Neural contribution to the effect of
glucagon-like peptide-1-(7
36) amide on arterial blood pressure in
rats
José Manuel
Barragán1,
John
Eng2,
Raquel
Rodríguez1, and
Enrique
Blázquez3
1 Department of Biochemistry
and Molecular Biology, University of Salamanca, 37007 Salamanca,
Spain; 2 Department of Medicine,
Veterans Affairs Medical Center, Bronx, New York 10468; and
3 Department of Biochemistry and
Molecular Biology, Faculty of Medicine, Complutense University,
28040 Madrid, Spain
 |
ABSTRACT |
This study was
designed to determine the contribution of the central nervous system
(CNS) to the effects of glucagon-like peptide-1-(7
36) amide (tGLP-1)
on arterial blood pressure and heart rate in rats. Accordingly,
intracerebroventricular administration of the peptide produced an
increase in cardiovascular parameters, which was blocked by previous
administration of exendin-(9
39) through the same route, but not when
it was intravenously injected. Intravenous administration of tGLP-1
produced a significant increase in arterial blood pressure and heart
rate, which was blocked by the previous intracerebroventricular or
intravenous administration of exendin-(9
39). Bilateral
vagotomy blocked the stimulating effect of intracerebroventricular
tGLP-1 administration on arterial blood pressure and heart rate. Also,
bilateral vagotomy prevented the blocking effect of
intracerebroventricular but not of intravenous exendin-(9
39) on
cardiovascular parameters after intravenous administration of tGLP-1.
These findings suggest that the action of tGLP-1 on cardiovascular
parameters is under a dual control generated in the CNS and in
peripheral structures and that the neural information emerging in the
brain is transmitted to the periphery through the vagus nerve.
cardiovascular parameters; neural control; vagal
mediation
 |
INTRODUCTION |
GLUCAGON-CONTAINING (glicentin and oxyntomodulin) and
glucagon-like peptides [GLP-1-(1
37), GLP-1-(7
37),
GLP-1-(7
36) amide (tGLP-1), and GLP-2] are components of the
proglucagon gene (4), which gives rise to an mRNA transcript that is
identical in sequence (20) in the pancreas, intestine, and brain,
although posttranslational processing of the precursor yields different
products in these organs. In the L cells of the gut, glucagon is
predominantly processed to glicentin, oxyntomodulin, GLP-1, and GLP-2,
and truncated and amidated forms of GLP-1 are produced by further
enzymatic processing. In the brain, the processing of proglucagon
resembles that of the intestine (18).
GLP-1-(1
37) has low biological activity, and the other component of
the COOH-terminal portion of mammalian proglucagon, or GLP-2, is
considered to be a stimulator of small bowel epithelial proliferation
(9). However, the truncated forms of GLP-1 such as GLP-1-(7
37) amide
and tGLP-1 are very active molecules, acting on both peripheral tissues
and the central nervous system (CNS). tGLP-1 is released after meals
and is a powerful stimulus for glucose-dependent insulin secretion
(19). It also inhibits gastric acid secretion and gastric emptying in
normal humans (39). Also, a role for tGLP-1 in pulmonary surfactant
secretion by type II pneumocytes (5), and also in arterial blood
pressure and heart rate (2, 3), has been described in the rat. In
calves, tGLP-1 administered intravenously increased heart rate but had
no effect on arterial blood pressure (11), whereas in humans the
subcutaneous injection of tGLP-1 increased both arterial blood pressure
and heart rate (12).
Cloning and functional expression of GLP-1 receptors (33) in pancreatic
islets have been reported. In addition, specific high-affinity binding
sites have been characterized in rat insulinoma cells (14), gastric
glands (35), lung (28), brain (6, 7, 17, 36), and adipocyte rat
membranes (37). There is experimental evidence that tGLP-1 and its own
receptors are actually synthesized in the same brain regions, which
leads to a better understanding of the actions of this peptide in the
CNS, such as the selective release of neurotransmitters from different
brain nuclei (21) after perfusion with tGLP-1 and the inhibitory effect on food and drinking intakes (1, 22, 32, 34) after the central
administration of the peptide. In addition, the colocalization of GLP-1
receptors with glucokinase and GLUT-2 (1, 22) in the same neurons
supports the idea that these cells may play an important role in
glucose sensing in the brain.
