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Regulation by midbrain raphe nuclei and locus ceruleus on cerebral vasomotor responses
Journal of the
ELSEVIER
Autonomic Nervous System Journal of the Autonomic Nervous System 49 (1994) $31-835
Regulation by midbrain raphe nuclei and locus ceruleus on cerebral vasomotor responses H. K i m , K. S h i m a z u *, T. O h k u b o , Y. M a r u k i , H. S u g i m o t o , Y. A s a n o , A. O n o d a , Y. N a k a z a t o , M. S a w a d a , D. F u r u y a , K. H a m a g u c h i Department of Neurology, Saitama Medical School, Saitama, Japan
Key words: R a p h e n u c l e u s ; Locus ceruleus; A u t o r e g u l a t i o n ; C O 2 reactivity
1. Introduction
2. Materials and Methods
It has been suggested that midbrain raphe nuclei have important roles in cerebral circulation and metabolism [1-3] by sending serotonergic fibers to both the large and small vessels of the brain [4,5] as well as to the locus ceruleus [6,7], which is the center of the adrenergic system. However, few studies [8,9] have been reported with regard to the functional significance of the serotonergic system in cerebral vasomotor responses to changes in arterial CO 2 tension (PaCOp. Moreover, no study was undertaken regarding the cerebral vasomotor responses to changes in perfusion pressure. The focus of the present study was directed towards the roles of these nuclei in the cerebral vasomotor responses to changes in cerebral perfusion pressure and PaCOz.
Twenty-eight monkeys (Macaca fuscata, 6.6 + 2.1 kg, mean + S.D.) were anesthetized with achloralose and urethane, and immobilized with pancuronium. Body temperature and PaCO 2 were maintained within physiological ranges (37.3 + 1.1°C, 36.3_+4.2 mmHg, respectively) using a heating pad and mechanical ventilation throughout the experiment. The femoral artery and vein, and superior sagittal sinus were cannulated for the withdrawal of blood samples and for monitoring blood pressure and heart rate. The subjects were divided into three groups (nucleus dorsalis raphes, NDR: n = 8; nucleus centralis superior, NCS: n = 8; locus ceruleus, LC: n = 12). The animals were operated stereotaxically and a bipolar electrode with 30 /~m tip was inserted to coagulate the unilateral nucleus dorsalis raphes, nucleus centralis superior, or locus ceruleus. The internal carotid blood flow (ICBF) was measured continuously with an electromagnetic flow probe, while simultaneously blood pressure, heart rate and end-tidal P C O 2 w e r e recording.
* Corrsponding author.
0165-1838/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved
SSDI 0 1 6 5 - 1 8 3 8 ( 9 4 ) 0 0 0 4 8 - O
$32
H. Kim et al. /Journal of the Autonomic Nervous System 49 (1994) $31-$35
Autoregulation index (A.I. --- AICBF/A MABP, m l / m i n / m m H g ) was calculated using the ratio between internal carotid blood flow and MABP. The chemical vasomotor index (C.V.I.= AICBF/APaCO2, m l / m i n / m m H g ) was also calculated, using the ratio between the internal carotid blood flow and PaCO 2. Comparisons between the three groups were statistically evaluated by the Student's unpaired t-test. Side-to-side comparisons were analyzed using Student's paired t-test. All tests were initially assessed at the P < 0.05 level of significance.
0.S"
U,<0.0s-q 0.4
1
-e E
0.3.
E
0.1-
E
0,0.
~
-o.1. -0.2
LC
NCS
i
NDR
Fig. 2. Autoregulation indexes of the three groups in induced hypotension: A.I. of the nucleus dorsalis raphes group was significantly ameliorated after coagulation
3. Results
became significantly less than before the coagulation (P < 0.05). Neither the nucleus centralis superior nor the locus ceruleus group showed any significant change in autoregulatory response to induced hypotension after the coagulation. (b) Autoregulatory response to induced hypertension (Figs. 3 and 4): The autoregulation index in induced hypertension of the locus ceruleus
3.1. Cerebral vasomotor responses to changes in cerebral perfusion pressure (a) Autoregulatory response to induced hypotension (Figs. 1 and 2): After the coagulation, the autoregulation index (A.I.) of the NDR group
_
ICBF
After
Before ~I:H~ i ....
