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CENTRAL MECHANISMS INVOLVED IN THE CONTROL OF ARTERIAL PRESSURE AND FLUID-ELECTROLYTE BALANCE: IMPORTANCE OF THE AV3V REGION José V. Menani Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil. - PowerPoint PPT Presentation
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CENTRAL MECHANISMS INVOLVED IN
THE CONTROL OF ARTERIAL PRESSURE
AND FLUID-ELECTROLYTE BALANCE:
IMPORTANCE OF THE AV3V REGION
José V. MenaniDepartment of Physiology and Pathology, School of
Dentistry, São Paulo State University, UNESP,
Araraquara, SP, Brazil.
CENTRAL MECHANISMS INVOLVED IN
THE CONTROL OF ARTERIAL PRESSURE
AND FLUID-ELECTROLYTE BALANCE:
IMPORTANCE OF THE AV3V REGION
José V. MenaniDepartment of Physiology and Pathology, School of
Dentistry, São Paulo State University, UNESP,
Araraquara, SP, Brazil.
IMPORTANT FOREBRAIN AND HINDBRAIN AREAS INVOLVED INCARDIOVASCULAR REGULATION
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
MSA = medial septal areaVMH = ventromedial hypothalamusSFO = subfornical organMnPO = median preoptic nucleusAVPV = anteroventral periventricular nucleiOVLT = organum vasculosum of the lamina terminalisPVN = paraventricular hypothalamic nucleusNTS = nucleus of the solitary tractRVL = rostroventrolateral medullaCVL = caudoventrolateral medullaIML = spinal intermediolateral column
CHEMORECEPTOR
BARORECEPTOR
IML
NTS
CVLRVL
N. AMBIGUUS
PARASYMPATHETIC
MSA
VMH
AV3V REGIONMnPO = median preoptic nucleusAVPV = anteroventral periventricular nucleiOVLT = organum vasculosum of the lamina terminalis(Brody and Johnson, 1978)
AV3V REGION(anteroventral 3rd ventricle region)
AV3V REGION
AV3V REGION
(Brody and Johnson, 1978)
ELECTROLYTIC AV3V LESION(ARROW)
500 m
SHAM LESION
ac
500 m
oc
* different from sham lesion
INC
RE
AS
E I
N M
AP
(m
mH
g)
0
10
20
30
40
*
SHAM LESION(n = 10)
AV3V LESION(n = 7)
EFFECTS OF AV3V LESIONS ON THE PRESSOR RESPONSE TO ICV ANG II (12 ng)
AV3V LESIONS ABOLISH THE PRESSOR RESPONSETO ANG II (12 ng) INTRACEREBROVENTRICULARLY
0 20 40 60 80 100 120 140-60
-40
-20
0
20
40
pilocarpine (1 mg/kg) ip
* *
** * * *
**
**
*
saline
time (min)
Ch
an
ge
s in
MA
P (
mm
Hg
)
++
+ + + ++
+ + + + +
++
++
+ ++ +
N = 8
1 h and 2 days after lesion
Sham (1 hour) Sham (2 days)AV3V lesion (1 hour) AV3V lesion (2 days)
*different from sham +different from pre-pilocarpine
Effects of AV3V lesion on the pressor response to ip pilocarpine
PILOCARPINE : cholinergic agonist
AV3V LESIONS ABOLISH THE PRESSOR RESPONSETO INTRAPERITONEAL PILOCARPINE (1 mg/kg)
* different from sham lesion (n = 6 - 13)
Injection site
INC
RE
AS
E I
N M
AP
(m
mH
g)
0
10
20
30
40
50
60
2 12 5 18 5 18 2 15 Days after lesion
LV7.5 nmol
SFO2 nmol
MSA2 nmol
VMH2 nmol
**
* * * *
*
*
SHAM LESION AV3V LESION
EFFECTS OF AV3V LESIONS ON THE PRESSOR RESPONSE TO CENTRAL CARBACOL
LV = lateral ventricleSFO = subfornical organ
MSA = medial septal areaVMH = ventromedial hypothalamus
CARBACHOL: muscarinic agonist
AV3V LESIONS REDUCE THE PRESSOR RESPONSETO INJECTION OF CARBACHOL (2 nmol) IN THE FOREBRAIN
* different from sham lesion (n = 6 - 13)
Injection site
Wa
ter
inta
ke
(m
l/6
0 m
in)
0
2
4
6
8
10
12
14
2 12 3 16 3 16 2 15 Days after lesion
LV7.5 nmol
SFO2 nmol
MSA2 nmol
VMH2 nmol
*
*
* * * **
*
