to the spinal cord. Although there is some evidence that projections ascend from the rostra1 VLM to the PVNy3, there is little information on the influence of this region on pituitary AVP release. Indeed, since it appears that the projections from C, to PVN may terminate in the parvocellular division of the nucleusy3, which does not contain cells projecting to the posterior pituitarys6, then there is no reason for supposing that this pathway might be involved in affecting release of AVP into plasma. Adrenergic terminals have, however, been localized in the magnocellular division of the PVN46. 2.2.2.1. Rabbits. To our knowledge there have been no studies in rabbits of the influence of the rostral VLM on AVP release. 2.2.2.2. Rats. The rostra1 VLM area in the rat coincides with the location of the adrenaline-containing cell bodies of the C1 area46. Stimulation of that region in chloralose-anaesthetized animals79 was shown to elicit an increase in BP, a variable heart rate response (mostly tachycardia), and an increase in plasma levels of noradrenaline, adrenaline, dopamine and AVP (Zfold). The rise in AVP was greater (5 fold) when the increase in BP was largely prevented by sectioning the spinal cord; under those conditions the small rise in BP that occurred was abolished by peripheral administration of a V, antagonist79. The
greater increase in plasma AVP levels in the spinally transected animals indicates that interference with the C, area in the intact rats had not abolished a baroreceptor-mediated inhibitory effect on AVP release. The pathways involved in the effects of Ci stimulation on AVP release are unknown. Since adrenalinecontaining neurons in this area do not project to the magnocellular division of the PVN (see above) it is likely that any adrenergic pathway is an indirect one; alternatively, the pathway may be non-catecholaminergic. It is not known whether or not lesioning the C, area influences AVP responses to baroreceptor unloading in rats. 2.2.2.3. Cats. In addition to the caudal site in the VLM (described above), Feldberg and his colleagues3’ identified a more rostra1 area that may be analogous to the site described above in rats. They showed that application of GABA or glycine to the rostra1 VLM in the cat reduced resting BP and the pressor response to bilateral occlusion of the carotid arteries, but did not influence the rise in plasma AVP that followed the manoeuvre. They concluded that some baroreceptor afferents reaching the ventral surface of the medulla synapsed at this rostra1 site and, through the mediation of an inhibitory aminoacid transmitter, caused suppression of sympathetic tone, without affecting AVP release. (Incidentally, it is interesting that the pressor response to bilateral carotid occlusion was reduced when plasma AVP levels were unaffected, since this is contrary to other reports showing a major contribution from AVP to the pressor response elicited by occlusion of the carotid arteriess3.) To summarize the available evidence, it appears that the rostra1 VLM is involved in the baroreflex modulation of sympathetic tone (affecting AVP release minimally, or not at all) whilst the caudal VLM is involved in modulating AVP release into plasma; whether or not the latter area has both excitatory and inhibitory influences remains to be determined. 2.2.3. ~orsomed~a~ medulla 2.2.3.1. Rabbits. To our knowledge there have been no studies directly concerned with the influence of the NTS region on AVP release in rabbits. 2.2.3.2. Rats.. Several years ago it was shown that electrolytic lesions placed bilaterally in the intermediate third of the NTS in halothane-anaesthetized
324 rats
resulted
started
in
fulminating
hypertension
once the administration
been terminated”*. with a reduction
The hypertension
adrenalectomy
(i.e. normalized
ied”.
with
that the
of an inhibitory
ence from the NTS on sympathetic More recently,
combined
the hypertension
BP) and so it was concluded
rise in BP was due to removal
hypertension
but no change in
with 6-OHDA abolished
had
was associated
in cardiac output,
heart rate. Treatment bilateral
which
of anaesthetic
efferent
a possible involvement
influ-
outflow.