.....
.....
. . . .
5
I: ° . [ 250
MABP
! l~4~
200
PR
-
* fN
I,o 200mmHsl
~00
BP
,, )
I
Imln (AS-ClaM. No.ql3)
Fig. 1. The real record during induced hypotcnsion of one of the nucleus dorsalis raphes group: The effect of induced hypotcnsion on ICBF, PR, MABP, and BP are illustrated before and after coagulation. The decrease of I C I ~ was much less after the coagulation.
H. Kim et al. /Journal of the Autonomic Nervous System 49 (1994) $31-$35
Before
$33
After
III
ICBF
-.------_...-_
~
120.0
. . . . T 20.Oml/mln /
~5.0
~5.0
T 2751mln
PR
275
"
-
-
-_.
~
.
.
.
L
175
175
MABP
[ 150mmHg
,
_..v- ]-'5°
.
.
-LSO
'J-50
175
BP 30 Imln
(AB-CBFM, No.'S$5) Fig. 3. The real records during induced hypertension of one of the locus ceruleus group: The effect of induced hypertension on ICBF, PR, MABP, and BP are illustrated before and after coagulation. The increase of ICBF was much greater after the coagulation.
group showed a significant increase after destruction ( P < 0.05). In contrast, no significant changes in the autoregulation index were observed in both the nucleus centralis superior group and the nucleus dorsalis raphes. 3.2. Cerebral vasomotor responses to changes in PaCO 2
(a) Chemical vasomotor response to induced hypercapnia (Fig. 5): After the coagulation, none of the three groups showed any changes in the
chemical vasomotor indexes when compared with those before the coagulation. (b) Chemical vasomotor response to induced hypocapnia (Fig. 6): The chemical vasomotor index of the nucleus dorsalis raphes group in induced hypocapnia tended worsened after coagulation (P < 0.058), while neither the nucleus centralis superior nor the locus ceruleus showed any significant change. The delta chemical vasomotor index of the nucleus dorsalis raphes group had significantly worsened (P < 0.02) when compared
0,6-
0.5 "IE E ._c E E
1.4
I-P<0"°5-1
/
1.2
0.4
1.0
0.3 0.2
c
0.8
o
0.8
0.1
C~
0.0
0.4 0.2
-0.1 0.0
-0.2
LC
NCS
NDR
Fig. 4. Autoregulation indexes of the three group in induced hypertension: A.I. of locus ceruleus group was significantly impaired after coagulation.
LC
NCS
NDR
Fig. 5. Cerebral vasomotor indexes of the three nuclei groups in induced hypercapnia: No significant changes of C.V.I. between before and after coagulation were observed in the 3 groups.
$34
H. Kim et al. /Journal of the Autonomic Nervous System 49 (1994) $31-$35 1.0 0.8
-~ T=
o.~ 0.4 0.2 0.0
Lp=o.o577J
LC
NCS
NDR
Fig. 6. Cerebral vasomotor indexes of the three nuclei in induced hypocapnia: C.V.I. of nucleus dorsalis raphes group tended to be worsened after coagulation.
to the locus ceruleus group during induced hypocapnia (Fig. 7).
4. Discussion and Comment In the brainstem nuclei which innervate vasoactive fibers to cerebral vessels [4,5], the midbrain raphe nuclei as well as the locus ceruleus, are speculated to be important in cerebral circulation and metabolism [1-3]. However, it is unclear which nucleus has a predominant role in the cerebral vasomotor responses. Moreover, few studies have been reported on the functional roles of the midbrain raphe nuclei in the cerebral vasomotor reactivities to changes in PaCO 2 [8], and there are no previous data with regard to cerebral peffusion pressure. Our present study demonstrated that the CBF autoregulatory response to induced hypotension was ameliorated following coagulation of the nucleus dorsalis raphes. This result suggests that the nucleus dorsalis raphes may regulate the lower part of autoregulatory response curve, possibly due to its vasoconstrictive effect via the serotonergic nervous system. In contrast, the autoregulatory response to induced hypertension was impaired after coagulation of the locus ceruleus. This result also suggests that the locus ceruleus may control the upper part of autoregulatory response curve by its vasoconstrictive function at the time of induced hypertension.