Besides the actions of the glucagon-related peptides cited previously,
the cardiovascular effects have also been defined. Glucagon has
positive inotropic and chronotropic effects (31); it affects regional
blood circulation and also produces a slight but significant increase
in arterial blood pressure (25). GLP-2 has no effect and GLP-1-(1
37)
produces a moderate increase in arterial blood pressure, whereas tGLP-1
induces a concentration-dependent increase in systolic and diastolic
blood pressure and heart rate (2, 3). The action of tGLP-1 on these
parameters seems to be mediated through its own receptors, because it
was tested after the intravenous administration of exendin-4 as an
agonist and exendin-(9
39) as an antagonist of that peptide (3). It is noteworthy that tGLP-1 and its own receptors have been found in significant amounts in the nucleus tractus solitarius (16, 18, 36),
which is involved in central control of cardiovascular function. Thus
the possibility that the effects of tGLP-1 on cardiovascular parameters
may be induced through a central mechanism should be taken into
account. Here we report the action of tGLP-1 on arterial blood pressure
and heart rate when this peptide was administered intravenously or
intracerebroventricularly. We also describe the contribution of the
vagus nerve to this process.
 |
MATERIALS AND METHODS |
Materials. Synthetic human
GLP-1-(7
36) amide was obtained from Peninsula Laboratories (St.
Helens, UK). Exendin-(9
39) was prepared as previously reported (27).
This peptide was produced on a solid-phase support of polyacrylic (PAL)
resin utilizing activated
N-(9-fluorenylmethoxycarbonyl) amino
acids on a Milligen 9050 peptide synthesizer (Milligen, Burlington, MA)
and was purified by preparative HPLC.
Experimental animals. Male
Sprague-Dawley rats weighing 250-300 g were housed under standard
conditions of lighting (12:12-h light-dark cycle) and at a temperature
of 21°C, with free access to food and water.
Surgical procedures. For
intracerebroventricular administration of the peptides, polyethylene
cannulas aimed at the third ventricle were implanted stereotaxically in
the rats. After being anesthetized, rats were positioned in a
stereotaxic head frame, the shaved scalp was incised, the periosteum
was removed, and the skull was exposed. Holes were drilled into the
frontal and parietal bones to receive one of three stainless-steel
anchoring screws. With the use of bregma as reference, the cannula was
lowered through a burr hole above the third ventricle and positioned
according to the stereotaxic coordinates of the atlas of Paxinos and
Watson (26) (7.7 interaural, 0.5 mm lateral right, and 4.5 mm
deep). The cannula was a thin-wall tubing that was fixed
to the skull and to the anchoring screws with dental cement. The
presence of the cannula in the third ventricle was checked postmortem,
after the injection of methylene blue.
A group of rats were bilaterally vagotomized at the cervical region,
after dissection of the nerves from the carotid arteries. Bilateral
vagotomy was carried out 1-2 h before experiments were done; this
surgical procedure did not cause lung congestion, edema, or death in
the rats used in our experiments. To determine cardiovascular parameters, rats were anesthetized with urethan (250 mg/kg ip) and then
placed upside down on a homeothermic blanket system, where temperature
was maintained at 37.0 ± 0.2°C by means of a rectal probe.
After induction of anesthesia, the trachea was cannulated with a
polyethylene tube and the animal was allowed to breathe room air
spontaneously. After this procedure had been completed, the right
common artery and the right jugular vein were cannulated for continuous
recording of arterial blood pressure and heart rate and for intravenous
injection of drugs, respectively. The cannula inserted into the right
common artery was connected through a Druck Prdr 75 transducer to a
Lectromed recorder apparatus.
