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.
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.
IMPORTANT FOREBRAIN AND HINDBRAIN AREAS INVOLVED IN
CARDIOVASCULAR REGULATION
MSA
CHEMORECEPTOR
NTS
VMH
BARORECEPTOR
N. AMBIGUUS
IML
MSA = medial septal area
RVL
VMH = ventromedial hypothalamus
CVL
SFO = subfornical organ
MnPO = median preoptic nucleus
AVPV = anteroventral periventricular nuclei
OVLT = organum vasculosum of the lamina terminalis
PARASYMPATHETIC
PVN = paraventricular hypothalamic nucleus
NTS = nucleus of the solitary tract
RVL = rostroventrolateral medulla
CVL = caudoventrolateral medulla
IML = spinal intermediolateral column
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
AV3V REGION
(anteroventral 3rd ventricle region)
AV3V REGION
AV3V REGION
MnPO = median preoptic nucleus
AVPV = anteroventral periventricular nuclei
OVLT = organum vasculosum of the lamina terminalis
(Brody and Johnson, 1978)
AV3V REGION
(Brody and Johnson, 1978)
SHAM LESION
ELECTROLYTIC AV3V LESION
(ARROW)
ac
500 mm
500 mm
oc
EFFECTS
OF AV3VTHE
LESIONS
ON THE
AV3V LESIONS
ABOLISH
PRESSOR
RESPONSE
PRESSOR
RESPONSE
TO ICV ANG II (12 ng)
TO ANG
II (12 ng)
INTRACEREBROVENTRICULARLY
SHAM LESION
(n = 10)
AV3V LESION
(n = 7)
INCREASE IN MAP (mmHg)
* different from sham lesion
40
30
20
10
0
*
AV3V LESIONS ABOLISH THE PRESSOR RESPONSE
TO INTRAPERITONEAL
PILOCARPINE
Effects of AV3V
lesion on the pressor
response(1tomg/kg)
ip pilocarpine
Sham (1 hour)
AV3V lesion (1 hour)
*different from sham
Sham (2 days)
AV3V lesion (2 days)
+different from pre-pilocarpine
Changes in MAP (mmHg)
PILOCARPINE : cholinergic agonist
1 h and 2 days after lesion
40
+
+
+ + +
+ + + +
+ + +
N=8
20
* * * *
*+
*+ +
*
+
*
+
* *+ + +
* *
0
-20
-40
-60
0
20
40
60
80
100
120
140
time (min)
saline
pilocarpine (1 mg/kg) ip
AV3V LESIONS
REDUCE
THEON
PRESSOR
RESPONSE
EFFECTS
OF AV3V
LESIONS
THE PRESSOR
TO INJECTION
OF CARBACHOL
(2 nmol)
IN THE FOREBRAIN
RESPONSE
TO CENTRAL
CARBACOL
AV3V LESION
SHAM LESION
60
LV = lateral ventricle
SFO = subfornical organ
MSA = medial septal area
VMH = ventromedial hypothalamus
50
CARBACHOL: muscarinic agonist
INCREASE IN MAP (mmHg)
* different from sham lesion
(n = 6 - 13)
40
30
20
*
*
*
*
*
*
10
0
*
2
*
12
LV
7.5 nmol
5
18
SFO
2 nmol
5
18
MSA
2 nmol
2
15 Days after lesion
VMH Injection site
2 nmol
AV3V LESIONS
REDUCE
THEON
DIPSOGENIC
RESPONSE
EFFECTS
OF AV3V
LESIONS
THE DIPSOGENIC
TO INJECTION
OF CARBACHOL
(2 nmol)
IN THE FOREBRAIN
RESPONSE
TO CENTRAL
CARBACOL
AV3V LESION
SHAM LESION
14
LV = lateral ventricle
SFO = subfornical organ
MSA = medial septal area
VMH = ventromedial hypothalamus
12
CARBACHOL: muscarinic agonist
Water intake (ml/60 min)
* different from sham lesion
(n = 6 - 13)
10
8
6
*
4
2
0
*
*
*
*
2
*
*
*
12
LV
7.5 nmol
3
16
SFO
2 nmol
3
16
MSA
2 nmol
2
15 Days after lesion
VMH Injection site
2 nmol
AV3V LESIONS
REDUCE
THE NATRIURETIC
RESPONSE