From the results of both the nucleus dorsalis raphes and the locus ceruleus in the CBF autoregulatory responses, the former may anti-protectively affect the lower part of autoregulatory response curve, whereas the latter may protect the upper part. Concerning the cerebral vasomotor response to changes in PaCO 2, the cerebral vasoconstrictive reactivity during induced hypocapnia was impaired after destruction of the nucleus dorsalis raphes. From our data, it is speculated that the nucleus dorsalis raphes may modulate the cerebral vasomotor response to induced hypocapnia, presumably through promoting vasoconstriction via the serotonergic nervous system. Few data have previously been reported about this issue. Underwood et al. [8] reported that the cerebrovascular response to changes in PaCO 2 had not changed, even after destruction of the nucleus dorsalis raphes. The disagreement between their data and ours may be based on the difference in species (rat), method (laser-Doppler) or measured site (parietal sensorymotor cortex). In conclusion, the nucleus dorsalis raphes has a significant role in the cerebral vasomotor responses to changes not only in cerebral perfusion pressure but also in PaCO 2 by its vasoconstrictive effect via the serotonergic nervous system. The locus ceruleus also regulates CBF-autoregulatory response, especially to the upper part, by its
1.0 0.8 0.6 0.4 (.) 0.2 <3 0.0 -0.2 -0.4 -0.6 -0.8
A ~ - - -
p < 0.02 -
j
-1.0 LC
NCS
NDR
Fig. 7. Delta-cerebral vasomotor indexes of the three nuclei in induced hypocapnia. AC,V.I. = (after coa~l;ulation - before) C.V.t./before C.V.I.: AC.V:L of nucleus dot,sails r a p h e s ~ p was significantly worsened in comparison with t h e locus ceruleus after coagulation.
H. Kim et al. /Journal of the Autonomic Nervous System 49 (1994) $31-$35
vasoconstrictive effect via the central adrenergic nervous system. References [1] Goasby, P.J., Piper, R.D., Lambert, G.A. et al., Effect of stimulation of nucleus raphe dorsalis on carotid blood flow. I. The monkey. Am. J. Physiol., 248 (1985) R257R262. [2] Bonvento, G., Lacombe, P., Seylaz, J., Effects of electrical stimulation of the dorsal raphe nucleus on local cerebral blood flow in the rat. J. CBF Metabol., 9 (1989) 251-255. [3] Cudennec, A., Duverger, D., MacKenzie, E.T., Nature of the regional increases in cerebral blood flow induced by raphe stimulation in the concious rat. J. CBF Metabol., 9 (1989) $375. [4] Edvinsson, L., Degueurce, A., Duverger, D. et al., Central serotonergic nerves project to the pial vessels of the brain. Nature, 306 (1983) 55-57.
$35
[5] Bonvento, G., Lacombe, P., MacKenzie, E.T. et al., Evidence for differing origins of the serotonergic innervation of major cerebral arteries and small pial vessels in the rat. J. Neurochem., 56 (199) 681-689. [6] Dahlgren, N., Lindvall, O., Sakabe, T. et al., Cerebral blood flow and oxygen consumption in the rat brain after lesions of the noradrenergic locus ceruleus system. Brain Res., 209 (1981) 11-23. [7] Goasby, P.J., Lambert, G.A., Lance, J.W., Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation. Brain Res. 249 (1982) 247-254. [8] Underwood, M.D., Bakalian, M.J., Arango, V. et al., Regulation of cortical blood flow by the dorsal raphe nucleus: Topographic organization of cerebrovascular regulatory regions. J. CBF Metabol. 12 (1992) 664-673. [9] Itakura, T., Yokote, H., Kimura, H. et al., 5-Hydroxytryptamine innervation of vessels in the rat cerebral cortex. Immunohistochemical findings and hydrogen clearance study of rCBF.J. Neurosurg., 62 (1985) 42-47.
