Vol. 276, Issue 3, R872-R879, March 1999
Vasopressin V2 receptor
enhances gain of baroreflex in conscious spontaneously hypertensive
rats
Donella B.
Sampey1,
Louise M.
Burrell2, and
Robert E.
Widdop1
1 Department of Pharmacology,
Monash University, Clayton, Victoria 3168; and
2 University of Melbourne,
Department of Medicine, Austin and Repatriation Medical Centre,
Heidelberg, Victoria 3084, Australia
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ABSTRACT |
The aim of the present study was to
determine the receptor subtype involved in arginine vasopressin
(AVP)-induced modulation of baroreflex function in spontaneously
hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats using novel
nonpeptide AVP V1- and V2-receptor antagonists.
Baroreceptor heart rate (HR) reflex was investigated in both SHR and
WKY rats which were intravenously administered the selective
V1- and
V2-receptor antagonists OPC-21268 and OPC-31260, respectively. Baroreflex function was assessed by
obtaining alternate pressor and depressor responses to phenylephrine and sodium nitroprusside, respectively, to construct baroreflex curves.
In both SHR and WKY rats baroreflex activity was tested before and
after intravenous administration of vehicle (20% DMSO), OPC-21268 (10 mg/kg), and OPC-31260 (1 and 10 mg/kg). Vehicle did not significantly
alter basal mean arterial pressure (MAP) and HR values or baroreflex
function in SHR or WKY rats. The
V1-receptor antagonist had no
significant effect on resting MAP or HR values or on baroreflex
parameters in both groups of rats, although this dose was shown to
significantly inhibit the pressor response to AVP (5 ng iv; ANOVA,
P < 0.05). In SHR but not WKY rats
the V2-receptor antagonist
significantly attenuated the gain (or slope) of the baroreflex curve
(to 73 ± 3 and 79 ± 7% of control for 1 and 10 mg/kg,
respectively), although AVP-induced pressor responses were also
attenuated with the higher dose of the
V2-receptor antagonist. These
findings suggest that AVP tonically enhances baroreflex function
through a V2 receptor in the SHR.
arginine vasopressin; OPC-21268; baroreceptor heart rate reflex
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INTRODUCTION |
ARGININE VASOPRESSIN (AVP) is a powerful
vasoconstrictor agent acting via specific
V1 receptors in vasculature, as
well as causing an antidiuretic effect via specific
V2 receptors in kidney. In
addition, it is well recognized that AVP enhances bradycardic function
for a given pressor response to a greater extent than do other
vasoconstrictors (2, 8, 9, 21), which thereby counteracts its own
vasoconstrictor action. The mechanism of the action of AVP to modulate
baroreflex control of heart rate (HR) is due to either a resetting of
the baroreflex to a lower pressure level or an enhancement of the gain
of the reflex (14, 20), although in the rat the latter mechanism
predominates. Many investigators have attempted to identify the
receptor subtype through which AVP acts to modulate baroreflex
function. A study by Imai et al. (18) using Brattleboro rats, a strain
that lacks endogenous AVP, showed that the reduced baroreflex
sensitivity in these rats could be restored by infusion of both AVP and
1-desamino-8-D-arginine vasopressin (DDAVP), a V2-receptor
agonist, whereas the specific V1-receptor antagonist
d(CH2)5Tyr(Me)AVP
had no effect on baroreflex reflex sensitivity in normal rats after
intravenous administration. These findings imply that AVP influences
baroreflex function through a
V2-like receptor. In a separate
study, Unger et al. (29) confirmed the findings of Imai et al. (18),
through the use of specific AVP-receptor antagonists. This study
demonstrated that the baroreflex was significantly attenuated by
intravenous treatment with a
V2-receptor antagonist but not a
V1-receptor antagonist. By
contrast, Brizzee and Walker (2) found that a selective
V2-receptor antagonist had no
effect on baroreflex sensitivity, although the
V2-receptor agonist-induced
enhancement of baroreflex sensitivity was attenuated by either a
V1- or
V2-receptor antagonist, indicating
a lack of receptor specificity of this effect.
