1. Regulation of Blood Pressure
Prof.Dr. Ümmühan İşoğlu-Alkaç
İ.Ü. İstanbul Tıp Fakültesi
Fizyoloji Anabilim Dalı
YU Medical Faculty,

2. Reference 1:

3. Reference 2:

4. Nervous Regulation of the Circulation
Adjustment of blood flow tissue by tissue is mainly the function of local tissue blood flow control mechanisms.
The nervous control of the circulation has more global functions, such as redistributing blood flow to different areas of the body, increasing or decreasing pumping activity by the heart, and, especially, providing very rapid control of systemic
arterial pressure.
The nervous system controls the circulation almost entirely through the autonomic nervous system.

5. Autonomic Nervous System
By far the most important part of the autonomic nervous system for regulating the circulation is the sympathetic nervous system.
The parasympathetic nervous system also contributes specifically to regulation of heart function.

6. Autonomic Nervous System

7. Sympathetic Nervous System
Sympathetic vasomotor nerve fibers leave the spinal cord through all the thoracic spinal nerves and through the first one or two lumbar spinal nerves. They then pass immediately into a sympathetic
chain, one of which lies on each side of the vertebral column. Next, they pass by two routes to the circulation:
through specific sympathetic nerves that innervate mainly the vasculature of the internal viscera and the heart,
almost immediately into peripheral portions
of the spinal nerves distributed to the vasculature of the peripheral areas.

8. Anatomy of sympathetic
nervous control of the
circulation.
Also shown by
the red dashed line is a
vagus nerve that carries
Parasympathetic signals to the heart.

9. Sympathetic
Nervous Activation

10. Sympathetic Innervation of the Blood Vessels
In most tissues all the vessels except the precapillary sphincters, metarterioles and capillaries, are
innervated.
The innervation of the small arteries and arterioles
allows sympathetic stimulation to increase resistance
to blood flow and thereby to decrease rate of blood
flow through the tissues.
The innervation of the large vessels, particularly of the
veins, makes it possible for sympathetic stimulation to
decrease the volume of these vessels.This can push
blood into the heart and thereby play a major role in
regulation of heart pumping.

12. Sympathetic Nerve Fibers to the Heart.
In addition to sympathetic nerve fibers supplying the
blood vessels, sympathetic fibers also go directly to the
heart.
It should be recalled that sympathetic stimulation
markedly increases the activity of the heart, both
increasing the heart rate and enhancing its strength
and volume of pumping.

13. Parasympathetic Control of the Heart Function
Parasympathetic plays a minor role in regulating of the circulation
Its most important circulatory effect is to control heart rate by way of parasymphatetic nerve fibers to the heart (N. Vagus)

14. Parasympathetic
Nervous Stimulation

16. Sympathetic Vasoconstrictor System and Its Control by the CNS
The sympathetic nerves carry tremendous numbers of vasoconstrictor nerve fibers and only a few vasodilatatory fibers
This sympathetic vasoconstrictor effect is especially powerful in the kidneys, intestines, spleen and skin but much less potent in skeletal muscle and the brain

17. Vasomotor Center in the Brain
Located in the reticular substance of the medulla and lower pons
Important areas in this center:
A vasoconstrictor area
A vasodilatator area
A sensory area, located in the nucleus tractus solitarius
Output signals from the sensory area provides a reflex control of many circulatory functions (e.g. baroreceptor reflex)

18. Vasomotor Center in the Brain

19. Control of the vasomotor center by higher nervous centers
Large numbers of small neurons located throughout the reticular substance of the pons, mesencephalon and diencephalon can excite or inhibit the vasomotor center
Role of hypothalamus – Limbic system
Many parts of the cerebral cortex can also excite or inhibit the vasomotor center
vasovagal syncope (emotional fainting)