ELSEVIER
Autonomic Nervous System Journal of the Autonomic Nervous System 49 (1994) $31-835
Regulation by midbrain raphe nuclei and locus ceruleus on cerebral vasomotor responses H. K i m , K. S h i m a z u *, T. O h k u b o , Y. M a r u k i , H. S u g i m o t o , Y. A s a n o , A. O n o d a , Y. N a k a z a t o , M. S a w a d a , D. F u r u y a , K. H a m a g u c h i Department of Neurology, Saitama Medical School, Saitama, Japan
Key words: R a p h e n u c l e u s ; Locus ceruleus; A u t o r e g u l a t i o n ; C O 2 reactivity
1. Introduction
2. Materials and Methods
It has been suggested that midbrain raphe nuclei have important roles in cerebral circulation and metabolism [1-3] by sending serotonergic fibers to both the large and small vessels of the brain [4,5] as well as to the locus ceruleus [6,7], which is the center of the adrenergic system. However, few studies [8,9] have been reported with regard to the functional significance of the serotonergic system in cerebral vasomotor responses to changes in arterial CO 2 tension (PaCOp. Moreover, no study was undertaken regarding the cerebral vasomotor responses to changes in perfusion pressure. The focus of the present study was directed towards the roles of these nuclei in the cerebral vasomotor responses to changes in cerebral perfusion pressure and PaCOz.
Twenty-eight monkeys (Macaca fuscata, 6.6 + 2.1 kg, mean + S.D.) were anesthetized with achloralose and urethane, and immobilized with pancuronium. Body temperature and PaCO 2 were maintained within physiological ranges (37.3 + 1.1°C, 36.3_+4.2 mmHg, respectively) using a heating pad and mechanical ventilation throughout the experiment. The femoral artery and vein, and superior sagittal sinus were cannulated for the withdrawal of blood samples and for monitoring blood pressure and heart rate. The subjects were divided into three groups (nucleus dorsalis raphes, NDR: n = 8; nucleus centralis superior, NCS: n = 8; locus ceruleus, LC: n = 12). The animals were operated stereotaxically and a bipolar electrode with 30 /~m tip was inserted to coagulate the unilateral nucleus dorsalis raphes, nucleus centralis superior, or locus ceruleus. The internal carotid blood flow (ICBF) was measured continuously with an electromagnetic flow probe, while simultaneously blood pressure, heart rate and end-tidal P C O 2 w e r e recording.
* Corrsponding author.
0165-1838/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved
SSDI 0 1 6 5 - 1 8 3 8 ( 9 4 ) 0 0 0 4 8 - O
$32
H. Kim et al. /Journal of the Autonomic Nervous System 49 (1994) $31-$35
Autoregulation index (A.I. --- AICBF/A MABP, m l / m i n / m m H g ) was calculated using the ratio between internal carotid blood flow and MABP. The chemical vasomotor index (C.V.I.= AICBF/APaCO2, m l / m i n / m m H g ) was also calculated, using the ratio between the internal carotid blood flow and PaCO 2. Comparisons between the three groups were statistically evaluated by the Student's unpaired t-test. Side-to-side comparisons were analyzed using Student's paired t-test. All tests were initially assessed at the P < 0.05 level of significance.
0.S"
U,<0.0s-q 0.4
1
-e E
0.3.
E
0.1-
E
0,0.
~
-o.1. -0.2
LC
NCS
i
NDR
Fig. 2. Autoregulation indexes of the three groups in induced hypotension: A.I. of the nucleus dorsalis raphes group was significantly ameliorated after coagulation
3. Results
became significantly less than before the coagulation (P < 0.05). Neither the nucleus centralis superior nor the locus ceruleus group showed any significant change in autoregulatory response to induced hypotension after the coagulation. (b) Autoregulatory response to induced hypertension (Figs. 3 and 4): The autoregulation index in induced hypertension of the locus ceruleus
3.1. Cerebral vasomotor responses to changes in cerebral perfusion pressure (a) Autoregulatory response to induced hypotension (Figs. 1 and 2): After the coagulation, the autoregulation index (A.I.) of the NDR group
_
ICBF
After
Before ~I:H~ i ....