The majority of previous studies investigating the receptor specificity
of the modulation of baroreflex function by AVP have used peptide
AVP-receptor antagonists in normotensive rats (2, 13, 29), although
there are no data concerning the effect of AVP blockade on baroreflex
function in spontaneously hypertensive rats (SHR). More recently,
selective nonpeptide AVP-receptor antagonists that do not exhibit
agonist properties have been developed. These include the
V1-receptor antagonist OPC-21268
(31) and the V2-receptor antagonist OPC-31260 (32). Binding studies using rat liver and kidney
membranes have demonstrated that OPC-21268 is more than 10,000 times
more selective for V1 receptors
than V2 receptors (6), whereas
OPC-31260 is approximately 25 times more selective for
V2 receptors than
V1 receptors (5). Therefore, the
first aim of this study was to investigate the tonic role of AVP in baroreflex modulation in normotensive Wistar-Kyoto (WKY) rats using the
selective, nonpeptide AVP V1- and
V2-receptor antagonists OPC-21268
and OPC-31260, respectively. It is also well recognized that baroreflex
control of HR is impaired in SHR resulting in impaired reflex
bradycardia and/or gain (15, 16, 19, 27, 30). Therefore, the
second aim was to examine whether the V1- and
V2-receptor antagonists exerted a differential effect on
baroreflex function in SHR compared with WKY rats.
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METHODS |
Animals.
Studies were performed in male WKY rats and SHR aged between 15 and 20 wk old and weighing approximately 300 g. Animals were obtained from the
Austin Hospital Research Laboratories and were housed and given food
and water ad libitum.
Surgical procedures.
Rats were anesthetized with methohexitone sodium (60 mg/kg ip,
supplemented as required) for implantation of two catheters into the
right jugular vein and also a catheter into the abdominal aorta via the
caudal artery. Mean arterial pressure (MAP) and HR were both
electronically derived from the phasic blood pressure signal, the
latter of which was recorded via a pressure transducer (Statham,
Oxnard, CA) with all signals being recorded on a polygraph (Grass
Instruments, Quincy, MA).
Baroreceptor reflex testing.
Baroreflex function was tested in both WKY rats and SHR. Alternate
pressor and depressor responses were obtained to phenylephrine (1-25 µg/kg iv) and sodium nitroprusside (1-50 µg/kg iv),
respectively, via two microsyringes (Scientific Glass Engineering,
Melbourne, Australia) attached to the two venous catheters. Each
baroreflex curve was constructed from approximately 15-20 random
doses of the two drugs, obtained by varying the volume injected
(2-20 µl). Peak changes in MAP (not actual doses) and the
associated reflex HR responses were recorded, and the data were fitted
to the sigmoidal logistic equation
where
P1 is the lower HR plateau, P2 is the HR range,
P3 is a curvature coefficient, and
P4 is the
BP50 value, which is the MAP value
at the midpoint of the HR range. The average gain or slope of the
MAP-HR curve calculated between the two inflection points is given by
P2 × P3/4.56, and the upper HR plateau
by P1 + HR range. This method has
previously been described in detail (17), and an example of a
baroreflex curve fitted to raw data is provided in Fig.
1.
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Fig. 1.
Example of baroreceptor-heart rate (HR) reflex curve (solid line)
fitted to raw data points ( ) from spontaneously hypertensive rat
(SHR). MAP, mean arterial pressure. See
METHODS for details.
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Baroreceptor reflex curves in WKY rats and SHR.