of AVP in the
caused by NTS lesions has been stud-
It was shown that in chloralose-anaesthetized
rats, lesions in the NTS caused a pressor response,
a
tachycardia, and a rise in plasma AVP levels”. The 3 events, however, were dissociated inasmuch as the pressor response peaked within 10 min of lesioning, the plasma AVP levels peaked 20 min after the lesioning, and heart rate increased progressively throughout the 60-min period of measurement. Ten min after the operation, when plasma AVP levels had risen from 16 to 80 pg/ml, and BP had increased by 56 mm Hg, administration of a V, antagonist lowered BP by 32 mm Hg, whereas it was without effect in rats which had received sham-lesions and were normotensive”. In the same series of experiments it was shown that lesioning the NTS caused equally large increases in BP (49 mm Hg) in rats which had been pretreated with a ganglion blocker, but under those conditions, treatment with the V, antagonist completely reversed the hypertension and, in fact, rendered the animals hypotensive”‘. The complication with those experiments, however, is that following ganglion blockade, BP was ‘normalized’ by the administration of phenylephrine. Sved and his colleagues” also included a series of experiments in conscious animals. (The experimental procedures, however, required the animals to be anaesthetized with halothane twice within a 2-h period). In those animals (as in the earlier description of the phenomenon3*) BP only began to rise in the rats with NTS lesions 1.5 min after termination of the anaesthesia, i.e. at a time when BP had reached its peak in the chloralose-anaesthetized rats. Sixty min later, plasma AVP levels were elevated (245 pgiml), BP had risen by 69 mm Hg, and administration of a V, antagonist caused BP to fall by 41 mm Hg. Thus, in the chloralose-anaesthetized, and in the conscious state, AVP may contribute directly to the
hypertension a subsequent
induced by lesioning study.
the NTS in rats. In
Sved”” showed
that treatment
with a ganglion blocker, after the induction of the hypertension, completely reversed the elevation in BP but did not affect the plasma AVP level or the subsequent response to the V, antagonist, i.e. ganglion blockade rendered the animals ‘normotensive’ and addition of the V, antagonist then caused hypotension. In that study, clonidine was shown to markedly reduce the elevated
plasma AVP levels in rats with
NTS lesions and to blunt the subsequent
response
to
the V, antagonistgo. The sites and mechanisms of this effect of clonidine require further investigation. The conclusion
from these recent studies was that
both the sympathetic nervous system and AVP contribute to the hypertension which follows bilateral lesioning of the NTS in rats”‘.“. Quantitation of the relative inputs from the two systems is difficult since combined blockade renders the animals hypotensive. If a ganglion blocker is given prior to the lesioning it appears that the contribution from AVP is enhanced, whereas treatment with a ganglion blocker after the lesions have been placed lowers BP, but does not appear to affect the contribution from AVP to the maintenance of BP. (The possibility that following acute hypotension elicited by ganglion blockade, activity in the renin-angiotensin system may contribute to BP maintenance38 has not been addressed.) The above-mentioned results are consistent with an inhibitory influence of the NTS region on AVP release, as are the results of Kubo et a1.5”. They showed that injection of kainic acid into the NTS (to cause depolarization blockade) evoked a pressor response in pentobarbital-anaesthetized rats with spinal cord transection. The pressor response was abolished by peripheral administration of a V, antagonist and was reduced (but not abolished) by blockade of the glutamate-sensitive cells in the caudal VLM (see section 2.2.1.2.). Kubo et a1.‘4 suggested that blockade of the NTS region had removed a tonic inhibitory influence on AVP release, transmitted partly via the glutamate-sensitive neurons in the caudal VLM. Since the response of plasma AVP to NTS blockade was not abolished by the application of kainic acid to the caudal VLM, it is likely that other inhibitory projections may ascend from the NTS; whether these are direct or indirect remains to be determined. In addition to an inhibitory influence of the NTS
325 region on AVP release, there is evidence for an excitatory influence. Thus, electrical stimulation of the intermediate portion of the NTS and DMX area in halothane-anaesthetized rats with spinal cord transection elicited a rise in BP@ and an elevation in plasma AVP 1eve1s’“; the pressor response was reversed by i.v. administration of a V1 antagonist and did not occur in Brattleboro rats69. (It is interesting to note that these findings are entirely consistent with the much earlier studies done in dogs* in which it was shown that electrical stimulation of the NTS caused antidiuresis and thus, by inference, AVP release.) In electrophysiological studies27 orthodromic responses of PVN neurones to electrical stimulation of the A, (NTS/DMX) region were monitored. Excitatory responses were obtained from 25% of the neurones tested, but these cells were identified as oxytocinergic rather than vasopressinergic. There does not appear to be any firm evidence for a direct pathway, from NTS to PVN, involved in modulating AVP release. To our knowledge, no studies have been directed towards determining the effects of lesioning, blocking or stimulating regions in the NTS on the AVP responses to baroreceptor unloading. The study