Long Term Regulation of Arterial

Blood Pressure and Hypertension

Balance Between Fluid Intake and Output

Pressure Natriuresis. Arterial pressure is a signal for regulation of NaCl excretion.

arterial pressure NaCl reabsorbed in the proximal tubule more NaCl to the macula densa TGF autoregulation RBF, GFR.

Pressure Natriuresis. Arterial pressure is a signal for regulation of NaCl excretion.

arterial pressure NaCl reabsorbed in the proximal tubule more NaCl to the macula densa TGF autoregulation RBF, GFR.

2. Decrease PT NaCl reabsorption

3. I ncrease [NaCl] at macula

densa generates TGF signal

Natriuresis

Diuresis “Pressure Natriuresis”

1. I ncrease BP & renal

perfusion pressure

I ncrease NaCl

delivery to

distal nephron

4. I ncrease aff erent arteriole resistance

5. Autoregulate RBF, GFR

40% increase volume flow f rom PT

?

Pressure natriuresis can normalize BP by decreasing the effective circulating volume – this response connects BP and ECFV.

Renal-Body Fluid System for Arterial Pressure Control

• When the body contains too much extracellular fluid,

the blood volume and arterial pressure rise

• Pressure Diuresis and Pressure Natriuresis

• At high pressure, the kidneys excretes the excess

volume into urine and relieves the pressure

• At low pressure, the kidney excretes far less fluid than

is ingested

Renal Urinary Output Curve

or Renal function curve

Pressure Control by Renal-Body Fluid Mechanism

• Over the long period, water

and salt output must equal

intake

• Equlibrium point

• Return of the arterial

pressure always exactly

back to the equlibrium point

in the “infinite feedback

gain” principle

Two Determinants of Long-Term Arterial

Pressure Level

• The degree of pressure shift of the renal output curve

for water and salt

• The level of water and salt intake line

• It is impossible to change the long-term mAP level to a

new value without changing one or both of the two

basic determinants of long-term AP

Two Determinants of Long-Term Arterial

Pressure Level

Failure of increased TPR to elevate the long-term level

of AP if fluid intake and renal function do not change

• AP = Cardiac output x Total Peripheral Resistance

• So, increase in TPR should elevate AP

• But this acute rise in AP is not maintained if the kidneys

function properly

• Why?

• Pressure diuresis and pressure natriuresis

Failure of increased TPR to elevate the long-term level

of AP if fluid intake and renal function do not change

Increased Fluid Volume Can Elevate AP by Increasing

Cardiac Output or Total Peripheral Resistance

Importance of salt (NaCl) in the renal-body fluid

diagram for arterial pressure regulation

• An increase in salt is far more likely to elevate AP than

is an increase in water intake

• Water can be eliminated easily, but salt not

• Accummulation of salt in the body

– Stimulation of thirst center in the brain

– Increased osmotic pressure stimulates release of

vasopressin (ADH)

Hypertension

“Hypertension is defined as sustained abnormal elevation of the

arterial blood pressure”

HypertensionHypertension

•Leads to wear and tear

•is a major risk factor for cardiovascular diseases such as:

•STROKESTROKE

•HEART FAILUREHEART FAILURE

•ATHEROSCLEROSISATHEROSCLEROSIS

30% of world’s deaths

Complications

Complications as a result of hypertension include:

Stroke

Dementia

Myocardial Infarction

Congestive Heart Failure

Retinal Vasculopathy

Renal Disease or Failure

Chronic Hypertension is Caused by Impaired

Renal Function

• Mean Arterial Pressure > 110 mmHg (normal is about 90

mmHg)

• Systolic >140, diastolic >90 mmHg

• Hypertension can be lethal

– Heart failure

– Damage of a large vessel in the brain (cerebral infarct or stroke)

– Kidney failure

• Volume-loading hypertension means hypertension caused

by excess accumulation of extracellular fluid in the body

Volume-loading hypertension

• Reduced renal mass and increased salt intake

Volume-loading hypertension:

Two separate sequential stages

• The first stage: increased fluid volume causing

increased cardiac output hypertension

• The second stage: High blood pressure, high TPR but

return of the cardiac output near the normal

1) Hypertension

2) Marked increase in TPR

3) Almost complete return of the extracellular fluid volume

blood volume and cardiac output back to normal

Volume-loading hypertension in patients who have no kidneys and need for dialysis

Hypertension caused by primary Aldosteronism

• Another type of volume-loading hypertension is caused

by excess aldosterone in the body – (other steroids)

• A small tumor of adrenal glands and primary

aldosteronism

• Aldesteron increases reabsorbtion of salt and water

increased blood volume and reduced urine output

• Consequently, hypertension develops

The Renin-Angiotensin System

Pressure control and Hypertension

• Renin is an enzyme released by the kidneys when the

arterial pressure falls too low

• It is synthesized and stored in inactive form called prorenin

in juxtaglomerular cells

• JG cells are modified smooth muscle cells in the walls of

afferent arterioles

• Renin acts on angiotensinogen (a plasma globulin)