EFFECTS
OF AV3V
LESIONS
ON THE NATRIURETIC
RESPONSE
TO CENTRAL
CARBACOL
TO INJECTION
OF CARBACHOL
(2 nmol)
IN THE FOREBRAIN
AV3V LESION
SHAM LESION
LV = lateral ventricle
SFO = subfornical organ
MSA = medial septal area
VMH = ventromedial hypothalamus
800
CARBACHOL: muscarinic agonist
600
400
*
200
*
+
Na excretion ( mEq/2 h)
* different from sham lesion
(n = 6 - 13)
0
* *
*
1
1
9
*
1
*
*
*
14
SFO
LV
LV
saline 7.5 nmol 2 nmol
1
14
MSA
2 nmol
2
15
Lesion (days)
Injection site
VMH
2 nmol Carbacol
PRESSOR, DIPSOGENIC AND NATRIURETIC RESPONSES
TO CHOLINERGIC ACTIVATION OF FOREBRAIN AREAS LIKE
MSA, SFO OR VMH DEPEND ON THE AV3V REGION
MSA
CHEMORECEPTOR
AV3V REGION
NTS
VMH
BARORECEPTOR
N. AMBIGUUS
IML
MSA = medial septal area
RVL
CVL
VMH = ventromedial hypothalamus
SFO = subfornical organ
MnPO = median preoptic nucleus
AVPV = anteroventral periventricular nuclei
OVLT = organum vasculosum of the lamina terminalis
PARASYMPATHETIC
PVN = paraventricular hypothalamic nucleus
NTS = nucleus of the solitary tract
RVL = rostroventrolateral medulla
CVL = caudoventrolateral medulla
IML = spinal intermediolateral column
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
IS THE AV3V REGION ALSO IMPORTANT FOR THE PRESSOR
RESPONSES PRODUCED BY THE ACTIVATION OF HINDBRAIN
AREAS LIKE THE NTS OR RVLM?
MSA
CHEMORECEPTOR
AV3V REGION
NTS
VMH
BARORECEPTOR
N. AMBIGUUS
IML
MSA = medial septal area
RVL
VMH = ventromedial hypothalamus
CVL
SFO = subfornical organ
MnPO = median preoptic nucleus
AVPV = anteroventral periventricular nuclei
OVLT = organum vasculosum of the lamina terminalis
PARASYMPATHETIC
PVN = paraventricular hypothalamic nucleus
NTS = nucleus of the solitary tract
RVL = rostroventrolateral medulla
CVL = caudoventrolateral medulla
IML = spinal intermediolateral column
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
AV3V lesion
NTS injection
glutamate
substance P
AV3V LESIONS ABOLISH THE PRESSOR RESPONSE
TO INJECTION OF GLUTAMATE INTO THE NTS
EFFECTS OF GLUTAMATE (5 nmol) INTO
THE NTS IN AV3V-LESIONED RATS
MAP increase (mmHg)
Sham lesion
40
AV3V lesion
* different from sham lesion
(10)
(8)
20
(9)
*
0
-20
-40
*
(10)
Changes in HR (bpm)
1 day
15 days
0
-30
-60
-90
-120
(8) (10)
(10)
(9)
MAP increase (mmHg)
AV3V LESIONS (1 DAY) PRODUCE NO EFFECT IN THE PRESSOR
RESPONSE TO INJECTION OF SUBSTANCE P INTO THE NTS
Sham lesion
AV3V lesion
30
25
(9)
(4)
(11)
(6)
20
15
10
5
0
S P
0.5 nmol
Increase in HR (bpm)
100
S P
1 nmol
(4)
(9)
80
60
40
20
0
(6)
(11)
AV3V LESION
RVLM injection
glutamate
AV3V LESIONS (1 DAY) REDUCE THE PRESSOR RESPONSE
TO INJECTION OF GLUTAMATE INTO THE RVLM
Sham lesion
AV3V lesion
* different from saline
+ different from sham lesion
*
MAP increase (mmHg)
70
(9)
*
60
(15)
+
+
*
50
(9)
*
*
(6)
(10)
40
30
+
20
10
(7)
(15)
(7)
0
saline
Changes in HR (bpm)
20
L-glu
1 nmol
L-glu
5 nmol
L-glu
10 nmol
(7)
0
(15) (7)
-20
(10)
(15)
-40
-60
(9)
(9)
(6)
-80