of Lightman et al.59 provided some information on the possible pathways concerned with transmitting cardiovascular information to the PVN or SON and thereby modulating AVP release in rats. Lesions were placed either in the DNAB (carrying projections from A6 and also, probably, A,; see section 2.1) or in the VNAB (carrying projections from AZ and, to some extent, A,), Interestingly there were no marked effects on basal BP or plasma AVP following the lesions (compared with the cardiovascular changes which follow either A, or A2 lesioning). While this might indicate an absence of any tonic influence from A,, AZ or A, on AVP release, it should be noted that the animals were anaesthetized with sodium pentobarbitone. Since the local application of pentobarbitone or GABA into the A, area has been shown to mimic the effects of lesioning that site76, it is feasible that a tonic influence on AVP release had been interrupted by the anaesthetic. Nevertheless, there were increases in plasma AVP in response to haemorrhage and these were reduced by 50% in rats with VNAB lesions and by 97% in rats with DNAB lesions59. The greater effectiveness of the DNAB lesions might indicate that the projection from A6 is the
most important in modulating AVP release, but it must be emphasized that projections from Ai may join the DNAB and that the A6 probably receives projections from A217,80,although the evidence for this is not unequivocal 61,77.It is feasible, therefore, that DNAB lesioning could have affected ascending projections from all 3 noradrenergic cell groups either directly or indirectly. 2.2.3.3. C&. Electrophysiological studies49*103*‘04 demonstrated two pathways from the NTS to the SON in cats, one with an excitatory influence on the neurosecretory cells (with a long latency) and one with an inhibitory influence (with a shorter latency). The cells were defined as being ‘neurosecretory’ if they lay within the histological boundaries of the SON and had axons which projected to the posterior lobe of the pituitary. Electrophysiological identification of the neurosecretory cells was on the basis of antidromic potentials being evoked by posterior lobe stimulation and the ‘collision’ technique. However, whether the cells were vasopressinergic or oxytocinergic was not established, since the characteristic firing patterns of such cells which is seen in rats is said to be less easily demonstrable in cats.
There is some evidence that the fastigial nucleus (FN), which projects to many of the brainstem regions involved in cardiovascular contro12, may modulate baroreflex responses60. More recent evidence suggests that the FN may also influence AVP release29,30.Electrical stimulation of the FN has been shown to elicit a sympathetically mediated pressor response in several species but in rats, if sympathetic efferent influences are removed (either by spinal cord transection or by chemical sympathectomy combined with adrenalectomy), there is a residual pressor response to FN stimulation which can be shown to be due to AVP29,30.Under conditions of sympathectomy or spinal cord transection, when the initial, large pressor response to FN stimulation was abolished, the rise in AVP levels during stimulation (7-fold) was greater than in the intact animals (3-fold). This might suggest that interference with the FN (by stimulation) had not interrupted the inhibitory influence of a rise in BP on AVP release. However, recent evidence suggests that interference with the FN does affect the release of AVP in response to haemor-
326 rhage”.
In that study”
ly in the FN and 4-6 conscious, arterial
lesions were placed bilateralh later,
when the rats were
BP and AVP responses
haemorrhage
measured.
to a standardized
ing the PVN or SON should be cautious unless the transmitter is identified. A further, potentially important.
(5 ml/300 g over 5 min) were
In the animals with FN lesions, basal plas-
point is that in the caudal region of the PVN
(from where projections to other brain areas arise: see below) some AVP neurones have axons which
ma AVP levels were lower (2 pgiml) than in sham-le-
give rise to short
sioned rats (4 pgiml) and haemorrhage
Thus the possibility
an increase
in plasma
caused less of
AVP levels (up to about
pg/ml) than in the controls
30
(up to 75 pg/ml). Despite
or long collateral
branches”‘-““.
exists that some neurones
may
project to more than one area, and hence elicit effects indirectly.
the lesser AVP response, however, the animals with FN lesions showed no impairment in their BP recov-
The distribution of immunocytochemically fied AVP-and oxytocin-containing cells,
ery following
and/or terminals has recently been reviewed thoroughly 31.85.86.The present brief resume will highlight
haemorrhage,
in contrast
ments in chloralose-anaesthetized recovery
following
significantly
impaired
to experi-
dogsb4 in which BP
haemorrhage
or endotoxin
in animals
was
with lesions in the
FN. The reason for this difference, as the authors suggestedy2, may be due to the recruitment of other compensatory mechanisms in the conscious rats which might have been impaired in the anaesthetized dogs. In no species is it clear which projections from the brainstem to the PVN and SON are involved in mediating the AVP response to baroreceptor unloading. Currently, it appears that there are both inhibitory and excitatory projections which traverse several brain regions, but the identity of transmitters involved and delineation of the major quires further investigation.
pathways
re-
VASOPRESSIN
ON
the vasopressinergic projections tial cardiovascular relevance.