20. Sympathetic Vasoconstrictor Transmitter Substance
Noradrenalin
Alpha adrenergic receptors of the vascular smooth muscle (Na+ ve Ca2+)
Adrenal medullae and their relation to the sympathetic vasoconstrictor system (α receptor, adrenalin and noradrenalin)
Sympathetic vasodilator system
(β1; HR & kontraction, β2 ; vasodil.) and its control by the central nervous system
Skeletal muscles and vasodilator fibers…

21. Role of the nervous system in rapid control of arterial pressure
Rapid control of arterial pressure within 5-10 seconds
Stimulation of entire vasoconstrictor and cardioaccelerator functions by the sympathetic system
Almost all arterioles of the systemic circulation are constricted
The veins are strongly constricted
The heart itself is directly stimulated by the ANS, further enhancing cardiac pumping

22. Increase in AP During Muscle Exercise and Other Types of Stress
During heavy exercise, skeletal muscle require increased blood flow – role of local vasodilation
Increase of AP (30-40%) in heavy exercise increases blood flow
Activation of vasomotor center
Other types of stress and increased AP
Alarm reaction
Fight or flight

23. Maintaining Blood Pressure: Short Term Mechanisms - CNS
Baroreceptor initiated reflex
located at carotid sinuses and aortic arch
monitors blood pressure
regulates the activity of the sympathetic nervous system (vascular tone)

24. Anatomy:
Baroreceptors are clusters of bare sensory nerve endings buried within the elastic layers of the aorta and the carotid sinus.
Information from the former is relayed to the brain via sensory afferents traveling in the aortic nerve and the vagus nerve (cranial nerve [CN] X).
Afferents from the carotid sinus travel in the sinus nerve, which joins with the glossopharyngeal nerve (CN IX) route to the brainstem.

25. b. Function:
In the absence of stretch, the baroreceptors are inactive. When MAP increases, the walls of the aorta and carotid sinus expand, and the embedded nerve endings are stretched.
The nerves respond with graded receptor potentials. If the degree of deformation is sufficiently high, the receptor potentials trigger spikes in the sensory nerve.

26. Baroreceptors are especially sensitive to changes in pressure, responding to the sharp rise in pressure that occurs during rapid ejection with strong depolarization and a train of high frequency spikes. During reduced ejection and diastole, the depolarization abates and spike frequency drops to a new steady-state level that reflects diastolic pressure.

27. Baroreceptor Reflexes
This reflex is initiated by stretch receptors (baroreceptors or pressoreceptors) located at specific points in the walls of large systemic arteries
Carotic and Aortic baroreceptors
Signals from carotid baroreceptors – small Hering’s nerves – N. Glossopharyngeus – NTS in the medulla
Aortic baroreceptors – N. Vagus – NTS in the medulla

28. Baroreceptor Reflexes

30. Sensitivity of Baroreceptors:
Stretch-sensitivity varies from one nerve ending
to the next, thereby allowing for responsiveness over a wide pressure range.
The carotid baroreceptors have a response threshold of around 50 mm Hg and saturate
at 180 mm Hg.
The aortic baroreceptors operate over a range of 110–200 mm Hg.

31. Circulatory Reflex Initiated by the Baroreceptors
After the signals from baroreceptors enter the NTS, secondary signals inhibit the vasoconstrictor center and excite vagal parasympathetic center
The net effects are:
Vasodilation of the veins and arterioles in the peripheral circulatory system
Decreased heart rate and strength of the heart contraction
Increased TPR (total peripheral resistance) and decreased cardiac output

33. Baroreceptors and Changes in Body Posture
AP in the head and upper parts of the body tends to fall immediately on standing
This may cause loss of consciousness
Falling pressure at the baroreceptors elicits an immediate reflex resulting in strong sympathetic discharge
Pressure Buffer Function of the Baroreceptor control system
Reduction of minute by minute variations in arterial BP
Long term regulation of arterial BP