AV3V LESIONS (15 DAYS) REDUCE THE PRESSOR RESPONSE TO
INJECTION OF GLUTAMATE INTO THE RVLM
MAP increase (mmHg)
70
AV3V lesion
Sham lesion
* different from saline
+ different from sham
*
60
(10)
+
+
*
(8)
*
50
(10)
*
40
(10)
30
*
+
20
(8)
10
*
(10)
(10)
(10)
0
saline
20
L-glu
1 nmol
L-glu
5 nmol
L-glu
10 nmol
Changes in HR (bpm)
(10)
0
(10)
-20
-40
(10) (8)
(8)
(10)
(10)
-60
-80
(10)
PRESSOR RESPONSES TO GLUTAMATERGIC ACTIVATION OF
HINDBRAIN AREAS LIKE NTS AND RVLM ALSO DEPEND
ON FACILITATORY SIGNALS FROM AV3V REGION
MSA
CHEMORECEPTOR
AV3V REGION
NTS
VMH
BARORECEPTOR
N. AMBIGUUS
IML
MSA = medial septal area
RVL
VMH = ventromedial hypothalamus
CVL
SFO = subfornical organ
MnPO = median preoptic nucleus
AVPV = anteroventral periventricular nuclei
OVLT = organum vasculosum of the lamina terminalis
PARASYMPATHETIC
PVN = paraventricular hypothalamic nucleus
NTS = nucleus of the solitary tract
RVL = rostroventrolateral medulla
CVL = caudoventrolateral medulla
IML = spinal intermediolateral column
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
AV3V
LESIONS
ALSO
REDUCE
HYPERTENSION
Effects
of AV3V
lesion
on 1 kidney
- 1 clip
renal
hypertension
OF 1-KIDNEY,
1-CLIP
HYPERTENSIVE RATS
Sham lesion
AV3V lesion
Sham lesion + renal hypertension
AV3V lesion + renal hypertension
* different from sham lesion
+ different from sham lesion + renal hypertension
200
(n = 9-12)
MAP (mmHg)
180
*
*
*
*
160
*+
140
+
*+
*+
120
100
0
7
14
TIME (days)
21
28
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 BRAIN
BE 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 TO
CHEMORECEPTOR ACTIVATION.
THEN, MIGHT COMMNTS LESIONS AFFECT HYPERTENSION
IN SHR?
ELECTROLYTIC LESION OF THE COMMNTS (arrows)
Basal MAPACUTE
of shamand commNTS-lesioned
SHR in theABOLISH
control day (day 0)
LESIONS
OF THE COMMNTS
HYPERTENSION
INcommNTS
SHR
and days 1, 2,
3, and 4 after sham or
lesions.
Akemi Sato M et al. Hypertension 2001;38:560-564
Basal MAP and HR in sham or commNTS-lesioned SHR on the control day (preCHRONIC
LESIONS OF THE COMMNTS PRODUCE NO EFFECT ON
lesion) and 1, 10, 20, and 30 days after lesions
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
Sato M A et al. Hypertension 2003;42:713-718
LESIONS OF THE COMMNTS ABOLISH CHEMOREFLEX
CHRONICALLY AND HYPERTENSION ONLY ACUTELY IN SHR
MSA
CHEMORECEPTOR
x
NTS
VMH
BARORECEPTOR
N. AMBIGUUS
IML
MSA = medial septal area
RVL
VMH = ventromedial hypothalamus
CVL
SFO = subfornical organ
MnPO = median preoptic nucleus
AVPV = anteroventral periventricular nuclei
OVLT = organum vasculosum of the lamina terminalis
PARASYMPATHETIC
PVN = paraventricular hypothalamic nucleus
NTS = nucleus of the solitary tract
RVL = rostroventrolateral medulla
CVL = caudoventrolateral medulla
IML = spinal intermediolateral column
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
WHICH MIGHT BE THE EFFECT OF COMBINED COMMNTS AND
AV3V LESIONS IN HYPERTENSION IN SHR?