identifibres.
to areas with poten-
From the SON, virtually all AVP- or oxytocin-containing neurones project to the posterior pituitary. Furthermore, all neurones projecting to the posterior pituitary from the SON stain for neurophysin and AVP or oxytocin85.X6. AVP- or oxytocin-staining neurones in the rostra1 and lateral portions (magnocellular division) of the PVN project to the posterior pituitary, but some neurones projecting to the posterior pituitary from those areas do not contain oxytotin or AVP85.86. It is from the caudal portion of the PVN (parvocellular division) that projections to other brain regions derive. Two major descending bundles have been identified using anterograde labelling technique@“. In the lower medulla, fibres have been
nuclei to
shown to traverse the lateral reticular nucleus and nucleus ambiguus (close to the A, region), the posterior part of the NTS. the DMX and area postrema and spinal cord6’. In all the above-mentioned areas, branching fibres, varicosities and terminal boutons
There are some general points to be made under this section. One is that the PVN and SON contain a large number of different types of neurones, each of which may contain a variety of neurotransmitters and/or neuromodulatorsY4. For instance, there are at least 5 different neuronal types projecting from the PVN to the spinal cord in rats; only about 20% of the projections are oxytocinergic or vasopressinergic and there is a preponderance of the former94. Thus, a response elicited by PVN stimulation does not necessarily imply an involvement of AVP in the process, and the interpretation of data obtained by stimulat-
were demonstrated. In the NTSiDMX region, both oxytocinergic and vasopressinergic terminals have been shown-the relative density of the former being much greater than the latterJ1~8”~8h.Using an in vitro system, the synaptic release of the peptides has been studied’“. In the NTS region, oxytocin was released in measurable amounts when the preparation was stimulated with veratridine. There was no measurable release of AVP in the NTS, although AVP was released in the lateral septal region where the density of AVP terminals is much greater”. Using a combination of staining techniques, Sladeks” demonstrated the presence of neurophysinpositive varicosities in juxtaposition to noradren-
3. INFLUENCE
OF ENDOGENOUS
BAROREFLEX
MECHANISMS
3.1. Anatomical
identification
of descending
tions from the supraoptic and paraventricular
projec-
specific brain regions
327 aline-containing perikarya in the A, and A, regions; the incidence of these appositions was higher in the Al region. Thus the anatomical substrate appears to exist for a reciprocal link between ascending aminergic and descending peptidergic neurones. There are also projections from the PVN to the locus coeruleus (A&. In that region it has been shown that AVP and noradrenaline are co-localized in some cell bodies’$ the projections of these neurones and the functional significance of the co-localization are unknown. The locus coeruleus also receives a vasopressinergic projection from the bed nucleus of the stria terminalis31s9’ which in turn receives a projection from A2 (see section 2.1); thus the potential for complex neuronal circuits is vast. 3.2. Functional assessment of the influence on barorejlex mechanisms of descending projections from the supraoptic and paraventricular nuclei to specific brain regions
For the most part, functional studies have involved the administration of AVP or oxytocin into selected brain areas (described above as receiving projections from PVN), and monitoring the cardiovascular changes. These have been reviewed elsewhere6 and will not be dealt with in this article. There have been relatively few studies dealing with the possible role of endogenous AVP in baroreflex mechanisms, and in none of these have the results been unequivocal. 3.2.1. Rabbits. We know of no published studies directly concerned with the influence of endogenous AVP on baroreceptor mechanisms in rabbits, although the data cited in section 2.2.1.1. are germane to this question. 3.2.2. Rats. In contrast to results in cats (see below), PVN stimulation in urethane-anaesthetized rats (of unidentified strain) caused hypotension and bradycardia’. The hypotension was associated with renal and mesenteric vasoconstriction, but a vasodilatation in the hindquarters. Increasing the stimulation frequency from 20 to 40 Hz diminished the bradycardic and depressor effects - the latter, presumably, because the vasoconstrictor responses increased proportionately more than the vasodilator responses’. Following sino-aortic denervation, PVN stimulation at 20 and 40 Hz caused pressor and tachycardic effects that increased with stimulation frequency. At both frequencies of stimuIation the vaso-