34. THE BARORECEPTOR REFLEX - AN EXAMPLE
CORRECTION OF POSTURAL HYPOTENSION
On standing up venous return falls
Cardiac output diminishes
Arterial blood pressure is reduced
Baroreceptor afferent firing reduced
Medullary centres inhibition reduced
Effect of gravity on
venous return
Preload diminished
- Starling’s Law
Subject possibly feels faint
as cerebral flow is reduced
Due to reduced arterial B.P.
Vasoconstriction
Tachycardia
Raised stroke work
Increased sympathetic tone to arterioles
Tend to restore arterial blood pressure
Reduced vagal tone to s.a. node
Increased myocardial sympathetic tone

37. Maintaining Blood Pressure: Short Term Mechanisms - CNS
Chemoreceptor initiated reflexes
Carotid bodies, aortic bodies
Monitor changes in indicator chemicals (O2, CO2, H+, HCO3-)
 CO2,  H+,  O2 (stresses) result in  sympathetic activity and  BP

38. Control of the Arterial Pressure by the Carotid and Aortic Chemoreceptors
Abundant blood flow and contact with the chemoreceptors
Signals from the chemoreceptors excite the vasomotor center and this elevates the AP back to normal
Chemoreceptor reflex is not a powerful AP controller until the AP falls below 80 mmHg
In low pressures this reflex becomes important

39. Chemoreceptors
Chemoreceptors monitor local metabolite levels, which reflect adequacy of perfusion pressure and flow.
Anatomy:
There are two groups of chemoreceptors, one located
in the brainstem medulla, the other peripheral.
Peripheral chemoreceptors are discrete, highly vascularized glomus cell clusters lying close to the aortic arch and carotid sinus (the aortic and carotid bodies, respectively).
Sensory fibers from the aortic bodies travel in the vagus nerve, whereas nerves from the carotid bodies travel with the sinus nerve and join the glossopharyngeal trunk en route to the medulla.

41. Function: Peripheral chemoreceptors activate when arterial
O2 levels fall (60 mm Hg) or when PCO2 or H levels rise (PCO2 40 mm Hg or pH 7.4).
Medullary chemoreceptors are sensitive to the pH of brain interstitial fluid, which is dependent on arterial PCO2.
The chemoreceptors seem designed to monitor lung function and are principally involved in respiratory control, but hypercapnia and acidosis can also reflect low perfusion pressures.

43. Other Reflexes Regulating Blood Pressure
Atrial and pulmonary artery reflexes that help regulate AP and other circulatory factors:
Both atria and pulmonary arteries have in their walls stretch receptors called low-pressure receptors
Atrial reflexes that activate the kidneys (volume reflex)
Stretch of the atria also causes reflex dilation of afferent arterioles in the kidney

44. Cardiopulmonary receptors (Atrial and pulmonary artery reflexes) :
A second set of baroreceptors is found in low-pressure regions of the cardiovascular system.
They provide the CNS with information about the “fullness” of the vascular system, and their principal role is in modulating renal function.
However, because fullness correlates with ventricular preload, they also have a role in maintaining MAP.

45. Anatomy:
The receptors are similar to those found in the arterial system: bare sensory nerve endings embedded in walls of the vena cavae, the pulmonary artery and vein, and the atria.
They relay information back to the CNS via the vagal nerve trunk.

46. Function: Atria contain two functionally distinct populations of
baroreceptors.
A receptors respond to tension that develops in the atrial wall during contraction.
B receptors are sensitive to atrial wall stretching during filling. B receptors are also involved in raising HR when central venous pressure (CVP) is high, a response known as the Bainbridge reflex.