All experiments were performed approximately 24-48 h after surgery
in conscious, unrestrained rats. Initially, a baroreflex curve was
commenced approximately 2 h before and approximately 15 min after
administration of the vehicle (a 20% solution of DMSO in distilled
water), i.e., two time control baroreflex curves were obtained. On a
separate day a baroreflex curve was begun approximately 2 h before and
approximately 15 min after the
V1-receptor antagonist OPC-21268
(10 mg/kg iv). The antagonist was infused over a period of 1 min. This
dose of OPC-21268 was chosen from preliminary studies, which
demonstrated marked attenuation of AVP-induced pressor responses. To
confirm an antagonist effect of OPC-21268, a submaximal dose of AVP (5 ng iv) was given before and approximately 10 min after vehicle or
V1-receptor antagonist administration. The posttreatment baroreflex curve was commenced after
the MAP and HR had returned to basal values following AVP injection. At
the conclusion of the baroreflex curve AVP (5 ng iv) was again
administered to confirm the degree of blockade caused by the
antagonist. In a separate group of rats the effects of the vehicle and
V2-receptor antagonist OPC-31260
(10 mg/kg iv) on baroreflex function were also tested in an identical
protocol to that described for OPC-21268. However, in some cases,
OPC-21268 and OPC-31260 were tested in the same WKY rats.
During the course of these studies (see
Results), it was found that the
V2-receptor antagonist partly
attenuated the
V1-receptor-mediated pressor
effect evoked by AVP, whereas the
V1-receptor antagonist failed to
block AVP for the duration of the experiment. Therefore, another group
of SHR was used in which both antagonists were given separated by at
least 2 days, but in this instance baroreflex testing was completed
within 45 min to ensure adequate
V1-receptor blockade, and a
10-fold lower dose of the
V2-receptor antagonist was given
(1 mg/kg) because this dose has previously been shown to cause diuresis
(12). Furthermore, in three additional SHR and three WKY rats, the
diuretic effect of the V2-receptor
antagonist (1 mg/kg) was measured over 1 h to determine if there was a
strain-related difference with respect to changes in blood volume. To
this end rats were placed in metabolic cages (Nalgene, Sybron
Corporation) and allowed to habituate for 2 h before any urine
collection took place.
Statistical analysis.
Changes in MAP and HR from baseline values, pressor and bradycardic
responses to AVP within treatment groups, as well as baroreflex curve
parameters (e.g., gain) were all analyzed using one-way ANOVA with
repeated measures. A statistical package (CLR ANOVA) on an Apple
Macintosh computer was used to perform all ANOVAs, and when appropriate
a Newman-Keuls post hoc test was performed. All results are given as
means, with SE represented by error bars. Statistical significance was
accepted as P < 0.05.
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RESULTS |
Baroreflex curves in WKY rats.
WKY rats received vehicle (n = 10) and
either OPC-21268 (10 mg/kg iv, n = 8)
or OPC-31260 (10 mg/kg iv, n = 7),
although in 5 WKY rats both compounds were tested. Resting MAP and HR
values were not significantly altered by vehicle or the
V1- or the
V2-receptor antagonist (Table
1). Similarly, there were no significant
differences in the baroreflex parameters of WKY rats obtained before or
after administration of vehicle, OPC-21268, or OPC-31260 (Fig.
2, Table 2).
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Fig. 2.
Mean baroreflex MAP-HR curves in Wistar-Kyoto (WKY) rats before (solid
lines) and after (dashed lines) administration of vehicle (DMSO,
n = 10, A),
V1-receptor antagonist OPC-21268
(10 mg/kg iv, n = 8, B), and
V2-receptor antagonist OPC-31260 (10 mg/kg iv, n = 7, C) (series
1). , resting values; vertical lines, SE of upper
and lower HR plateaus. See Table 2 for baroreflex curve parameters.
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In the same animals, AVP (5 ng iv) was tested before and at various
times (10 and 90 min) after vehicle (20% DMSO), OPC-21268, and
OPC-31260 to confirm functional blockade of AVP receptors. In the
vehicle control both the pressor and bradycardic (data not shown)
responses evoked by AVP (5 ng iv) were highly reproducible throughout
the duration of the baroreflex curves in WKY rats (Fig. 3). However, the MAP responses to
intravenous AVP were significantly attenuated 10 min after
administration of either V1- or
V2-receptor antagonist and also at
the completion of the curve (P < 0.01; Fig. 3).