constrictor responses were enhanced, whereas the hindlimb vasodilator response was attenuated with stimulation at 40 Hz. These results are not easily reconciled with the proposition that PVN stimulation attenuates baroreflexes, and provide no evidence that the effects observed were due to activation of central vasopressinergic mechanisms, although preliminary data were cited as showing that PVN stimulation in Brattleboro rats evoked little or no cardiovascular response’. More recently, Porter and Brody7r found that electrical stimulation of the PVN in urethane-anaesthetized Sprague-Dawley rats produced increases rather than decreases’ in blood pressure. However, like Berecek et al.’ they found the blood pressure effects were accompanied by increases in mesenteric and renal resistance but vasodilatation in the hindquarters. The latter response was inhibited by interruption of the PVN-dorsal medullary pathway, whereas interference with the PVN-ventrolateral medullary pathway blocked the vasoconstrictor and pressor responses to PVN stimulation. Ganglion blockade caused marked attenuation of the responses to PVN stimulation, while adrenalectomy preferentially diminished the hindquarters vasodilatation. Surprisingly, peripheral administration of a Vi-receptor antagonist had no effect on the responses to PVN stimulation, indicating that release of AVP from the pituitary was not involved. However, Porter and Brady” did not determine whether or not the central pathways concerned in the cardiovascular responses were vasopressinergic. Lawrence et al.“5 also found that PVN stimulation in urethane-anaesthetized Sprague-Dawley rats caused a tachycardia and a pressor response. Following stimulation, BP returned towards baseline, but there was a profound bradycardia. During the poststimulus period there was a secondary slow rise in BP. Vagotomy or atropine abolished the bradycardia and tended to enhance the tachycardia. Surprisingly, under these conditions, the pressor response was unaffected, although abolition of the tachycardia (with propranolol) diminished it. Intravenous administration of an antagonist of Vi-receptors caused a substantial fall in resting BP and heart rate (consistent with activation of AVP-mediated mechanisms in urethane-anaesthetized rats4). Under these conditions, the poststimulus, pressor response was delayed - an observation that is difficult
32x
to interpret. sponses
particularly
since all cardiovascular
to PVN stimulation
were abolished
ganglion blocker, chlorisondamine. tral administration that
thalamic.
to PVN
Lawrence
thus no evidence
Results with cen-
of the AVP antagonist
the responses
affected.
stimulation
et al.” concluded for an involvement
vasopressinergic
re-
by the
might be taken
as an indication
indicated
absence of hypothalamic
were
reflex
un-
that there was of extrahypo-
projections
reduction in BP was attributable to the effects ot AV3V stimulation on heart rate and inotropy. and
in the
re-
effects
(but
Evans heterozygotes
strictor deficiency
indicating
partially
that there were few (3 out of 26) pregangli-
onic vagal motor neurones by PVN stimulation’(’
orthodromically
activated
and that there was no correla-
tion between inputs from the PVN and carotid sinus afferents to neurones in the NTS in rat?‘. However,
L.ongresponses the abili-
AVP”. The vasocon-
in Brattleboro
in peripheral
corrected
However,
in spite of possessing
hypothalamic
sponses to PVN stimulation. These results are consistent with evidence from electrophysiological studies
abnormalities
see below).
also showed abnormal
to AV3V stimulation, ty to synthesize
that the congenital
AVP augments cardiac baro-
rats was not due to
mechanisms,
by peripheral
but was
administration
of
AVP, although central administration of AVP was more effective in this regardx. But in neither case did AVP treatment
influence
the diminished
hindquarter
of endogenous AVP in baroreflex mechanisms has involved comparative studies of Brattleboro rats and
vasodilator response to AV3V stimulation. Peripheral administration of a V,-receptor antagonist to Long-Evans rats resulted in the responses to AV3V stimulation resembling those seen in Brattleboro rats’. Conversely. following sino-aortic denervation. the responses to AV3V stimulation in Brattleboro rats were not dissimilar to those seen in Long-Evans rats’. Nelson et al.“’ found that PVN stimulation caused frequency-dependent increases in heart rate and blood pressure in anaesthetized Long-Evans and Brattleboro rats. However, the latter strain were less sensitive to, and had a higher threshold for, PVN stimulation. As in the experiments described above,
animals of the parent strain (Long-Evans rats). Electrical stimulation of the brain region anteroventral to the third ventricle (AV3V) in urethane-anaesthetized, Long-Evans rats caused a fall in BP and heart rate, accompanied by renal and mesenteric vasoconstriction, and vasodilatation in the hindquarters ” . Although the authors claimed these effects were frequency-dependent, the traces presented show that the depressor and bradycardiac effects were frequency-independent in some animals. The vasoconstrictor responses increased proportionally more than the vasodilator responses at the higher stimulation frequencies; an explanation of the dissociation between changes in pressure and vascular resistance was not offered, although the contrast with the responses to PVN stimulation is striking’. AV3V stimulation in Brattleboro rats caused greater depressor and bradycardic effects than seen in LongEvans rats and these differences were accompanied by much less marked changes in regional vascular resistance in the former animals. Presumably, then, the