Experimental protocols. After surgical
preparation, arterial blood pressure was recorded and the animals were
allowed to stabilize for 60 min. At the end of this period, recording
of cardiovascular parameters was started and control values were
obtained over a further 30-min period. Groups of 6-10 animals were
used for each treatment.
At the end of the control period, 0.9% NaCl or tGLP-1 was injected
intravenously through the jugular vein or intracerebroventricularly into the third ventricle. The total injection volume for the jugular vein was 0.2-0.3 ml, and the total volume injected into the third ventricle was 5 µl. After the injection, cardiovascular parameters were recorded for a further 30-min period. The action of
exendin-(9
39) was investigated by jugular administration of 2,500 ng
of the peptide 5 min before intravenous or intracerebroventricular
administration of 100 ng of tGLP-1.
Experimental recordings. During the
experiments, arterial blood pressure was recorded via a physiological
pressure transducer (Druch Prdr 75). A parallel output was taken from
the preamplifier stage of the polygraph, passed via a Lectromed
apparatus with thermosensitive millimetric paper, and then appropiate
calibration values for systolic, diastolic, and mean arterial blood
pressure (mmHg) and heart rate (beats/min) were obtained.
Statistical analysis. Results are
expressed as means ± SE from groups of 6-10 rats. Because
arterial blood pressure and heart rate values remained stable after
0.9% NaCl administration, statistical comparisons were performed in
each animal between time
0 and each period of time after
administration of the peptides. In these cases, statistical
significance was accessed for P < 0.05 with Student's t-test. ANOVA
with the Newman-Keuls test was used when statistical comparisons were
done with the data obtained from two different groups of animals. The
percent variation of mean arterial blood pressure or heart rate was
calculated as follows
 |
RESULTS |
Effects of intracerebroventricular administration of
tGLP-1 on arterial blood pressure and heart rate. To
determine the effects of tGLP-1 on arterial blood pressure and heart
rate, this peptide was administered either intravenously or
intracerebroventricularly at doses of 10, 50, and 100 ng. The effects
obtained were compared with those observed after the administration of
0.9% NaCl (control values). After it had been seen that arterial blood
pressure and heart rate values remained unchanged from the control
values after the administration of 0.9% NaCl in one group of rats
(Fig. 1), the mean of the control period
values of each individual animal was used for statistical comparisons
of the data between time 0 and each time point after the
peptide administration.

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Fig. 1.
Effect of intracerebroventricular (icv) administration of glucagon-like
peptide-1-(7 36) amide (tGLP-1) on mean arterial blood pressure
(A) and heart rate
(B). Peptide was injected into third
ventricle at doses of 10 ( ), 50 ( ), and 100 ( ) ng. Control
(dashed line) values were obtained after administration of 0.9% NaCl
alone. Results are expressed as means ± SE;
n = 6-8 rats. Statistical
comparisons were performed between
time
0 and each period of time after
administration of peptide, with Student's
t-test.
* P < 0.01;
** P < 0.001;
*** P < 0.0001.
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|
As previously reported (2), intravenous administration of 10, 50, and
100 ng of tGLP-1 produced an increase in mean arterial blood pressure
and heart rate (data not shown). Also, when the results were plotted as
the percentage of variation of mean arterial blood pressure and heart
rate (beats/min) after intracerebroventricular administration of 10, 50, and 100 ng of tGLP-1 (Fig. 1, A
and B), an increase in the values
was observed. In the same way, after intravenous or
intracerebroventricular injections of tGLP-1, an increase in both
systolic and diastolic blood pressure was obtained (Fig.
2), compared with the results found in
control rats. The route used for the administration of the peptide may
influence its effects on cardiovascular parameters (Table
1). Thus the intravenous administration of
tGLP-1 produced a greater maximum percent change of mean arterial blood
pressure and heart rate, compared with the data obtained after
intracerebroventricular injection of the peptide, whereas
central administration of tGLP-1 resulted in a greater time at maximum percent change and time to 50% maximum response then when it was
injected peripherally (Table 1).