47. Other Reflexes Regulating Blood Pressure
Atrial reflex control of the heart rate (Bainbridge reflex)
Increased atrial pressure also increases heart rate
Direct effect of increased atrial volume to stretch the sinus node
Additional 40-60% increase in rate is caused by a nervous reflex (Bainbridge reflex) that transmits afferent signals to the medulla of the brain

48. Occulo-Cardiac Reflex

49. Central Nervous System Ischemic Response
Most nervous control of BP is achieved by baroreceptors, chemoreceptors and low-pressure receptors: These are all located in the peripheral circulation
However, cerebral ischemia causes strong excitation of the vasomotor center
Accumulation of carbon dioxide
Other factors (build up of lactic acid)
CNS ischemic response is one of the most powerful of all the activators of the sympathetic vasoconstrictor system
Importance of the CNS ischemic response
Activated only at 60 mmHg or below
Emergency pressure control system

50. Special Features of Nervous Control of Arterial Pressure
Abdominal compression reflex
Compression of large abdominal veins and other vessels by skeletal muscles of the body, especially abdominal muscles
Increased cardiac output and arterial pressure caused by skeletal muscle contraction during exercise
Compression of blood vessels by skeletal muscles

51. Respiratory Waves in the Arterial Pressure
4 to 6 mmHg fall in AP during respiratory cycle
Breathing signals arise in the respiratory center of the medulla “spill over” into the vasomotor center with each respiratory cycle
With inspiration, pressure in thoracic cavity becomes negative allowing blood vessels in the chest to expand
* This reduces the venous return and decreases the cardiac output
Pressure changes in the thoracic vessels by respiration can excite vascular and atrial stretch receptors

52. Long Term Regulation of Arterial Blood Pressure and Hypertension
Balance Between Fluid Intake and Output

53. LONG-TERM CONTROL PATHWAYS
A drop in arterial pressure activates the baroreceptor reflex , but it also initiates pathways that require 24–48 hr to become fully effective.
These pathways converge on the kidney, which is responsible for long-term control of blood pressure through regulation of vascular fullness
(circulating blood volume).

54. LONG-TERM CONTROL PATHWAYS
Because blood is principally water, this necessarily involves regulation of
water output and
water intake, but it also requires regulation of Na levels
because this is the ion that governs how water partitions between the intracellular and extracellular compartments.

55. Water output
Water output is controlled by ADH, a peptide that is synthesized by the hypothalamus and
then transported to the posterior pituitary for release.
It stimulates water reabsorption by the renal collecting tubule and collecting ducts.
At high concentrations, ADH also increases SVR by constricting resistance vessels.

56. Water output
Several sensors and pathways regulate ADH release including
osmoreceptors,
baroreceptors, and
Ang-II.

57. 1. Osmoreceptors:
The brain contains a number of regions that have the potential to monitor plasma osmolality, including areas surrounding the third ventricle in close proximity to the hypothalamus
Tissue osmolarity is a reflection of total body water and salt concentration. When osmolarity exceeds 280 mOsm/kg, the receptors cause ADH to be released into the circulation.

58. 2. Baroreceptors: A decrease in circulating blood volume causes CVP to fall, which is sensed by the cardiopulmonary receptors.
Loss of preload also causes arterial pressure to fall and triggers a baroreceptor reflex. The CNS cardiovascular control centers respond by increasing sympathetic activity and promoting ADH release.

59. 3. Angiotensin II:
Activating the renin-angiotensin-aldosterone system (RAAS) causes circulating Ang-II levels to rise. The list of target organs for Ang-II includes the hypothalamus, where it stimulates ADH release.

61. B. Water intake
Water enters the body along with food, but the bulk of liquid intake occurs through drinking, driven by thirst. The sensation is triggered by decreasing blood volume and arterial pressure, suggesting a prominent role for the cardiovascular control center.
C. Sodium output
Osmoreceptors control water retention and excretion, but they sense the “saltiness” of body fluids rather than water per se. Thus, if tissue osmolality remains high, they will urge retention of water regardless of total accumulated volume. The primary determinant of circulating blood volume is Na concentration, which is regulated through RAAS

62. 1. Renin-Angiotensin-Aldosterone system:
Renin is a proteolytic enzyme synthesized by granular cells in the wall of glomerular afferent arterioles. The cells form a part of the juxtaglomerular apparatus (JGA), which senses and regulates Na recovery by the renal tubule. When the JGA is stimulated appropriately, it releases renin into the bloodstream. Here, renin breaks down angiotensinogen (a circulating plasma protein formed in the liver), to release angiotensin I.