pretreatment of Brattleboro rats with exogenous AVP (either peripherally or centrally) improved their pressor responsiveness. (In no publication demonstrating the normalization of impaired cardiovascular regulation in Brattleboro rats by administration of exogenous AVP have the authors proferred an explanation for this finding. It seems most unlikely that administration of large doses of exogenous AVP could exert subtle neurotransmitter or neuromodulatory influences.) Collectively. these results point to a variety of factors other than AVP being involved in the different responses to brain stimulation seen in Long-Evans and Brattleboro rats. Electrical stimulation of the brain may have non-specific effects. and the results are frequently complicated by the use of anaesthetics that, themselves, may influence vasopressinergic mechanisms in normal animals. Such problems may be avoided by the use of ‘physiological’ stimuli in conscious animals. While there is evidence for differences in cardiac baroreflex sensitivities in conscious Long-Evans and
Lawrence et al.” failed to demonstrate that administration of the AVP antagonist into the lateral ventricle would have reliably antagonized the effects of endogenous AVP in specific brain areas. Indeed, a more recent publication from this group showed that administration of a V, antagonist into the NTS reduced the pressor and tachycardic responses to PVN stimulation”. The authors did not comment upon their disparate conclusions in these two studies. Another approach to the investigation of the role
329 Brattleboro rats37,47,we have elsewhere3 cautioned against a simplistic interpretation of such findings47. At present there is no unequivocal support for the assertion that the deficiency of hypothalamic and extrahypothalamic AVP in Brattleboro rats is associated with straightforward abnormalities of cardiovascular regulation. Hatzinikolaou et al.45found that i.v. infusion of hypertonic saline elicited AVP release into the plasma, and caused activation of the sympathoadrenal system in conscious, nephrectomized Wistar rats. The resulting hypertension was due to differential vasoconstriction in peripheral vascular beds, accompanied by a reduction in cardiac output and a bradycardia45.The vasoconst~ction and cardiac output effects were antagonized by i.v. administration of a Vi-receptor antagonist, but there was still a marked bradycardia under those conditions. Charocopos et al.19 suggested that these effects might have been due to AVP interacting with baroreflex mechanisms, and it is possible that the failure of the AVP antagonist to abolish the bradycardia was due to a central effect of AVP at a site not accessible to the antagonist (see above). However, there is conflicting evidence that osmotic stimuli activate extrahypothalamic descending vasopressinergic pathways57.105. Since blockade of a- and B-adrenoceptors augmented the contribution of AVP to the hypertension resulting from administration of hypertonic saline, Hatzinikolaou et al.45 suggested that an intact adrenergic system somehow offsets the effect of AVP. But it seems more likely that these results reflect an enhanced recruitment of AVP-mediated mechanisms following adrenoceptor antagonism when the action of the renin-angiotensin system was absent3g.101.The overlapping, interactive nature of the influences of the sympathoadrenal axis, the renin-angiotensin system and AVP on cardiovascular regulation make it difficult to demonstrate an obvious involvement of AVP in the maintenance of BP when the other systems are intact3%38.‘01. Although this is usually the case when BP is normal or elevated, there are also hypotensive conditions in which AVP does not exert an overt pressor effect5$98.It has been argued that this is due to AVP interacting with baroreflex mechanisms to offset its own pressor influence9*, but the physiological purpose of such an effect is obscure unless it is to do with regulation of regional blood flow