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Fig. 2.
Effect of icv administration of tGLP-1 on systolic ( ) and diastolic
( ) blood pressure (A) and heart
rate ( ; B). Peptide was injected
into third ventricle at the dose of 100 ng. Results are means ± SE; n = 6-8 rats.
Statistical comparisons were performed between
time
0 and each period of time after
administration of peptide, with Student's
t-test.
* P < 0.01;
** P < 0.001;
*** P < 0.0001.
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Table 1.
Maximum change, time at maximum change, and time to 50% maximum
response of mean arterial blood pressure and heart rate after
intravenous or intracerebroventricular administration of tGLP-1
in rats
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Blocking effect of exendin-(9
39) on the action of
tGLP-1 on arterial blood pressure and heart rate.
Having observed that intracerebroventricular administration of tGLP-1
has a potent stimulating effect on arterial blood pressure and heart
rate, we next tested the antagonist effect of exendin-(9
39) on the same parameters. First, the effect of exendin-(9
39) alone on arterial
blood pressure and heart rate was studied. Intracerebroventricular administration of 2,500 ng of exendin-(9
39) alone did not produce changes in cardiovascular parameters. To ensure that the action of
tGLP-1 on arterial blood pressure and heart rate was indeed a direct
effect, 100 ng of the peptide were either intravenously or
intracerebroventricularly injected 5 min after the administration of
25-fold the dose of exendin-(9
39) through one route or the other,
respectively. Intracerebroventricular administration of tGLP-1 produced
an increase in both arterial blood pressure and heart rate (Fig.
3, A and
B), but when the rats were
pretreated with 2,500 ng of exendin-(9
39) 5 min before
intracerebroventricular injection of 100 ng of tGLP-1, no effects of
the latter peptide on either cardiovascular parameter were observed. As
reported previously (3), intravenous administration of 100 ng of tGLP-1 produced a significant increase in arterial blood pressure and heart
rate, but these effects were completely blocked by previous intravenous
administration of 2,500 ng of exendin-(9
39).

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Fig. 3.
Effect of icv administration of tGLP-1 on mean arterial blood pressure
(A) and heart rate
(B) in rats pretreated with ( ) or
without ( ) exendin-(9 39). Animals were injected with either 2,500 ng of exendin-(9 39) ( ) or 0.9% NaCl ( ) into third ventricle 5 min before icv administration of 100 ng of tGLP-1. Results are means ± SE; n = 6-8 rats. ANOVA
with Newman-Keuls test was used for statistical comparisons between
data obtained in 2 groups of animals.
* P < 0.01.
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To determine whether the effect of tGLP-1 on the cardiovascular
parameters was due to a central or peripheral mechanism of action, this
peptide was administered either intracerebroventricularly or
intravenously, and in each case exendin-(9
39) was injected through
the opposite route. As shown in Fig. 4,
A and
B, the intravenous administration of
100 ng of tGLP-1 produced a significant increase in arterial blood
pressure and heart rate, which was blocked by previous
intracerebroventricular administration of 2,500 ng of exendin-(9
39).
In addition, intravenous injection of exendin-(9
39) abolished the
action of the intravenous administration of tGLP-1. Also,
intracerebroventricular administration of 100 ng of this peptide
increased arterial blood pressure (Fig. 5,
A and
B), but this effect was blocked by
previous intracerebroventricular administration of exendin-(9
39).
However, intravenous injection of exendin-(9
39) did not block the
effect of intracerebroventricularly administered tGLP-1 (Fig. 5,
A and
B).

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Fig. 4.
Effect of iv administration of tGLP-1 on mean arterial blood pressure
(A) and heart rate (B) in rats pretreated with
exendin-(9 39) administered either iv or icv. Animals were injected
with 2,500 ng of exendin-(9 39) either iv ( ) or icv ( ) 5 min
before intravenous administration of 100 ng of GLP-1 ( ). Results are
means ± SE; n = 6-8 rats.
