CENTRAL MECHANISMS INVOLVED IN THE CONTROL OF ARTERIAL PRESSURE AND FLUID-ELECTROLYTE BALANCE: IMPORTANCE OF THE AV3V REGION José V. Menani Department.

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


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

*

*

* * * **

*


EFFECTS OF AV3V LESIONS ON THE DIPSOGENIC RESPONSE TO CENTRAL CARBACOL




AV3V LESIONS REDUCE THE DIPSOGENIC RESPONSETO INJECTION OF CARBACHOL (2 nmol) IN THE FOREBRAIN


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

** **

*

*

**


EFFECTS OF AV3V LESIONS ON THE NATRIURETIC RESPONSE TO CENTRAL CARBACOL

Carbacol

*1

LVsaline




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



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?



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


* 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)


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



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



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?



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



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?



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

CENTRAL MECHANISMS INVOLVED IN THE CONTROL OF ARTERIAL PRESSURE AND FLUID-ELECTROLYTE BALANCE: IMPORTANCE OF THE AV3V REGION José V. Menani Department.

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