central control of blood pressure. what is wrong in ... is wrong in patients with essential...

Central control of blood pressure. What is wrong in

patients with essential hypertension?

Central control of blood pressure. What is wrong in

patients with essential hypertension?

Dr. Sergey Kasparov M.D., PhD

Department of PhysiologyE9

[email protected]



[email protected]

SK Teaching Website:SK Teaching Website: http://www.bris.ac.uk/Depts/Physiology/Staff/Pysk/Teaching/

05

10152025303540

MenWomen

34%30%

Data Source: www.heartstats.orgData Source: www.heartstats.org

%age of Men & Women with hypertension in England

%age of Men & Women with hypertension in England

% with highblood

pressure

% with highblood

pressure

For 2005:The cost of cardiovascular diseases (including high blood pressure) in the USAalone is estimated to be $393.5 billion

For 2005:The cost of cardiovascular diseases (including high blood pressure) in the USAalone is estimated to be $393.5 billion

Financial Burden of HypertensionFinancial Burden of Hypertension

Data Source: www.heartstats.org

% with Un-controlled hypertension

% with Un-controlled hypertension

0102030405060708090

Men Women

Are We Good at Treating High Blood Pressure?

Are We Good at Treating High Blood Pressure?

78% 67%

Evidence for higher sympathetic tone?

WHAT IS SYMPATHETIC N.S. and how brain controls it?

Autonomic - ???Autonomic - ???Can you change your heart rate?Can you change your heart rate?

Can you change the diameter of the pupilin your eye?Can you change the diameter of the pupilin your eye?

ANS operates without our conscious commandANS operates without our conscious command

C N S

Effector organ

?Adrenalgland

Parasympathetic N.S. Sympathetic N.S.

ANS anatomy

Modified from Gannongs textbook

III

XIX

VII

PARASYMPPARASYMPsympatheticsympathetic

What do these two systems do?What do these two systems do?

WE ONLY DO SYMPATHETIC in class. Please have a look at parasympathetic system effects at your own time later

WE ONLY DO SYMPATHETIC in class. Please have a look at parasympathetic system effects at your own time later

SYMPATHETIC

Fight or Flight

SYMPATHETIC

Fight or Flight

PARASYMPATHETIC

Rest and digest

PARASYMPATHETIC

Rest and digest

Fight or Flight

Effects related to cardio-vascular system. For other effects see handouts.

Effects related to cardio-vascular system. For other effects see handouts.

Heart:1. Increase in heart rate2. Increased force of contraction more blood pumped, more oxygen delivered to the tissues

Heart:1. Increase in heart rate2. Increased force of contraction more blood pumped, more oxygen delivered to the tissues

Blood vessels

Arterioles: re-distribution of blood infavour of the critical organs

Relaxation or weak constrictionRelaxation or weak constriction

Strong constriction

HeartBrainLungsSkeletal muscles

HeartBrainLungsSkeletal muscles

Veins: in many areas veins also constrict, thus more blood returns to the heart for faster re-circulation.

Veins: in many areas veins also constrict, thus more blood returns to the heart for faster re-circulation.

SkinAbdominal visceraKidneys

1. Cardiac output increase1. Cardiac output increase

2. Increased resistance to blood flow (constriction of arteries) 2. Increased resistance to blood flow (constriction of arteries) 3. Increased return of venous blood3. Increased return of venous blood

Systemic blood pressure increases:Systemic blood pressure increases:

Parasympathetic system: dominates at rest and during sleep. Night is the realm of vagus (the main parasympathetic nerve)Rest and digest.

Important effects of parasympathetic system on the heart:1. DEcrease in heart rate2. DEcrease in forceof contraction

As less oxygen is requiredby peripheral tissuesthe heart may alsohave a rest

Important effects of parasympathetic system on the heart:1. DEcrease in heart rate2. DEcrease in forceof contraction

As less oxygen is requiredby peripheral tissuesthe heart may alsohave a rest

200200

7070

8080

5050

ArterialPressureArterialPressure

HeartRateHeartRate

Reflex fall in heart rate triggered by afferent baroreceptors

Reflex fall in heart rate triggered by afferent baroreceptors

An increase in blood pressure An increase in blood pressure b) dilation of blood vesselsb) dilation of blood vesselsa) decrease in heart ratea) decrease in heart rate