rather than control of systemic perfusion pressure. In conscious rats with DOCA-saline hypertension, Rascher et al.74 found elevated circulating levels of AVP. The administration of a V,-receptor antagonist reduced total peripheral resistance but mean arterial BP was maintained because there was a concurrent increase in cardiac output. Animals undergoing sinoaortic denervation prior to the induction of DOCA-saline hypertension showed a marked hypotensive response to the Vi-receptor antagonist because total peripheral resistance fell with no associated change in cardiac output. While these results might indicate a specific interaction between endogenous AVP and baroreflex mechanisms, it is noteworthy that the sinoaortic-dene~ated and sham-operated animals showed similar elevations in plasma AVP, but there were no consistent differences in resting cardiac output or total peripheral resistance in the two groups (if anything, the latter variable was Iower in sinoaortic-denervated than in sham-operated animals). Thus these observations are not entirely consistent with an interaction between endogenous AVP and the reflex control of cardiac output or vascular resistance. 3.23. Cats. Ciriello and Calaresu” investigated the cardiovascular effects of hypothalamic stimulation in chloralose-anaesthetized cats. Electrical stimulation of certain areas caused tachycardia in spinalized animals, while stimulation of other areas caused tachycardia in bilaterally vagotomized cats. In the latter, pressor responses were also seen, but not always with stimulation that caused tachycardia. Generally, those areas that caused pressor and tachycardisc responses due to sympathetic effects corresponded to ‘paraventricular tracts’ descending to the ILC, whereas those areas responsible for increases in heart rate due to vagal withdrawal corresponded to the ventrolateral PVN projecting to medullary vagal neurones2’. Ciriello and Calaresu*’ also found sites in the PVN-SON region that, when activated, caused attenuation of the bradycardia elicited by ipsi- or contra-lateral carotid sinus nerve stimulation. In no experiment did activation of the PVN-SON region influence the cardiac response to stimulation of the aortic nerve. (No comments were made about the influence of hypothalamic stimulation on the responses of BP to activation of afferent nerves.) Between one and 3 h after bilateral PVN-SON lesions (in 9 ani-
330
mals) there was a significant increase in the bradycardie response to carotid sinus nerve stimulation, but no change in the response
to stimulation
of the aortic
ulating endogenous
nerve. There is no evidence that the effects observed by Ciriello and Calaresu’” were due to stimulation of
giotensin
vasopressinergic
chycardic
neurones.
is no evidence that neurons
Furthermore,
region other than the posterior 3.1), it is likely that the responses stimulation
pituitary obtained
were due to activation
from the PVN2”. The intriguing hypothalamic
stimulation
since there
in the SON project to any (see section with SON
of fibres arising
differential
effects of
on carotid sinus and aortic
nerve reflexes remain to be investigated. 3.2.4.
Dogs.
Several
studies
have examined
the
possibility that ‘physiological’ release of endogenous AVP influences cardiovascular regulation in dogs. Montani et a1.68found that there was a significant increase in circulating AVP in conscious dogs following the intra-carotid injection of 2.52 M saline. This effect was unaccompanied by any change in mean arterial BP because the significant increase in total peripheral resistance that occurred was associated with a reduction in cardiac output. (It is notable that the latter was independent of any change in heart rate.) The increase in total peripheral resistance following hypertonic saline administration into the carotid artery was about the same as that seen with i.v. infusion of exogenous AVP at a rate of 40 pg.kg-t.min-‘. However, the latter manoeuvre caused an increase in plasma AVP that was about half that seen with saline administration. One possible interpretation of these results is that the increase in total peripheral resistance due to the direct vasoconstrictor effects of endogenous AVP was more effectively buffered than that due to exogenous AVP because osmotic stimulation also activated descending extrahypothalamic vasopressinergic pathways that augmented the baroreflex mediated withdrawal of peripheral vasoconstrictor tone. However, barodenervation had no significant effect on the change in total peripheral resistance seen with osmotic stimulatio@. Furthermore, there is no evidence that osmotic stimuli have any effect on AVP levels in extrahypothalamic regions of the central nervous system, at least in rats’05. Attempts to demonstrate, directly, an involvement of endogenous AVP in the regional vascular adjustments following water deprivation were unsuccessful”. Recent studies utilizing other procedures for stim-
AVP release have not provided
clear-cut evidence of an interaction tide with baroreflex mechanisms. II injected
anaesthetized
into
dogs elicited
responses”. magna
AVP at a central
the vertebral modest
artery
pressor
These responses
uated by prior administration the cisterna
of this neuropepFor example, an-
were atten-
of a VI-antagonist
(indicating
in
and ta-
an involvement
into of
level), but this effect was not seen
when the antagonist tery or i.v. Michelini
was given into the vertebral et a1.“5 suggested
ar-
that endoge-
nous AVP may have been acting centrally
to inhibit
baroreflexes and that, following administration of the AVP antagonist, the disinhibited baroreflex mechanisms would have been more likely to prevent