.....
.....
. . . .
5
I: ° . [ 250
MABP
! l~4~
200
PR
-
* fN
I,o 200mmHsl
~00
BP
,, )
I
Imln (AS-ClaM. No.ql3)
Fig. 1. The real record during induced hypotcnsion of one of the nucleus dorsalis raphes group: The effect of induced hypotcnsion on ICBF, PR, MABP, and BP are illustrated before and after coagulation. The decrease of I C I ~ was much less after the coagulation.
H. Kim et al. /Journal of the Autonomic Nervous System 49 (1994) $31-$35
Before
$33
After
III
ICBF
-.------_...-_
~
120.0
. . . . T 20.Oml/mln /
~5.0
~5.0
T 2751mln
PR
275
"
-
-
-_.
~
.
.
.
L
175
175
MABP
[ 150mmHg
,
_..v- ]-'5°
.
.
-LSO
'J-50
175
BP 30 Imln
(AB-CBFM, No.'S$5) Fig. 3. The real records during induced hypertension of one of the locus ceruleus group: The effect of induced hypertension on ICBF, PR, MABP, and BP are illustrated before and after coagulation. The increase of ICBF was much greater after the coagulation.
group showed a significant increase after destruction ( P < 0.05). In contrast, no significant changes in the autoregulation index were observed in both the nucleus centralis superior group and the nucleus dorsalis raphes. 3.2. Cerebral vasomotor responses to changes in PaCO 2
(a) Chemical vasomotor response to induced hypercapnia (Fig. 5): After the coagulation, none of the three groups showed any changes in the
chemical vasomotor indexes when compared with those before the coagulation. (b) Chemical vasomotor response to induced hypocapnia (Fig. 6): The chemical vasomotor index of the nucleus dorsalis raphes group in induced hypocapnia tended worsened after coagulation (P < 0.058), while neither the nucleus centralis superior nor the locus ceruleus showed any significant change. The delta chemical vasomotor index of the nucleus dorsalis raphes group had significantly worsened (P < 0.02) when compared
0,6-
0.5 "IE E ._c E E
1.4
I-P<0"°5-1
/
1.2
0.4
1.0
0.3 0.2
c
0.8
o
0.8
0.1
C~
0.0
0.4 0.2
-0.1 0.0
-0.2
LC
NCS
NDR
Fig. 4. Autoregulation indexes of the three group in induced hypertension: A.I. of locus ceruleus group was significantly impaired after coagulation.
LC
NCS
NDR
Fig. 5. Cerebral vasomotor indexes of the three nuclei groups in induced hypercapnia: No significant changes of C.V.I. between before and after coagulation were observed in the 3 groups.
$34
H. Kim et al. /Journal of the Autonomic Nervous System 49 (1994) $31-$35 1.0 0.8
-~ T=
o.~ 0.4 0.2 0.0
Lp=o.o577J
LC
NCS
NDR
Fig. 6. Cerebral vasomotor indexes of the three nuclei in induced hypocapnia: C.V.I. of nucleus dorsalis raphes group tended to be worsened after coagulation.
to the locus ceruleus group during induced hypocapnia (Fig. 7).
4. Discussion and Comment In the brainstem nuclei which innervate vasoactive fibers to cerebral vessels [4,5], the midbrain raphe nuclei as well as the locus ceruleus, are speculated to be important in cerebral circulation and metabolism [1-3]. However, it is unclear which nucleus has a predominant role in the cerebral vasomotor responses. Moreover, few studies have been reported on the functional roles of the midbrain raphe nuclei in the cerebral vasomotor reactivities to changes in PaCO 2 [8], and there are no previous data with regard to cerebral peffusion pressure. Our present study demonstrated that the CBF autoregulatory response to induced hypotension was ameliorated following coagulation of the nucleus dorsalis raphes. This result suggests that the nucleus dorsalis raphes may regulate the lower part of autoregulatory response curve, possibly due to its vasoconstrictive effect via the serotonergic nervous system. In contrast, the autoregulatory response to induced hypertension was impaired after coagulation of the locus ceruleus. This result also suggests that the locus ceruleus may control the upper part of autoregulatory response curve by its vasoconstrictive function at the time of induced hypertension.