Blood PressureDecreaseBlood PressureDecrease

Afferentsof the ANS

Carotid artery

Brainstem autonomic centresBrainstem autonomic centres

-50

80

100

50

Time

Bloodpressuremm Hg

Bloodpressuremm Hg

Activityof a baroreceptivenerve

Activityof a baroreceptivenerve

Data from Dr. H.Waki

AMPLIFIERAMPLIFIER

Brain in informed about the blood pressure by peripheral baroreceptorsBrain in informed about the blood pressure by peripheral baroreceptors

Carotid arteryCarotid artery

These sensory nerve endings get excited by stretch: the higher blood pressure the stronger the signal

These sensory nerve endings get excited by stretch: the higher blood pressure the stronger the signal

Effector organ heart or blood vessel

Afferentsof the ANS

Information processingby the brain

Para

sympa

thet

ic

INCR

EASE

Sympa

thet

ic

DEC

REASE

200200

7070

8080

5050


HeartRateHeartRate

220220

9090

90907070


HeartRateHeartRate

NORMALNORMAL

HYPERTENSIVEHYPERTENSIVE

Is there as abnormality within the central link in

hypertension?

Is there as abnormality within the central link in

hypertension?

?

?

?

?

?

sympa

thet

icpara

sympa

thet

ic

Can you identify thesestructures on your diagram?

Can you identify thesestructures on your diagram?

sympa

thet

icpara

sympa

thet

ic

Is there something wrong going on here in hypertension ???Is there something wrong going on here in hypertension ???

End of lecture 1End of lecture 1

Lecture 2. New insights into the central control

of blood pressure

Lecture 2. New insights into the central control

of blood pressure



[email protected]



[email protected]

SK Teaching Website:SK Teaching Website: http://www.bris.ac.uk/Depts/Physiology/Staff/Pysk/Teaching/

OR: USING VIRAL VECTORS TO STUDY HYPERTENSION

OR: USING VIRAL VECTORS TO STUDY HYPERTENSION

The BrainstemThe Brainstem

RVLM

NTS

CVLMNA

DMN Medulla oblongataSpinal cord

Cerebellum

(+)(+)

(+)

(+)

(+)

ParasympatheticHeart slowsParasympatheticHeart slows

SympatheticVasoconstrictionIncrease HR

SympatheticVasoconstrictionIncrease HR

(-)

(+)(+)BaroreceptorsBaroreceptors

A hypothesis:1.In hypertension transmission

of baroreceptor information is inhibited at the level of NTS

2.This effect may be due to the actions of nitric oxide

A hypothesis:1.In hypertension transmission

of baroreceptor information is inhibited at the level of NTS

2.This effect may be due to the actions of nitric oxide

Q. How can we test this hypothesis?A. Use a genetic tool to inhibit NO production in NTS and measure cardio-vascular parameters in a freely moving animal.

Q. How can we test this hypothesis?A. Use a genetic tool to inhibit NO production in NTS and measure cardio-vascular parameters in a freely moving animal.

Some facts about nitric oxide:1. A gas produced by (mainly) two enzymes, neuronal

nitric oxide synthase and endothelial nitric oxide synthase (eNOS)

2. Acts on various neurones and can activate inhibitory synapses in NTS (therefore can inhibit baroreflex pathway)

Some facts about nitric oxide:1. A gas produced by (mainly) two enzymes, neuronal

nitric oxide synthase and endothelial nitric oxide synthase (eNOS)

2. Acts on various neurones and can activate inhibitory synapses in NTS (therefore can inhibit baroreflex pathway)

Our tools: replication-deficient viral vectorsOur tools: replication-deficient viral vectors

VIRUSES AS VECTORSVIRUSES AS VECTORS

To make a virus act as vector we need to delete part of its genome to:1) Make it unable to replicate and therefore to cause a disease2) Clear room to accommodate the expression cassette, i.e. delete a part of the viral genome3) Learn how to proliferate the vectors and how to purify them to high titres4) Establish efficient transfection protocols

To make a virus act as vector we need to delete part of its genome to:1) Make it unable to replicate and therefore to cause a disease2) Clear room to accommodate the expression cassette, i.e. delete a part of the viral genome3) Learn how to proliferate the vectors and how to purify them to high titres4) Establish efficient transfection protocols

Viral vectors- high efficiency of gene delivery in vivo- high levels of transgene expression- stability of expression

Vectors derived from1) Adenovirus (common cold virus)2) Lenti/Retrovirus (relatives of HIV)And several others