SHAM LESION AV3V LESION
EFFECTS OF AV3V LESIONS ON THE DIPSOGENIC RESPONSE TO CENTRAL CARBACOL
LV = lateral ventricleSFO = subfornical organ
MSA = medial septal areaVMH = ventromedial hypothalamus
CARBACHOL: muscarinic agonist
AV3V LESIONS REDUCE THE DIPSOGENIC RESPONSETO INJECTION OF CARBACHOL (2 nmol) IN THE FOREBRAIN
* different from sham lesion (n = 6 - 13)
Injection site
Na+
ex
cre
tio
n (
E
q/2
h)
0
200
400
600
800
1 9 1 14 1 14 2 15 Lesion (days)
LV7.5 nmol
SFO2 nmol
MSA2 nmol
VMH2 nmol
** **
*
*
**
SHAM LESION AV3V LESION
EFFECTS OF AV3V LESIONS ON THE NATRIURETIC RESPONSE TO CENTRAL CARBACOL
Carbacol
*1
LVsaline
LV = lateral ventricleSFO = subfornical organ
MSA = medial septal areaVMH = ventromedial hypothalamus
CARBACHOL: muscarinic agonist
AV3V LESIONS REDUCE THE NATRIURETIC RESPONSETO INJECTION OF CARBACHOL (2 nmol) IN THE FOREBRAIN
PRESSOR, DIPSOGENIC AND NATRIURETIC RESPONSESTO CHOLINERGIC ACTIVATION OF FOREBRAIN AREAS LIKE
MSA, SFO OR VMH DEPEND ON THE AV3V REGION
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
MSA = medial septal areaVMH = ventromedial hypothalamusSFO = subfornical organMnPO = median preoptic nucleusAVPV = anteroventral periventricular nucleiOVLT = organum vasculosum of the lamina terminalisPVN = paraventricular hypothalamic nucleusNTS = nucleus of the solitary tractRVL = rostroventrolateral medullaCVL = caudoventrolateral medullaIML = spinal intermediolateral column
CHEMORECEPTOR
BARORECEPTOR
IML
NTS
CVLRVL
N. AMBIGUUS
PARASYMPATHETIC
MSA
VMH
AV3V REGION
IS THE AV3V REGION ALSO IMPORTANT FOR THE PRESSOR RESPONSES PRODUCED BY THE ACTIVATION OF HINDBRAIN
AREAS LIKE THE NTS OR RVLM?
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
MSA = medial septal areaVMH = ventromedial hypothalamusSFO = subfornical organMnPO = median preoptic nucleusAVPV = anteroventral periventricular nucleiOVLT = organum vasculosum of the lamina terminalisPVN = paraventricular hypothalamic nucleusNTS = nucleus of the solitary tractRVL = rostroventrolateral medullaCVL = caudoventrolateral medullaIML = spinal intermediolateral column
CHEMORECEPTOR
BARORECEPTOR
IML
NTS
CVLRVL
N. AMBIGUUS
PARASYMPATHETIC
MSA
VMH
AV3V REGION
NTS injectionglutamate
substance P
AV3V lesion
Ch
an
ge
s i
n H
R (
bp
m)
-120
-90
-60
-30
0
MA
P i
nc
rea
se
(m
mH
g)
-40
-20
0
20
40
1 day 15 days
(10)
(9)
(10)
(8) (10)
(10)
(9)
* different from sham lesion
*
*
(8)
Sham lesion AV3V lesion
EFFECTS OF GLUTAMATE (5 nmol) INTO THE NTS IN AV3V-LESIONED RATS
AV3V LESIONS ABOLISH THE PRESSOR RESPONSETO INJECTION OF GLUTAMATE INTO THE NTS
MA
P i
nc
re
as
e (
mm
Hg
)
0
5
10
15
20
25
30
S P0.5 nmol
Sham lesion
AV3V lesionIn
cre
as
e i
n H
R (
bp
m)
0
20
40
60
80
100
(4)
(6)
(9)
(9)
(11)
(11)
S P 1 nmol
(6)
(4)
AV3V LESIONS (1 DAY) PRODUCE NO EFFECT IN THE PRESSOR RESPONSE TO INJECTION OF SUBSTANCE P INTO THE NTS
RVLM injectionglutamate
AV3V LESION
MA
P in
cre
as
e (
mm
Hg
)
0
10
20
30
40
50
60
70
saline L-glu1 nmol
L-glu5 nmol
Sham lesion AV3V lesion
* different from saline
Ch
an
ge
s in
HR
(b
pm
)
-80
-60
-40
-20
0
20
(15)
(15)
(7)
(7)
(10)
(10)
(7)
(7)
(15)
(15)
(9)
(9)
*
L-glu10 nmol
(9)
(9)
(6)
(6)
*
different from sham lesion
+
+
++
*
**
AV3V LESIONS (1 DAY) REDUCE THE PRESSOR RESPONSETO INJECTION OF GLUTAMATE INTO THE RVLM
MA
P in
cre
as