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Fig. 3.
Pressor responses evoked by arginine vasopressin (AVP, 5 ng iv) in WKY
rats before (pre) and approximately 10 and 90 min after vehicle (DMSO,
n = 10, A),
V1-receptor antagonist OPC-21268
(10 mg/kg iv, n = 8, B), and
V2-receptor antagonist OPC-31260
(10 mg/kg iv, n = 7, C).
** P < 0.01 vs. control AVP
response (ANOVA).
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Baroreflex curves in SHR.
Initially, two different groups of SHR received vehicle and either
OPC-21268 (10 mg/kg iv, n = 7) or
OPC-31260 (10 mg/kg iv, n = 6).
Neither vehicle (combined groups) nor the
V1- or the
V2-receptor antagonist had a
significant effect on resting MAP and HR values (Table 1).
In the two groups of SHR, vehicle had a negligible effect on the
baroreflex, and for clarity these data have been combined. In SHR,
baroreflex parameters were not significantly altered after treatment
with either vehicle or V1-receptor
antagonist (Fig. 4, Table
3). However, treatment with
V2-receptor antagonist resulted in
a significant attenuation of the gain of the curve (3.13 ± 0.35 to 2.38 ± 0.19 beats · min
1 · mmHg1) and an
increase in the BP50 (152 ± 5 to 163 ± 5 mmHg, P < 0.05; Fig.
4, Table 3). In the same SHR, AVP (5 ng iv) caused highly reproducible
pressor and bradycardic (data not shown) responses throughout the
vehicle control baroreflex curves. Therefore, these data have been
combined (n = 13; Fig.
5). Pressor responses evoked by AVP were
significantly attenuated immediately after administration of OPC-21268,
although the V1 receptor blockade
was not sustained over the 90-min observation period. Surprisingly, the
V2-receptor antagonist also
attenuated the pressor effect of AVP
(P < 0.05; Fig. 5).
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Fig. 4.
Mean baroreflex MAP-HR curves in SHR before (solid lines) and after
(dashed lines) administration of vehicle (DMSO,
n = 13, A),
V1-receptor antagonist OPC-21268
(10 mg/kg iv, n = 7, B), and
V2-receptor antagonist OPC-31260
(10 mg/kg iv, n = 6, C) (series
1). , resting values; vertical lines, SE of upper
and lower HR plateaus. See Table 3 for baroreflex curve parameters.
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Fig. 5.
Pressor responses evoked by AVP (5 ng iv) in SHR before (pre) and
approximately 10 and 90 min after vehicle (DMSO,
n = 13, A),
V1-receptor antagonist OPC-21268
(10 mg/kg iv, n = 7, B), and
V2-receptor antagonist OPC-31260
(10 mg/kg iv, n = 6, C).
* P < 0.05 and
** P < 0.01 vs. control AVP
response (ANOVA).
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Given that the effect of the
V1-receptor antagonist waned
during baroreflex testing and the
V2-receptor antagonist exhibited some degree of nonselectivity, a second series of baroreflex
experiments was performed. The
V1-receptor antagonist was tested
at the same dose, but the baroreflex testing was completed within 45 min to ensure substantial V1
receptor blockade, whereas the
V2-receptor antagonist was
administered at a 10-fold lower dose. As noted previously, neither
antagonist altered MAP or HR. However, as can be seen in Fig.
6, the pressor responses evoked by AVP were markedly attenuated by the
V1-receptor antagonist throughout
duration of the baroreflex testing but not by the
V2-receptor antagonist at this
dose. Furthermore, under these conditions, the
V1-receptor antagonist was still
unable to modify the baroreflex function, whereas OPC-31260, at 1 mg/kg, again significantly decreased the gain of the baroreflex (Table
4, Fig. 7).