• Half life of renin is about 30 mins

• Angiotensin I, converting enzyme and Angiotensin II

The Renin-Angiotensin System

Pressure control and Hypertension

Rapidity and Intensity of Vasoconstrictor Pressure

Response to the Renin-Angiotensin System

• Renin-angiotensin vasoconstrictor system requires about

20 mins to become fully active

Effect of Angiotensin in the Kidneys to Cause

Renal Retention of Salt and Water

1) Angiotensin acts directly on the kidneys to cause salt

and water retention

- Makes the kidneys retain salt and water

- Causes vasoconstriction in renal arteries

2) Angiotensin causes the adrenal gland to secrete

aldosterone

- Aldosterone increases salt and water retention by the kidneys

Role of Renin-Angiotensin System in Maintaining a Normal

Arterial Pressure Despite Wide Variations in Salt Intake

• When the renin-

angiotensin system

functions normally,

pressure rises no

more than 4 to 6

mmHg in response

to as much as a 50-

fold increase in salt

intake

Other Types of Hypertension Caused by Combinations of

Volume-Loading and Vasoconstriction

• Aort Coarctation –

hypertension

• High BP in the upper

body, but BP is

normal in the lower

body

• Autoregulation of

hypertension

Coarctation of the Aorta

• Coarctation usually occurs

just distal to the left

subclavian artery at the

ligamentum arteriosum

– May also occur just proximal

to the left subclavian.

• Causes systemic

hypertension and secondary

LVH with heart failure.

Other Types of Hypertension Caused by Combinations of

Volume-Loading and Vasoconstriction

• Hypertension in pre-eclampsia (toxemia of pregnancy)

• Ischemia of the placenta and subsequent release of toxic

factors causing hypertension

• Endothelial dysfunction – reduction of Nitric Oxide

• Impaired renal pressure natriuresis

• Development of hypertension

• Thickening of the kidney glomerular membranes

(auotoimmune process)

Other Types of Hypertension Caused by Combinations of

Volume-Loading and Vasoconstriction

• Neurogenic Hypertension

• Acute neurogenic hypertension can be caused by

strong stimulation of the sympathetic nervous system

• Excitement, anxiety induces sympathetic activity which

causes peripheral vasoconstriction and acute

hypertension occurs

• Acute neurogenic hypertension caused by sectioning

the baroreceptor nerves

Primary (Essential) Hypertension

• 90 to 95% of hypertension cases are of primary

• It is of unknown origin

– Genetics: there is a strong hereditary tendency

– Environment: Excess weight and sedentary life style

– Neurohormonal mediators

Some Characteristics of Primary Hypertension

1) Cardiac output is increased due to additional blood flow required

for the extra adipose tissue and increased metabolism

2) Sympathetic nerve activity (especially in kidneys) is increased in

OW patients (leptin – vasomotor center ?)

3) Angiotensin II and aldosterone are increased (sympathetic

stimulation-renin-aldosterone …)

4) Renal-pressure natriuresis mechanism is impaired

• If hypertension is not treated, there may also be vascular damage

in the kidney that can reduce glomerular filtration rate

Graphical Analyses of AP Controling

Primary Hypertension

Reason for the difference between non-salt and salt-sensitive hypertension is

probably related to structural and functional differences in kidney (nephrons..)

Treatment of Primary Hypertension

• Two general classes of drugs are used

– Vasodilator drugs that increase renal blood flow

– Natriuretic and diuretic drugs that decrease

tubular reabsorption of Na and water

• Vasodilator drugs

– Inhibiting sympathetic nerve activity to kidneys

– Direct relaxation of smooth muscle of renal

vasculature

– Blocking the action of renin-angiotensin system

on renal vasculature or tubules

Summary for Arterial Pressure Regulation

• AP is regulated not by a single pressure controlling

system (several inter-related systems)

• To achieve

– Survival

– Returning the blood volume and pressure back to normal

• Mechanisms

1) Rapidly acting pressure control mechanisms

2) Intermediate mechanisms that act after several minutes – hours

3) Long-term arterial pressure regulation

Summary for Arterial Pressure Regulation

Intermediate mechanisms that act after several

minutes – hours

• Renin-Angiotensin vasoconstrictor mechanism

• Stress-relaxation of the vasculature

• Shift of fluid through capillary walls in and out of

circulation

* These mechanisms become mostly activated within

30 mins to several hours

• Role of the kidneys

• Many factors can affect pressure-regulating

level of the renal-body fluid mechanism

– Aldosterone

– Renin-Angiotensin system

– Nervous system (increased sympathetic activity)

Long term mechanisms for AP regulation