Statistical comparisons were performed between data obtained after iv
administration of tGLP-1 and those determined after either iv or icv
injection of exendin-(9 39), using ANOVA with Newman-Keuls test.
* P < 0.01.
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Fig. 5.
Effect of icv administration of tGLP-1 on mean arterial blood pressure
(A) and heart rate
(B) in rats pretreated with
exendin-(9 39) administered either iv or icv. Animals were injected
with 2,500 ng of exendin-(9 39) either iv ( ) or icv ( ), 5 min
before the icv administration of 100 ng of tGLP-1 ( ). Results are
means ± SE; n = 6-8 rats.
ANOVA with Newman-Keuls test was used for statistical comparisons
between data obtained after icv administration of tGLP-1 and those
determined either after iv or icv injection of exendin-(9 39).
* P < 0.01.
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|
Effect of tGLP-1 on mean arterial blood pressure and
heart rate in bilateral vagotomized rats. In an attempt
to determine whether the signal generated by the tGLP-1 on the CNS was
transmitted from the brain to the periphery by the vagus nerve, the
effect of this peptide on cardiovascular parameters was studied in
bilaterally vagotomized rats. As expected, mean arterial blood pressure
(sham-operated: 58.1 ± 2.3 and vagotomized: 68.0 ± 1.7) and heart
rate (sham-operated 381.0 ± 9.0 and vagotomized: 436.7 ± 10.1)
increased significantly (P < 0.001)
in vagotomized rats before tGLP-1 treatment. As shown in Fig.
6, intracerebroventricular administration
of 100 ng of tGLP-1 to intact rats produced the already known increase
in mean arterial blood pressure, but this effect disappeared in
bilaterally vagotomized animals. Interestingly, bilateral vagotomy did
not prevent the stimulating action of intravenous tGLP-1 on mean
arterial blood pressure (Fig. 7,
A and
B), although this effect was lower in vagotomized than in intact rats. Also, bilateral vagotomy abolished the blocking effect of intracerebroventricular exendin-(9
39) on mean
arterial blood pressure after intravenous administration of tGLP-1
(Fig. 8, A
and B).

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Fig. 6.
Effect of icv administration of tGLP-1 on arterial blood pressure
(A) and heart rate
(B) in rats with bilateral vagotomy.
Animals with ( ) or without ( ) bilateral vagotomy at cervical
region were injected in third ventricle with 100 ng of tGLP-1. Results
are means ± SE; n = 6-8 rats.
ANOVA with Newman-Keuls test was used for statistical comparisons
between data obtained in 2 experimental groups.
* P < 0.01.
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Fig. 7.
Effect of peripheral administration of tGLP-1 on mean arterial blood
pressure (A) and heart rate
(B) in rats with bilateral vagotomy.
Animals with ( ) or without ( ) bilateral vagotomy at cervical
region were injected in jugular vein with 100 ng of tGLP-1. Results are
means ± SE; n = 6-8 rats.
ANOVA with Newman-Keuls test was used for statistical comparisons
between data obtained in 2 experimental groups.
* P < 0.01.
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Fig. 8.
Effect of iv administration of tGLP-1 on mean arterial blood pressure
(A) and heart rate
(B) in rats with bilateral vagotomy
and pretreated with icv administration of exendin-(9 39). Animals with
( ) or without ( ) bilateral vagotomy at cervical region were
injected icu with 2,500 ng 5 min before iv administration of 100 ng of
tGLP-1. Results are means ± SE; n = 6-8 rats. ANOVA with Newman-Keuls test was used for statistical
comparisons between data obtained in 2 experimental groups.
* P < 0.01.
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 |
DISCUSSION |
Previous studies carried out in rats (2) have shown that peripheral
administration of tGLP-1 induces an increase in systolic and diastolic
blood pressure and in heart rate. Glucagon and other glucagon-related
peptides were less effective when the same parameters were considered.
