Importância da região AV3V e de mecanismos colinérgicos e angiotensinérgicos centrais para os efeitos cardiovasculares produzidos pela ativação da área rostroventrolateral do bulbo
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2008-03-27Autor
Vieira, Alexandre Antonio
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Cardiovascular responses are integrated at different levels of the central
nervous system (CNS). In the brainstem, there are different areas related to the
cardiovascular control such as the rostral ventrolateral medulla (RVLM) that
activates sympathetic pre-ganglionic neurons in the spinal cord (IML) inducing
pressor response. Like glutamatergic activation, central cholinergic and
angiotensinergic activation modulates sympathetic activity and increases arterial
pressure. The RVLM receives inhibitory and excitatory projections from different
areas of the central nervous system that are important to modulate cardiovascular
responses. One of the areas that send projection to the RVLM is the anteroventral
third ventricle (AV3V) region. AV3V lesion impairs many forms of hypertension and
reduces pressor responses like those produced by central cholinergic and
angiotensinergic activation.
Recent study in unanesthetized rats has shown that the AV3V lesion
attenuates the pressor response to glutamatergic activation into the RVLM.
Besides glutamate, injections of angiotensin II (ANG II) or carbachol (cholinergic
agonist) into the RVLM evoke increase in the sympathetic activity and blood
pressure. For this reason, in the present study, we investigated the effects of acute
(1 day) or chronic (15 days) AV3V lesions on pressor responses produced by ANG
II (200 ng/100 nl) or carbachol (1 nmol/100 nl) into the RVLM. Male Holtzman rats
(280 a 320 g) with sham or electrolytic AV3V lesions and a stainless steel cannula
implanted into the RVLM were used. Mean arterial pressure (MAP) and heart rate
(HR) were recorded in unanesthetized rats that had polyethylene tubing (PE 10)
implanted into the abdominal aorta through the femoral artery on day before the experiments. A second polyethylene tubing was inserted in the femoral vein for
baroreflex and chemoreflex tests. Central injections were made using 5 ml Hamilton
syringes. The volume of the central injections into the RVLM was 100 nl. The
results have shown that both acute and chronic AV3V lesion attenuate the pressor
responses to ANG II (12 ± 3 and 12 ± 5 vs. control: 26 ± 4 mmHg) but not the
pressor responses to carbachol (38 ± 4 and 29 ± 3 vs. control: 34 ± 4 mmHg)
suggesting that some mechanisms belonging to the RVLM are affected and other
are not affected by AV3V lesions. Besides, AV3V lesion does not alter baro and
chemoreflex responses produced by endovenous (i.v) injections of phenylephrine,
sodium nitroprusside and potassium cyanide.
After these results, another question arose: which would be the possible
mechanisms impaired by the AV3V lesion that attenuate the pressor responses to
RVLM activation? The AV3V region is important for the activation of pressor
mechanism like sympathetic activity and vasopressin secretion produced by central
cholinergic and angiotensinergic activation. Therefore, the pressor response to
glutamate into the RVLM was tested in rats with central cholinergic blockade
produced by the injection of atropine (4 nmol/1 ml) or angiotensinergic blockade
produced by injection of losartan (100 mg/1 ml) or ZD 7155 (50 mg/1 ml) into the
lateral ventricle (LV). Male Holtzman rats with stainless steel cannula implanted
into the LV and unilaterally into the RVLM were used. MAP and HR were recorded
in unanesthetized rats with polyetylene tubing inserted into the abdominal aorta
through the femoral artery and vein. The volume of the central injections into the
LV was 1 ml. The results showed that the pressor response to glutamate injected into the RVLM (51 ± 4 mmHg) in control condition was attenuated after injection of
atropine (36 ± 5 mmHg), losartan (22 ± 5 mmHg) or ZD 7155 (26 ± 7 mmHg) into
the LV. However, a question that remained was about the possible spreading of
these antagonists into the brain blocking the receptors directly into the RVLM. For
this reason, we tested the pressor responses to glutamate into the RVLM after
cholinergic or angiotensinergic blockade into the own RVLM.
Mean arterial pressure (MAP) and heart rate (HR) were recorded in
unanesthetized rats with cannula only into the RVLM and polyethylene tubing
implanted into the abdominal aorta through the femoral artery. The results showed
that atropine (4 nmol/100 nl) injected into the RVLM did not alter the pressor
response to glutamate into the same site (49± 4 vs. control: 50 ± 4 mmHg). So,
only cholinergic mechanisms belonging to forebrain or areas outside the RVLM are
important for the pressor response to glutamate into the RVLM. However, the
pressor response to glutamate into the RVLM was almost abolished and
attenuated after injection of the losartan (5 ± 3 mmHg) or ZD 7155 (33 ± 4 mmHg),
respectively, into the RVLM, which did not solve the question about the possible
spread of losartan or ZD 7155. With the same purpose we tested the pressor
response to ANG II into the RVLM after losartan or ZD 7155 into the LV. In this
experiment, the pressor response to ANG II into the RVLM in control condition (26
± 3 mmHg) was not impaired after losartan or ZD 7155 into the LV (20 ± 3 e 23 ± 1
mmHg, respectively) suggesting that these antagonists injected into the LV do not
reach the RVLM. Therefore, angiotensinergic mechanisms belonging in the RVLM
or from outside the RVLM (probably forebrain) are important for the pressor response to glutamate into the RVLM. However, it is important to consider that
AV3V lesion reduces the pressor response to ANG II into the RVLM, while icv
injection of the angiotensinergic antagonists showed no effect in this response,
which suggests that the effects of AV3V lesion reducing the pressor response to
ANG II into the RVLM are not related to any impairment of forebrain
angiotensinergic mechanisms by the lesion.
Another aim was to study if glutamatergic receptor activation in the RVLM
was necessary for the pressor response to central cholinergic or angiotensinergic
activation. For this, male Holtzman rats with stainless steel cannulas implanted into
the LV and bilaterally into the RVLM were used. The results showed no difference
between the cardiovascular responses produced by carbachol into the LV after
kynurenic acid (1 nmol/100 nl) bilaterally into the RVLM (36 ± 1 mmHg and 22 ± 10
bpm) when compared with control condition (39 ± 2 mmHg and 23 ± 14 bpm). Also,
there was not difference between the cardiovascular responses produced by ANG
II into the LV after kynurenic acid (1 nmol/100 nl) into the RVLM (28 ± 3 mmHg and
10 ± 13 bpm) when compared with control condition (26 ± 2 mmHg and -12 ± 5
bpm). This dose of kynurenic acid almost abolished the pressor response to
glutamate (2 nmol/100 nl) injected into the RVLM but not the cardiovascular
reflexes produced by baro and chemoreflex activation. Therefore, the pressor
response to forebrain cholinergic or angiotensinergic activation does not depend
on glutamatergic synapses in the RVLM. Besides, the results also showed that the
pressor response to chemoreflex activation does not depend on release of
glutamate into the RVLM