Viral vectors- high efficiency of gene delivery in vivo- high levels of transgene expression- stability of expression

Vectors derived from1) Adenovirus (common cold virus)2) Lenti/Retrovirus (relatives of HIV)And several others

Adenoviral (Ad) vectors- non-enveloped double stranded DNA virus associated with mild human infections

Adenoviral (Ad) vectors- non-enveloped double stranded DNA virus associated with mild human infections

0

ITRTRANSGENE An

Late transcription

0 20 40 60 80 100

ITR ITR

E1 E2 E3 E4

L1 L2 L3 L4 L5

Early E genes

pentonbases

fibreprojections

Late L genes

36 kb genome

Entry of adenoviruses into the cellsEntry of adenoviruses into the cells

Receiver

Calibrated Pressure Output Adapter

Calibrated Pressure Output Adapter

Ambient PressureReference

Ambient PressureReference

Automated analysis SystemAutomated analysis System

TransmitterTransmitter

Receiver

Radiotelemetry: Measuring cardiovascular parameters in conscious freely moving rats

Radiotelemetry: Measuring cardiovascular parameters in conscious freely moving rats

How to block eNOS?How to block eNOS?

Functionalhomo-dimerFunctionalhomo-dimer

Non-functionaldimer

Non-functionaldimer

Nativemonomers

Nativemonomers

TruncatedmonomerTruncatedmonomer

Inhibition of endothelial NOS by expression of its dominant negative truncation mutant (Lee et al. 1995).The expression was driven by a non-selective HCMV promoter.

Inhibition of endothelial NOS by expression of its dominant negative truncation mutant (Lee et al. 1995).The expression was driven by a non-selective HCMV promoter.

eNOSeNOS

eNOSeNOSeNOSeNOS

http://images.google.co.uk/imgres?imgurl=http://www.globalspec.com/NpaPics/89/180213_071520047443_ExhibitPic.jpg&imgrefurl=http://www.globalspec.com/FeaturedProducts/Detail/kdScientific/KDS_100_Single_Syringe_Infusion_Pump/16049/1&h=214&w=300&sz=36&hl=en&start=11&tbnid=jud6jrf7xoaGFM:&tbnh=83&tbnw=116&prev=/images%3Fq%3Dinfusion%2Bpump%26ndsp%3D20%26svnum%3D10%26hl%3Den%26lr%3D%26sa%3DN

The outcome:Expression of eNOS dominant negative decreases blood pressure in SHR

The outcome:Expression of eNOS dominant negative decreases blood pressure in SHR

Waki et al Hypertension 2006

00 77 1414

SystolicBloodpressure

SystolicBloodpressure eNOSi in SHReNOSi in SHR

EGFP in SHREGFP in SHR

eNOSi in WKYeNOSi in WKY

p

Conclusion:In this experiment viral gene transfer has been used to prove a role for the eNOS (endothelial nitric oxide synthase) in pathological hypertension

Conclusion:In this experiment viral gene transfer has been used to prove a role for the eNOS (endothelial nitric oxide synthase) in pathological hypertension

Other uses of viral technology:Other uses of viral technology:In experimental medicineIn experimental medicine

1. To increase concentration of a protein under study in a cell and study its function (over-expression)

1. To increase concentration of a protein under study in a cell and study its function (over-expression)

2. To make the cell produce a protein with functions which are not yet understood. Then - see what happens 2. To make the cell produce a protein with functions which are not yet understood. Then - see what happens 3. To make the cell produce indicator proteins (for example, fluorescent). These may be used to monitor various variables within the living cells

3. To make the cell produce indicator proteins (for example, fluorescent). These may be used to monitor various variables within the living cells

Other uses of viral technology:Other uses of viral technology:In clinical medicine Gene therapy - to deliver therapeutic genesIn clinical medicine Gene therapy - to deliver therapeutic genes

Examples:Genes which protect heart from damage caused by ischemia (during heart attacks)

Genes which improve survival of vascular grafts used for transplantation

Genes which produce proteins which can lower blood pressure

Examples:Genes which protect heart from damage caused by ischemia (during heart attacks)

Genes which improve survival of vascular grafts used for transplantation

Genes which produce proteins which can lower blood pressure

WHAT IS WRONG WITH THE SYMPATHETIC N.S. In HYPERTENSION?

The Brainstem

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