The action of tGLP-1 on arterial blood pressure and heart rate seems to
be mediated through its own receptors because exendin-4 acts as an
agonist and exendin-(9
39) blocks the effects of that peptide on
cardiovascular parameters (3). Because both tGLP-1 and its receptors
have been found in significant amounts in the nucleus tractus
solitarius (15, 16, 30, 36), which is involved in the central control
of cardiovascular function (8), the possibility exists that exogenously
administered tGLP-1 alters cardiovascular parameters through a central
mechanism. The area postrema is also significantly involved in
cardiovascular regulation (13) and has significant amounts of GLP-1
receptors (24), suggesting that the action of tGLP-1 on arterial blood pressure would be the consequence of previous binding of this peptide
to the nucleus tractus solitarius and area postrema.
Accordingly, experiments were designed in an attempt to elucidate
the possible control of the CNS on the effect of tGLP-1 on arterial
blood pressure and heart rate. Here we report that
intracerebroventricular administration of tGLP-1 produces an increase
in systolic and diastolic blood pressure and heart rate, these effects
being blocked by previous injection of exendin-(9
39). It is
noteworthy to mention that the potency and timing of tGLP-1 effects
were different depending of the route of its administration. Thus
intravenous injection of the peptide produces a more potent and rapid
response on cardiovascular parameters then when it was
intracerebroventricularly administered, whereas central injection of
tGLP-1 induced a more prolonged time of action. Further studies are
needed for a better understanding of these differences, although the
possibility of a greater dilution of the peptide in the blood
circulation, a slower degradation of tGLP-1 in the CNS, and/or a
different number of GLP-1 receptors on peripheral or central locations
should kept in mind. Our results suggest a specific role of the CNS on
the stimulating effect of tGLP-1 on cardiovascular parameters. It
should be considered that the hypothalamus and brain stem are both the
sites of highest tGLP-1 content and of high GLP-1 receptor densities
and that the nucleus of the solitary tract is involved in
cardiorespiratory regulation and in metabolic homeostasis. Also,
microinjection of neuropeptide Y into the caudal nucleus of the
solitary tract produces significant dose-related reductions in mean
arterial blood pressure, pulse pressure, and respiratory minute volume (10). This peptide antagonizes the effects of tGLP-1 on cardiovascular parameters as well as food and drink intake.
Exendins are a group of peptides isolated from
Helodermatidae venoms, with structural
and functional analogies with tGLP-1, in which exendin-4 works as an
agonist and exendin-(9
39) as an antagonist of the truncated forms of
GLP-1. These facts open the possibility for the use of this peptide as
a tool to test the role of tGLP-1 in physiological states.
In an attempt to know whether the action of tGLP-1 on cardiovascular
parameters was due to a peripheral and/or central effect, the peptide
was injected either intravenously or intracerebroventricularly, whereas
the antagonist exendin-(9
39) was administered through the same or the
other route. With this procedure, we found that previous
intracerebroventricular administration of exendin-(9
39) prevents the
stimulating action of intravenous injection of tGLP-1 on arterial blood
pressure, indicating the contribution of the CNS to this process. By
contrast, when injected into the peripheral blood circulation,
exendin-(9
39) did not antagonize intracerebroventricular administration of tGLP-1. These results suggest that exendin-(9
39) cannot cross the blood-brain barrier or that the circulating amounts of
this peptide are not sufficient to block the action of
intracerebroventricularly administered tGLP-1.
A key finding of our experiments is that intracerebroventricular
exendin-(9
39) blocks the effects of intravenously administered tGLP-1. This result can be explained in terms of a "leakage" of the antagonist peptide to the periphery. This view, however, is inconsistent with our finding that intracerebroventricular tGLP-1 has
no physiological effect in bilaterally vagotomized animals, and more so
because bilateral vagotomy prevents the central antagonism blockade of
peripheral agonist activity. Interestingly, peripheral administration
of tGLP-1 into the jugular vein of bilaterally vagotomized rats
produced a significant increase in mean arterial blood pressure,
suggesting that this peptide may act through two pathways, one under
parasympathetic influence and the other one generated at the periphery.