63. 1. Renin-Angiotensin-Aldosterone system:
The latter serves as a substrate for angiotensin-converting enzyme (ACE). ACE is expressed by many tissues, including the kidney, but conversion largely occurs during transit through the lungs. The product is Ang-II, which constricts resistance vessels,
stimulates ADH release from the posterior pituitary, stimulates thirst, and
promotes aldosterone release from the adrenal cortex.

64. 2. Aldosterone: Aldosterone targets principal cells in the renal
collecting tubule epithelium. It has multiple actions,
all of which promote recovery of Na and osmotically obligated water from the tubule.
Aldosterone acts by modifying expression of genes that encode Na channels and pumps, which is why it takes up to 48 hours for this pressure control pathway to become maximally effective.

65. 3. Renin:
The afferent arteriole of the renal glomerulus is a baroreceptor that triggers renin release from the granular cells when arteriolar pressure falls. Release is potentiated by the SNS, which activates following a drop in MAP.

67. 4. Atrial natriuretic peptide: Atrial myocytes synthesize and store atrial natriuretic peptide (ANP), releasing it when stretched by high filling volumes.
ANP has multiple sites of action along the length of the kidney tubule, all of which are geared toward excretion of Na and water.
The ventricles release a related compound, brain natriuretic peptide, which has similar release characteristics and actions as ANP.

68. D. Sodium intake
Just as thirst stimulates water intake, salt craving triggers a need to ingest NaCl.
Salt appetite is controlled through the nucleus accumbens in the forebrain and is stimulated by aldosterone and Ang-II.

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

70. 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

71. 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

72. 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

73. Failure of increased TPR to elevate the long-term level of AP if fluid intake and renal function do not change

74. Increased Fluid Volume Can Elevate AP by Increasing Cardiac Output or Total Peripheral Resistance

75. 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)

76. Hypertension
“Hypertension is defined as sustained abnormal elevation of the arterial blood pressure”

77. Hypertension STROKE HEART FAILURE ATHEROSCLEROSIS
Leads to wear and tear
is a major risk factor for cardiovascular diseases such as:
STROKE
HEART FAILURE
ATHEROSCLEROSIS
30% of world’s deaths

78. Complications Complications as a result of hypertension include:
Stroke
Dementia
Myocardial Infarction
Congestive Heart Failure
Retinal Vasculopathy
Renal Disease or Failure
Slide #18:
Untreated, resistant or uncontrolled hypertension can result in these complications. Mild hypertension left untreated can progress into severe or malignant hypertension. Hypertension is usually asymptomatic until it reaches severe stages (Brashers, 2006).

79. 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

80. 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
Hypertension
Marked increase in TPR
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

81. 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

82. 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

83. The Renin-Angiotensin System Pressure control and Hypertension

84. Rapidity and Intensity of Vasoconstrictor Pressure Response to the Renin-Angiotensin System
Renin-angiotensin vasoconstrictor system requires about 20 mins to become fully active

85. Effect of Angiotensin in the Kidneys to Cause Renal Retention of Salt and Water
Angiotensin acts directly on the kidneys to cause salt and water retention
Makes the kidneys retain salt and water
Causes vasoconstriction in renal arteries
Angiotensin causes the adrenal gland to secrete aldosterone
- Aldosterone increases salt and water retention by the kidneys

86. 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

87. 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

88. Some Characteristics of Primary Hypertension
Cardiac output is increased due to additional blood flow required for the extra adipose tissue and increased metabolism
Sympathetic nerve activity (especially in kidneys) is increased in OW patients (leptin – vasomotor center ?)
Angiotensin II and aldosterone are increased (sympathetic stimulation-renin-aldosterone …)
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

89. 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
Rapidly acting pressure control mechanisms
Intermediate mechanisms that act after several minutes – hours
Long-term arterial pressure regulation

90. 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

91. Long term mechanisms for AP regulation
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)

92. Summary for Arterial Pressure Regulation