Indeed, the percentage changes in gain (to 73 ± 3 and 79 ± 7%
of control) were very similar in both series of experiments using the
V2-receptor antagonist at either 1 or 10 mg/kg, respectively (Fig. 7). Additionally, the
V2-receptor antagonist induced
diuresis, which was similar in SHR and WKY rats (1.36 ± 0.39 ml/h
and 1.28 ± 0.67 ml/h, respectively, both
n = 3), whereas there was no diuresis
in the preceding control period (0.07 ± 0.07 ml/h and 0 ml/h,
respectively).
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Fig. 6.
Pressor responses evoked by AVP (5 ng iv) in SHR before (pre) and
approximately 10 and 45 min after
V1-receptor antagonist OPC-21268
(10 mg/kg iv, n = 8, A) and
V2-receptor antagonist OPC-31260
(1 mg/kg iv, n = 8, B).
** P < 0.01 vs. control AVP
response (ANOVA).
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Fig. 7.
Mean baroreflex MAP-HR curves in SHR before (solid lines) and after
(dashed lines) administration of
V1-receptor antagonist OPC-21268
(10 mg/kg iv, n = 8, A) and
V2-receptor antagonist OPC-31260
(1 mg/kg iv, n = 8, B) (series
2). C: summary of
antagonist-induced change in gain of baroreflex MAP-HR curves in SHR.
Effect of V1 antagonist OPC-21268
in which there was incomplete (open bar) or complete (vertically lined
bar) AVP blockade (data from Figs. 4B
and 7A, respectively), and
V2 antagonist OPC-31260 at 10 mg/kg (with partial AVP blockade, solid bar) and 1 mg/kg (no AVP
blockade, horizontally lined bar) (data from Figs.
4C and
7B, respectively). , resting
values; vertical lines, SE of upper and lower HR plateaus. See Table 4
for baroreflex curve parameters.
* P < 0.05 vs. control.
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DISCUSSION |
This study investigated the effects of the novel nonpeptide AVP
V1- and
V2-receptor antagonists OPC-21268
and OPC-31260, respectively, on baroreflex function in both SHR and WKY
rats and has provided an insight into the involvement of AVP in the
tonic modulation of baroreflex function and the specific receptor
subtype involved in this effect.
The peripheral administration of the
V1-receptor antagonist OPC-21268
had no effect on baroreflex parameters in either SHR or WKY rats,
although this dose was shown to significantly attenuate the pressor and
bradycardic responses to exogenously applied AVP. However, OPC-21268
failed to maintain a substantial
V1-receptor blockade, as evidenced
by the partial restoration of the AVP-induced pressor response in SHR
at the end of baroreflex testing. This relatively short duration of
action is in keeping with the effect of the
V1-receptor antagonist in binding
studies in kidney membranes (6). Nevertheless, in a second series of
experiments when the baroreflex was tested during maximal AVP blockade,
a similar lack of effect of the
V1-receptor antagonist on
baroreflex function was noted. These data are consistent with studies
by Brizzee and Walker (2) and Unger et al. (29) who found that the
peptide V1-receptor antagonist
d(CH2)5Tyr(Me)AVP
had no effect on baroreflex function in normotensive rats when given intravenously.
In SHR the V2-receptor antagonist
OPC-31260 (10 mg/kg iv) significantly decreased the gain of the
baroreflex curve and increased the
BP50, although in WKY rats there
was no significant change in the gain of the curve. However, these
results were complicated by the fact that the
V2-receptor antagonist also caused
an attenuation of the pressor and bradycardic responses of AVP, which
was surprising because the pressor effect of AVP is mediated via
V1 receptors. Thus, whereas
OPC-31260 preferentially blocks V2
receptors (4, 5, 32), these results confirm other in vitro studies
which have shown that OPC-31260 also possesses
V1-receptor antagonist activity
(4, 5). Therefore, in a second series of experiments, we used a 10-fold
lower dose of the V2-receptor
antagonist, which did not alter AVP-induced vasoconstriction but which
produced a remarkably similar reduction in baroreflex gain.