This second option points to the possibility that the presence of GLP-1
receptors in the heart (38) might play a role in the stimulating effect
of the peptide on cardiovascular parameters, as well as open the
question of whether or not there are GLP-1 receptors in vascular beds
or in adrenal medulla. Also, the effects of the central sympathetic
outflow on the GLP-1 system should be considered. However, the effects
of tGLP-1 on arterial blood pressure and heart rate are not mediated by
catecholamines through either
- or
-adrenergic receptors (2).
Earlier studies indicated that tGLP-1 is a potent insulin secretagogue
(19) acting directly on pancreatic
-cells, but later on it was
reported that other extrapancreatic biological effects of this peptide are mediated via the brain rather than in peripheral tissues (21, 22,
32, 34). These actions include the effects of tGLP-1 on the release of
neurotransmitters from selective brain nuclei (21), the inhibition of
gastric acid secretion and motility (39), and control of food and water
intake (22, 32, 34). Here, we also report a role of the CNS in the
effect of tGLP-1 increasing arterial blood pressure and heart rate and
also that the signal arising in the brain is transmitted by the vagus
nerve to the periphery. Other regulatory peptides, such as neuropeptide Y and pancreatic polypeptide, produce some of their effects by mediation of the parasympathetic nervous system. Thus bilateral subdiaphragmatic vagotomy prevents both basal and glucose-induced hyperinsulinemia of rats chronically intracerebroventricularly treated
with neuropeptide Y (29). Taking as an example pancreatic polypeptide,
this peptide enters the brain through the blood-brain barrier-free area
postrema and adjacent subpostrema area and then binds to the dorsal
vagal motor nucleus and nucleus of the solitary tract. The binding of
pancreatic polypeptide to these nuclei inhibits vagal inputs to the
gastrointestinal system (40). Because tGLP-1 enters the brain by
binding to GLP-1 receptors located in the area postrema and the
subfornical organ (24), it has been suggested (15) that this peptide,
as well as pancreatic polypeptide, may play a similar role in a
putative gut-brain axis. Also, tGLP-1 inhibits gastric acid secretion,
gastric emptying, and pancreatic enzyme secretion (39). These effects
of the peptide are not found in vagotomized subjects, suggesting a
centrally mediated effect (23).
A central effect of tGLP-1 on cardiovascular parameters may be induced
by the peptide synthesized either in the gut and/or the brain.
Peripheral blood-borne tGLP-1 might enter the brain by binding to
blood-brain barrier-free organs, such as the area postrema and
subfornical organ (24), or might be transported into the brain by the
choroid plexus, which has a high density of GLP-1 receptors (1). In
addition, the tGLP-1 released from the brain may also play a
physiological role. Gut-derived tGLP-1 and brain-derived tGLP-1 are
structurally identical, and both may interact with GLP-1 receptors in
the central nervous system. These receptors are identical to its
counterparts located peripherally. GLP-1 receptor cDNA from human (38)
and rat (1) brain has been cloned and sequenced, and the deduced amino
acid sequences are the same as the sequence found in pancreatic islets.
In summary, our findings indicate that the stimulating effect of tGLP-1
on arterial blood pressure and heart rate in the rat is under dual
control emerging from the CNS and from peripheral structures. It seems
that the neural activity generated in this process is transmitted from
the brain to the periphery through the vagus nerve, while the presence
of GLP-1 receptors in peripheral cardiovascular sites may be useful for
the extraparasympathetic influence of tGLP-1 on arterial blood pressure
and heart rate.
 |
ACKNOWLEDGEMENTS |
This work was supported by grants from the Dirección General
de Investigación Científica y Técnica, and Fondo de
Investigaciones Sanitarias, Spain.
 |
FOOTNOTES |
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 and other correspondence: E. Blázquez, Departamento de Bioquímica y Biología
Molecular, Facultad de Medicina, Universidad Complutense, 28040 Madrid,
Spain.
Received 21 January 1999; accepted in final form 9 July 1999.
 |
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