MSA
AV3V REGION
CHEMORECEPTOR
x
x
NTS
VMH
BARORECEPTOR
N. AMBIGUUS
IML
MSA = medial septal area
RVL
VMH = ventromedial hypothalamus
CVL
SFO = subfornical organ
MnPO = median preoptic nucleus
AVPV = anteroventral periventricular nuclei
OVLT = organum vasculosum of the lamina terminalis
PARASYMPATHETIC
PVN = paraventricular hypothalamic nucleus
NTS = nucleus of the solitary tract
RVL = rostroventrolateral medulla
CVL = caudoventrolateral medulla
IML = spinal intermediolateral column
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
COMBINED COMMNTS AND AV3V LESIONS
PERMANENTLY REDUCE HYPERTENSION IN SHR
Sham lesions (n = 6)
AV3V lesion (n = 8)
commNTS lesion (n = 7)
AV3V + commNTS lesions (n = 8)
* Different from sham lesions
MAP (mmHg)
220
200
180
*
160
140
120
100
*
*
*
* ** *
** * *
-2 0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30
Days
LESION
COMBINED COMMNTS AND AV3V LESIONS
PERMANENTLY REDUCE HYPERTENSION IN SHR
MSA
AV3V REGION
CHEMORECEPTOR
x
x
NTS
VMH
BARORECEPTOR
N. AMBIGUUS
IML
MSA = medial septal area
RVL
VMH = ventromedial hypothalamus
CVL
SFO = subfornical organ
MnPO = median preoptic nucleus
AVPV = anteroventral periventricular nuclei
OVLT = organum vasculosum of the lamina terminalis
PARASYMPATHETIC
PVN = paraventricular hypothalamic nucleus
NTS = nucleus of the solitary tract
RVL = rostroventrolateral medulla
CVL = caudoventrolateral medulla
IML = spinal intermediolateral column
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
WHICH MIGHT BE THE EFFECT OF CHEMORECEPTOR
DENERVATION IN HYPERTENSION IN SHR?
x x
MSA
CHEMORECEPTOR
NTS
VMH
BARORECEPTOR
N. AMBIGUUS
IML
MSA = medial septal area
RVL
VMH = ventromedial hypothalamus
CVL
SFO = subfornical organ
MnPO = median preoptic nucleus
AVPV = anteroventral periventricular nuclei
OVLT = organum vasculosum of the lamina terminalis
PARASYMPATHETIC
PVN = paraventricular hypothalamic nucleus
NTS = nucleus of the solitary tract
RVL = rostroventrolateral medulla
CVL = caudoventrolateral medulla
IML = spinal intermediolateral column
(Modified from Westerhaus and Loewy, J. Comp. Neurol., 1999)
THE REMOVAL OF CHEMORECEPTOR SIGNALS BY CAROTID SINUS
DENERVATION (CSD) REDUCES HYPERTENSION IN SHR
SHR SHAM
SHR CSD
WISTAR SHAM
200
BLOOD
PRESSURE 150
(mmHg)
100
HEART
RATE
(bpm)
400
300
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.
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
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
Débora S.A. Colombari
Laurival A. De Luca Jr
Thiago S. Moreira
Alexandre A. Vieira
Ana C.T. Takakura
Antonio S. Valladão
Monica A. Sato
Departamento de Fisiologia e Patologia, Faculdade de
Odontologia de Araraquara, UNESP