Collectively, these results imply that even at the higher dose of the
V2-receptor antagonist, there was
a clear functional separation between
V1-receptor blockade (i.e.,
attenuated AVP pressor activity) and
V2-receptor blockade (i.e.,
decreased baroreflex gain) caused by OPC-31260. Thus these data are
consistent with the well-documented enhancement of baroreflex function
by either AVP or the selective
V2-receptor agonist dVDAVP (2, 18,
28), together with the demonstration that the peptide
V2-receptor antagonist
d(CH2)5(D-Ile2,
Abu4)AVP significantly
attenuated the gain of the baroreflex (29). Collectively, these data
suggest that the AVP-induced enhancement of baroreflex gain is mediated
through V2 receptors.
It is unclear why the V2-receptor
antagonist did not alter baroreflex function significantly in WKY rats
but did so in SHR. It is well recognized that baroreflex function is
attenuated in SHR. This is largely due to an impairment of the cardiac
vagal component of the baroreflex in SHR (16), resulting in a reduced reflex bradycardia and/or gain (15, 19, 27, 30). Therefore, it
may have been expected that rather than cause further impairment of the
baroreflex of the SHR, OPC-31260 would attenuate baroreflex gain in WKY
rats, as observed in a previous study using a peptide V2-receptor antagonist (29).
However, this effect did not occur in the present study with a
nonpeptide V2-receptor antagonist nor in a previous study with a different peptide
V2-receptor antagonist (2).
Interestingly, our baroreflex data are consistent with the recent
finding that administration of this
V2-receptor antagonist to young
SHR actually augmented the development of hypertension (23). Therefore,
it is feasible that a further blunting of baroreceptor reflex function
in SHR caused by the V2-receptor
antagonist may have exacerbated the development of hypertension in this
model (23).
Alternatively, it is feasible that the
V2-receptor antagonist caused
diuresis and that baroreflex was altered by volume contraction. The
lower dose of OPC-31260 used in the present study did cause diuresis as
has previously been reported (12). However, there was no evidence of an
enhanced diuretic response to the
V2-receptor antagonist in SHR
which indicates that stain-related differences in volume contraction do
not account for baroreflex changes in SHR. Moreover, this idea seems
unlikely because the V2-receptor antagonist did not reduce the baroreflex gain in the WKY group even at
the 10-fold higher dose of the compound.
Another possible explanation for the inhibitory effect of the
V2-receptor antagonist on
baroreflex function solely in SHR may relate to circulating AVP levels.
Previous studies have shown that plasma AVP levels are elevated in SHR
(11, 22), possibly to help offset the impairment of baroreflex
function. Thus the V2-receptor
antagonist may have blocked the tonic effect of the increased
circulating levels of AVP on enhancing baroreflex gain in SHR. This may
explain why this antagonist had no effect in WKY rats, whereas the
decrease in gain in SHR may represent the blockade of AVP-induced
facilitation of baroreflex function. However, this interpretation is
complicated by the fact that AVP levels are not always elevated in SHR
(7).
The site(s) where AVP may act to modulate baroreflex function are
beyond the scope of the present experiments. However, others have
suggested that circumventricular organs accessible from the periphery,
such as the area postrema (26), as well as regions within the
periphery, such as the carotid sinus (28), may be involved in this
effect. In both rabbits (10, 28) and normotensive rats (25),
investigators have found that lesioning of the area postrema abolishes
the differential reflex bradycardic effects of AVP and phenylephrine,
thereby suggesting that the area postrema does in fact mediate the
AVP-induced facilitation of the baroreflex (14). Interestingly, a
recent review points out that there are data that implicate
V1 receptors in the resetting of the baroreflex toward
lower pressure and the likely role of the area postrema (14). Indeed,
it was suggested that the reported ability of AVP to increase
baroreflex gain was related to experimental design, in that AVP evoked
a larger decrease in HR compared with other agents causing
equieffective pressor responses, but the situation was complicated by
the concomitant increase in arterial pressure caused by AVP (14).