the
sympathetic activation due to angiotensin II stimulating the area postrema. However. it is notable that in none of the experiments were pressor effects accompanied by a bradycardia, i.e. there was no evidence that cardiac baroreflexes were functiona16’. The extent to which endogenous AVP contributes to the pressor responses resulting from administration of hypertonic saline is in debate’“.4’,‘s. As elsewhere, the use of anaesthetics in some studies adds to the confusion. However, it is of interest that recent experiments showed that a V,-antagonist administered i.v. converted the response to intraventricular hypertonic saline from a decrease into an increase in renal sympathetic nerve activity”‘. This effect was not seen when the AVP antagonist was given into the ventricular system. Although the site of this interaction has yet to be determined, the above effects occurred in association with a diminution in the pressor responses and an increase in the tachycardia associated with administration of hypertonic saline into the ventricular system. Thus the findings are not consistent with a straightforward involvement of endogenous AVP in baroreflex mechanisms. Recent studies in conscious dogs’” produced results that indicated endogenous AVP may exert an inhibitory influence on the activation of sympathetic efferent activity following hypertension due to interruption of vagal afferent activity. Teleologically such an interaction would seem to be undesirable in hypotensive states unless it resulted in a fine-tuning of the control of regional blood flows in the face of diminished perfusion pressure, as mentioned above. In summary, in no species under any condition is
332 there unequivocal evidence of a defined interaction between endogenous AVP and baroreflex mechanisms. However, various bits of evidence are suggestive of such an interaction and it now remains to do the appropriate experiments. 4. SUMMARY
This article reviews the anatomical and functional evidence for ascending pathways from specific brain regions ta the PVN and SQI\I which could influence AVP release. The majority of evidence favours the main projection being from a region in the caudal VtM which ivlay coincide with the noradrenergic neurons of the AI ceelfgroup However, the transmitter(s) involved have yet to be identified, and whether the pathway is excitatory and/or inhibitory remains to be fully resolved. Anatomical and functional evidence is reviewed
REFERENCES 1 Amendt, J,, Czachurski, J.. Dembowski, K. and Seller, H., Bulbospinal projections to the intermedioiateral cell cohzmn: a ne~r~~atomjGa~ study, j. Au&m. New. $sr., 1 (1979) m-217. 2 Andre&k, J.A., Fastigial nucleus projeciions
3
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6
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to the brain stem in beagles: pathways for autonomic regulation, Negroscictw, ll(1984) 497-507. Bennett, T. and Gardiner. S.M., Involvement of vasopressin in cardiovascular regulation, Cardiovasr. Res., 19 (1985) 57-68. Bennett, T. and Gardirier, S.&Z., ffypo*ensiou ~~~~~~~ng antagonism of the cardi~~~~ascu~ar actions of \;asopressin in urethaneanaesthetized Long-Evans, W&tar and Sprague-Dawley rats, J. Physvsiol. (London), 366 (1985) 51P. Bennett, T. and Gardiner, SM., Factors influencing the maintenaxe of blood pressure in salt-maintained adrenalectomized rats, d. P&y&& ~~~~d#~~~371(1986) 245 p, Bennett, T. and Gardincr, S-M., Infhzence of exogenons vasopressin on baroreflex mechanisms, Clin. Sci., 70 (1986) 307-31s. Berccek, K.H., Webb, R.L,. Barron, K.W. and Brody, M.J. I Vasopressin projections and central control of cardiovascuiar function, Arm N.Y. Acad. Sci., 394 (1%2]
X29-734 * 8 Berecek, K.H., Webb, R.L. and Brady, M.f,, Evidence
for a central role for vasopressin in cardiovascular reguIation, Am. /. Physiol., 244 (1983) H852-H859. 9 Blessing, W. W., Costa, M., Furness, J.B., West, M.J. and Chalmers, J.P., Projection from A, neurons towards the nucleus t’ractus solitarius in rabbit, Cell T&-rue Res., 220 (1982) 27-40. 20 Blessing. W.W., G~dcb~~d, AX._ Dampney, R.A.L. and Chatmers, J.P., Ceil group in the rower brainstem of
t’ordescending projections from the SON and PVN to specific brain regions involved in cardiovascular coatrol, and their possible involvement in baroreflex rn~~an~~s is discussed. However, there is Me unequivocaI evidence that AVP is the main neurotra~s~ mitter utilized by descending projections from PVH to NTS and DMX. While, in some situations, circulating endogenous AVP exerts cardiovascular effects, details of its putative influences on baroreflex rnec~~~~~ are facking,
ACKNOWLEDGEMENTS
Work from the author% ~a~rat~~~ was sup~~e~ by grants from the British Heart Foundation. We are grateful to colleagues who sent us reprints and/or preprints of their work, and are indebted to Rosemary Alefounder for her expert typing of this review,
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