e (
mm
Hg
)
0
10
20
30
40
50
60
70
saline L-glu1 nmol
L-glu5 nmol
L-glu10 nmol
* different from saline
Ch
an
ge
s in
HR
(b
pm
)
-80
-60
-40
-20
0
20
*
**
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(8)
(8)
(8)
(8)
(10)
(10)
Sham lesion AV3V lesion
different from sham+
+
++
*
**
AV3V LESIONS (15 DAYS) REDUCE THE PRESSOR RESPONSE TO INJECTION OF GLUTAMATE INTO THE RVLM
PRESSOR RESPONSES TO GLUTAMATERGIC ACTIVATION OF HINDBRAIN AREAS LIKE NTS AND RVLM ALSO DEPEND
ON FACILITATORY SIGNALS FROM AV3V REGION
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
MSA = medial septal areaVMH = ventromedial hypothalamusSFO = subfornical organMnPO = median preoptic nucleusAVPV = anteroventral periventricular nucleiOVLT = organum vasculosum of the lamina terminalisPVN = paraventricular hypothalamic nucleusNTS = nucleus of the solitary tractRVL = rostroventrolateral medullaCVL = caudoventrolateral medullaIML = spinal intermediolateral column
CHEMORECEPTOR
BARORECEPTOR
IML
NTS
CVLRVL
N. AMBIGUUS
PARASYMPATHETIC
MSA
VMH
AV3V REGION
Effects of AV3V lesion on 1 kidney - 1 clip renal hypertension
TIME (days)
MA
P (
mm
Hg
)
100
120
140
160
180
200
Sham lesionAV3V lesionSham lesion + renal hypertensionAV3V lesion + renal hypertension
0 7 14 21 28
(n = 9-12)
* **
* different from sham lesion+ different from sham lesion + renal hypertension
*
*
* *+ + +
+
AV3V LESIONS ALSO REDUCE HYPERTENSION OF 1-KIDNEY, 1-CLIP HYPERTENSIVE RATS
IN SPITE OF THE ANTI-HYPERTENSIVE EFFECTS OF AV3V LESIONS IN DIFFERENT MODELS OF EXPERIMENTAL
HYPERTENSION, THESE LESIONS ALONE PRODUCE NO EFFECT IN SPONTANEOULY HYPERTENSIVE RATS (SHR).
MIGHT ANOTHER AREA OF THE BRAINBE INVOLVED IN HYPERTENSION IN SHR?
PERIPHERAL CHEMORECEPTOR ACTIVITY IS HIGH IN SHR AND LESIONS OF THE COMMISSURAL PORTION OF THE NTS
(COMMNTS) ABOLISH THE PRESSOR RESPONSE TOCHEMORECEPTOR ACTIVATION.
THEN, MIGHT COMMNTS LESIONS AFFECT HYPERTENSIONIN SHR?
ELECTROLYTIC LESION OF THE COMMNTS (arrows)
Basal MAP of sham- and commNTS-lesioned SHR in the control day (day 0)
and days 1, 2, 3, and 4 after sham or commNTS lesions.
Akemi Sato M et al. Hypertension 2001;38:560-564
ACUTE LESIONS OF THE COMMNTS ABOLISH HYPERTENSION IN SHR
Basal MAP and HR in sham or commNTS-lesioned SHR on the control day (pre-lesion) and 1, 10, 20, and 30 days after lesions
Sato M A et al. Hypertension 2003;42:713-718
CHRONIC LESIONS OF THE COMMNTS PRODUCE NO EFFECT ON HYPERTENSION IN SHR
Sato M A et al. Hypertension 2003;42:713-718
ACUTE OR CHRONIC LESIONS OF THE COMMNTS ABOLISH THE PRESSOR RESPONSE TO CHEMOREFLEX ACTIVATION IN SHR
LESIONS OF THE COMMNTS ABOLISH CHEMOREFLEX CHRONICALLY AND HYPERTENSION ONLY ACUTELY IN SHR
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
MSA = medial septal areaVMH = ventromedial hypothalamusSFO = subfornical organMnPO = median preoptic nucleusAVPV = anteroventral periventricular nucleiOVLT = organum vasculosum of the lamina terminalisPVN = paraventricular hypothalamic nucleusNTS = nucleus of the solitary tractRVL = rostroventrolateral medullaCVL = caudoventrolateral medullaIML = spinal intermediolateral column
CHEMORECEPTOR
BARORECEPTOR
IML
NTS
CVLRVL
N. AMBIGUUS
PARASYMPATHETIC
MSA
VMH
x
WHICH MIGHT BE THE EFFECT OF COMBINED COMMNTS ANDAV3V LESIONS IN HYPERTENSION IN SHR?