However, in the present and previous (1, 3, 24, 30) studies, we have
used a baroreflex procedure involving raising and lowering MAP and have
examined the endogenous effects of peptides by determining baroreflex
function in the presence of selective receptor antagonists. Thus, under
these conditions, our data point to a tonic enhancement by AVP via
V2 receptors of baroreceptor
reflex gain at least in SHR, and so directly contrasts with reports
that AVP resets the baroreflex to a lower pressure by a
V1-sensitive mechanism (14, 20). Moreover, our baroreflex methodology was virtually identical to that
used in conflicting studies (20). One possible reason for this
discrepancy may be related to a species difference since the latter
mechanism is invariably reported to occur in rabbits (14). To our
knowledge there have been no other studies that have examined
baroreflex function with the new generation of nonpeptide vasopressin-receptor antagonists. Thus it is likely that the modulatory effect observed with the
V2-receptor antagonist involved an
action at central sites accessible following systemic administration, particularly since it has been shown that
V1-receptor activation at neuronal
sites within the blood-brain barrier actually inhibits baroreflex
function, at least in rats (29). Alternatively, it is possible that the
nonpeptide V2-receptor antagonist
may gain greater access to central sites compared with peptide AVP
analogs. In any case, a central site of action of OPC-31260 is
consistent with the concept that most agents that act within the
central nervous system are more likely to affect baroreflex gain as
opposed to HR range (15).
In conclusion, in the present study it was demonstrated that the
V1-receptor antagonist OPC-21268
had no effect on any of the baroreflex parameters measured in either
SHR or WKY rats, whereas the
V2-receptor antagonist OPC-31260
significantly attenuated the gain of the baroreflex curve in SHR. These
findings implicate a role for a V2
receptor in the modulation of baroreflex function by AVP in SHR.
Perspectives
AVP is well known to enhance baroreflex function and thereby offsets
its own vasoconstrictor effect. Various mechanisms are proposed to
mediate this effect; however, previous studies have been hampered by
the use of peptide antagonists that exhibit both agonist and antagonist
activity, which often cause opposing effects. This study has used new
nonpeptide V1- and
V2-receptor antagonists (with no
agonist activity) and has shown that the
V2-receptor antagonist attenuated
the gain of the baroreflex in SHR but not in their normotensive
counterpart. These data suggest that AVP is helping to maintain the
otherwise impaired gain in this hypertensive strain, although there are
likely to be significant species differences since the
V1 receptor appears to be involved
in the rabbit. Nevertheless, at appropriate doses, these compounds were
clearly able to dissect out
V1-mediated pressor effects and
V2-mediated baroreflex effects, emphasizing their value as experimental tools.
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ACKNOWLEDGEMENTS |
We thank Dr. G. A. Head (Baker Medical Research Institute, Prahran,
Australia) for providing the sigmoidal baroreflex curve fitting
program. We also thank Otsuka Pharmaceutical for the gifts of OPC-21268
and OPC-31260.
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FOOTNOTES |
This work was supported by grants from the National Health and Medical
Research Council of Australia.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: R. Widdop, Dept. of Pharmacology, Monash
Univ., Clayton, Victoria 3168, Australia.
Received 10 February 1998; accepted in final form 10 November
1998.
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Am J Physiol Regul Integr Compar Physiol 276(3):R872-R879
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Abstract
Introduction
![HR = P<SUB>1</SUB> + P<SUB>2</SUB>/[1 + <IT>e</IT><SUP>P<SUB>3</SUB>(MAP−P<SUB>4</SUB>)</SUP>]](/content/vol276/issue3/fulltext/R872/img001.gif)