From the results of both the nucleus dorsalis raphes and the locus ceruleus in the CBF autoregulatory responses, the former may anti-protectively affect the lower part of autoregulatory response curve, whereas the latter may protect the upper part. Concerning the cerebral vasomotor response to changes in PaCO 2, the cerebral vasoconstrictive reactivity during induced hypocapnia was impaired after destruction of the nucleus dorsalis raphes. From our data, it is speculated that the nucleus dorsalis raphes may modulate the cerebral vasomotor response to induced hypocapnia, presumably through promoting vasoconstriction via the serotonergic nervous system. Few data have previously been reported about this issue. Underwood et al. [8] reported that the cerebrovascular response to changes in PaCO 2 had not changed, even after destruction of the nucleus dorsalis raphes. The disagreement between their data and ours may be based on the difference in species (rat), method (laser-Doppler) or measured site (parietal sensorymotor cortex). In conclusion, the nucleus dorsalis raphes has a significant role in the cerebral vasomotor responses to changes not only in cerebral perfusion pressure but also in PaCO 2 by its vasoconstrictive effect via the serotonergic nervous system. The locus ceruleus also regulates CBF-autoregulatory response, especially to the upper part, by its
1.0 0.8 0.6 0.4 (.) 0.2 <3 0.0 -0.2 -0.4 -0.6 -0.8
A ~ - - -
p < 0.02 -
j
-1.0 LC
NCS
NDR
Fig. 7. Delta-cerebral vasomotor indexes of the three nuclei in induced hypocapnia. AC,V.I. = (after coa~l;ulation - before) C.V.t./before C.V.I.: AC.V:L of nucleus dot,sails r a p h e s ~ p was significantly worsened in comparison with t h e locus ceruleus after coagulation.
H. Kim et al. /Journal of the Autonomic Nervous System 49 (1994) $31-$35
vasoconstrictive effect via the central adrenergic nervous system. References [1] Goasby, P.J., Piper, R.D., Lambert, G.A. et al., Effect of stimulation of nucleus raphe dorsalis on carotid blood flow. I. The monkey. Am. J. Physiol., 248 (1985) R257R262. [2] Bonvento, G., Lacombe, P., Seylaz, J., Effects of electrical stimulation of the dorsal raphe nucleus on local cerebral blood flow in the rat. J. CBF Metabol., 9 (1989) 251-255. [3] Cudennec, A., Duverger, D., MacKenzie, E.T., Nature of the regional increases in cerebral blood flow induced by raphe stimulation in the concious rat. J. CBF Metabol., 9 (1989) $375. [4] Edvinsson, L., Degueurce, A., Duverger, D. et al., Central serotonergic nerves project to the pial vessels of the brain. Nature, 306 (1983) 55-57.
$35
[5] Bonvento, G., Lacombe, P., MacKenzie, E.T. et al., Evidence for differing origins of the serotonergic innervation of major cerebral arteries and small pial vessels in the rat. J. Neurochem., 56 (199) 681-689. [6] Dahlgren, N., Lindvall, O., Sakabe, T. et al., Cerebral blood flow and oxygen consumption in the rat brain after lesions of the noradrenergic locus ceruleus system. Brain Res., 209 (1981) 11-23. [7] Goasby, P.J., Lambert, G.A., Lance, J.W., Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation. Brain Res. 249 (1982) 247-254. [8] Underwood, M.D., Bakalian, M.J., Arango, V. et al., Regulation of cortical blood flow by the dorsal raphe nucleus: Topographic organization of cerebrovascular regulatory regions. J. CBF Metabol. 12 (1992) 664-673. [9] Itakura, T., Yokote, H., Kimura, H. et al., 5-Hydroxytryptamine innervation of vessels in the rat cerebral cortex. Immunohistochemical findings and hydrogen clearance study of rCBF.J. Neurosurg., 62 (1985) 42-47.