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
MSA = medial septal areaVMH = ventromedial hypothalamusSFO = subfornical organMnPO = median preoptic nucleusAVPV = anteroventral periventricular nucleiOVLT = organum vasculosum of the lamina terminalisPVN = paraventricular hypothalamic nucleusNTS = nucleus of the solitary tractRVL = rostroventrolateral medullaCVL = caudoventrolateral medullaIML = spinal intermediolateral column
CHEMORECEPTOR
BARORECEPTOR
IML
NTS
CVLRVL
N. AMBIGUUS
PARASYMPATHETIC
MSA
VMH
xxAV3V REGION
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30100
120
140
160
180
200
220
MA
P (
mm
Hg
)
Days
* Different from sham lesions
* *
AV3V + commNTS lesions (n = 8)
commNTS lesion (n = 7)
Sham lesions (n = 6)
*
*
AV3V lesion (n = 8)
***
*
* ***
COMBINED COMMNTS AND AV3V LESIONS PERMANENTLY REDUCE HYPERTENSION IN SHR
LESION
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
MSA = medial septal areaVMH = ventromedial hypothalamusSFO = subfornical organMnPO = median preoptic nucleusAVPV = anteroventral periventricular nucleiOVLT = organum vasculosum of the lamina terminalisPVN = paraventricular hypothalamic nucleusNTS = nucleus of the solitary tractRVL = rostroventrolateral medullaCVL = caudoventrolateral medullaIML = spinal intermediolateral column
CHEMORECEPTOR
BARORECEPTOR
IML
NTS
CVLRVL
N. AMBIGUUS
PARASYMPATHETIC
MSA
VMH
xxAV3V REGION
COMBINED COMMNTS AND AV3V LESIONS PERMANENTLY REDUCE HYPERTENSION IN SHR
WHICH MIGHT BE THE EFFECT OF CHEMORECEPTORDENERVATION IN HYPERTENSION IN SHR?
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
MSA = medial septal areaVMH = ventromedial hypothalamusSFO = subfornical organMnPO = median preoptic nucleusAVPV = anteroventral periventricular nucleiOVLT = organum vasculosum of the lamina terminalisPVN = paraventricular hypothalamic nucleusNTS = nucleus of the solitary tractRVL = rostroventrolateral medullaCVL = caudoventrolateral medullaIML = spinal intermediolateral column
CHEMORECEPTOR
BARORECEPTOR
IML
NTS
CVLRVL
N. AMBIGUUS
PARASYMPATHETIC
MSA
VMH
x x
School of Physiology & Pharmacology, Bristol Heart Institute, Medical Sciences Building, University of Bristol, Bristol BS81TD, UK. Neuroscience, Physiology & Pharmacology, University College London,
London WC1E6BT,UK
THE REMOVAL OF CHEMORECEPTOR SIGNALS BY CAROTID SINUS DENERVATION (CSD) REDUCES HYPERTENSION IN SHR
Abdala AP, McBryde FD, Marina N, Hendy EB, Engelman Z, Fudim M, Sobotka PA, Gourine A, Paton J . Hypertension is critically dependent on the carotid body input in the spontaneously hypertensive rat.
J Physiol. 590, 4269-4277, 2012.
BLOODPRESSURE
(mmHg)
100
150
200
400
300
HEARTRATE(bpm)
SHR SHAM SHR CSD WISTAR SHAM
BRITISH SCIENTIST PROPOSAL:
THEY PLAN TO START TESTING THE EFFECTS OF SURGICAL
REMOVAL OF CHEMORECEPTOR AFFERENCES ON
HYPERTENSION IN HUMANS, PARTICULARLY IN PATIENTS
THAT DO NOT RESPOND TO TRADITIONAL TREATMENTS.
Eduardo Colombari Alexandre A. VieiraDébora S.A. Colombari Ana C.T. TakakuraLaurival A. De Luca Jr Antonio S. ValladãoThiago S. Moreira Monica A. Sato
Departamento de Fisiologia e Patologia, Faculdade de Odontologia de Araraquara, UNESP