Lecture 13: Local and Humoral control of blood flow Flashcards
How is blood distributed throughout the circulatory system?
Different vascular beds receive different amounts of blood (measured as a percentage of cardiac output)
depends on the normal metabolic needs of the tissue.
See figure
Variations in blood flow to different organs
Some organs tend to receive much more blood than they typically need, and can survive large fluctuations in blood flow without damage.
Other organs including brain and heart (equipped almost solely for aerobic respiration) are sensitive to changes in blood flow, and are easily damaged by insufficient flow
Blood flow to the kidneys, skin and digestive organs may change drastically in the course of normal physiology (i.e. exercise).
What physical factors determine blood flow?
Pressure
Resistance
CO = MAP/TPR
Flow = delta P/ Resistance
What is the main driving force for flow through a vessel?
Pressure gradient (delta P)
**it is the difference in pressure, NOT the absolute pressure that is critical
See figure
What forces are responsible for resistance to flow?
Friction from the blood rubbing against vessel wall
Relationship of resistance to vessel surface area
Greater vessel surface area in contact with blood (small diameter arteriole) causes greater resistance to flow
Energy is lost as blood moves from great arteries through the arteriolar network
See figure
Relationship of resistance to vessel radius and flow
Resistance is inversely related to the fourth power of vessel radius (r)
What would happen to resistance if arteriolar radius increased by 2x? What would happen to flow rate?
16 fold decrease in resistance
16 fold increase in flow rate (flow rate is inversely related to resistance)
See figure
What is Poseuille’s law?
Describes the factors that affect flow rate through a vessel
See figure
Which component of poseuille’s law has the largest and most important contribution to resistance?
Radius of the vessel
Actively regulated
What is atheroscleorosis?
Radius narrows due to plaque
In order to maintain flow, the heart must work harder
Where is pressure lost in the circulatory system?
Mostly in arterioles
Comparison of blood vessels
See table
Which vessels are the major resistance vessels of the vascular tree?
Arterioles
As blood flows through these vessels, the mean pressure falls from ~93 mm Hg (i.e. mean arterial pressure) to 37 mm Hg (pressure at the beginning of capillaries).
What does arteriolar resistance create?
the pressure differential which encourages blood to flow from the heart to various organs downstream.
also converts pulsatile pressure swings to non-fluctuating pressure in the capillaries.
Role of arterioles in organs
Each organ has a complement of arterioles that can be adjusted independently to determine the distribution of cardiac output and to regulate blood pressure.
Arteriolar wall composition
little connective tissue
relatively thick layer of smooth muscle allowing for robust contraction.
Regulation of arteriolar diameter
Any alteration in the resistance (TPR) will influence the mean arterial pressure upstream of the point of resistance
If all arteriolar beds open maximally all at once = blood pressure drops
See figure
How is tissue blood flow regulated?
Regulation of arteriolar diameter results in regulation
More blood flows to areas whose arterioles offer the least resistance to its passage
What is vasoconstriction?
Reduction of arteriolar circumference due to contraction of smooth muscle lining the vessel.
What is vasodilation?
Enlargement of the circumference and radius of a vessel due to relaxation of smooth muscle.
What is vascular tone? What does it allow?
Partial constriction of the arteriole. Normally, some tone is present.
Vascular tone allows for fine control of resistance (vasodilation and vasoconstriction).
What would happen if tone did not exist?
No vasodilatory control
Structure of the circulatory system in local tissues
Conduit artery
Feed artery
Primary arteriole
Terminal arteriole
Capillary
Capillary
Venule
Vein
See figure
Role of conduit arteries
Designed to transport blood to areas of the body
Role of feed arteries
Vascular resistance vessels designed to regulate flow to specific areas of the body.
account for ~ 50% of TPR.
Role of terminal arterioles
last control point for regulating blood flow into capillaries.
Therefore, to
perfuse a microvascular unit, the terminal arteriole must be dilated.
What is an MVU?
Microvascular unit
all of the capillaries arising from a common terminal arteriole
Role of capillaries
Capillaries are considered to be the primary location
where oxygen transfer occurs in muscle.
There is no VSM in capillaries, rather there is only an endothelial layer.
This promotes diffusion by limiting the distance that oxygen must diffuse.
Which vessels are surrounded by SNS nerves? Role?
The feed arteries and arterioles
may activate vasoconstriction to increase systemic TPR to enhance blood pressure and to limit blood flow to areas of low metabolic demand.
Veins, but not venules are surrounded by SNS nerves
How may venules become constricted?
spillover from the arterioles may constrict venules to promote venous return.
This type of control is not as important as the control of vasoconstriction of arterioles because veins are very elastic and can stretch to accommodate more volume
How does vasodilation migrate in response to metabolic accumulation?
Distal to proximal vessels
Step 1. Metabolic accumulation is sensed by the capillaries and terminal arterioles, which triggers local vasodilation as well as upstream vasodilatation of the terminal arterioles.
Step 2. GAP junctions within the endothelium and VSMC send a signal up the arterial tree to vasodilate primary
arterioles and feed arteries.
This is particularly important Because feed arteries are not located in muscle and
are not exposed to metabolic stimuli.
Step 3. Conduit arteries are located outside of muscle and therefore are physically removed from the local metabolite and vasoactive stimuli produced by skeletal muscle.
Why does vasodilation ascend from distal to proximal vessels? Why not dilate upstream feed arteries to perfuse all the vessels downstream?
It does this so that the system is able to specifically match perfusion of local tissues with the metabolic demand of the specific tissue.
Thus, the system optimizes local blood flow by making sure the system is able to accommodate and needs the added blood flow without sacrificing blood flow to other parts of the body
See figure
What causes arteriolar vasoconstriction
Increased myogenic activity
Increased O2
Decreased CO2 and other metabolites
Increased SNS stimulation, vasopressin, angiotension II, cold
See figure
What causes arteriolar vasodilation?
Decreased myogenic activity
Decreased O2
Increased CO2 and other metabolites
Decreases SNS stimulation, histamine, heat
Systemic/extrinsic factors vs local/intrinsic factors
Systemic factors affect arterioles throughout the body (exception: brain). Regulate systemic blood pressure
Local factors either reinforce or oppose systemic factors. Restricted to specific vascular bed. Regulate net flow to the tissue
LOCAL OVERRIDES SYSTEMIC
See figure
What is extrinsic control of arteriolar resistance important for?
important in overall regulation of arterial blood pressure.
What are the important factors for extrinsic control of arteriolar resistance?
Neural and hormonal factors
Effects of SNS nerves are most important
What do sympathetic nerve fibres supply?
descend from the cardiovascular control centre of the brain
supply all smooth muscle except that in brain tissue.
How is vascular tone maintained?
maintained by a basal level of sympathetic activity, which generally causes vasoconstriction.
What does elevated SNS activity cause to arterioles? Decreased SNS?
Elevated SNS = arteriolar vasoconstriction
Decreased SNS = arteriolar vasodilation
How does SNS activation cause big increase in MAP?
sympathetic activation of the heart results in increased contractility and heart rate
overall sympathetic activation thus can greatly increase blood pressure by increasing cardiac output and total peripheral resistance
Central regulation of pressure/resistance/output
Central command
Arterial baroreflex
Skeletal muscle afferents
See figure
What is central command?
A feed forward system
volitional activity can influence cardiovascular responses.
The activation of the motor cortex can influence the regulation of PNS and SNS systems, thereby affecting cardiovascular regulation.
What is the arterial baroreflex?
Baroreceptors are pressure-sensitive receptors located in the carotid sinus (neck) and the aortic arch (immediately after the heart) .
These receptors are activated in response to high or low blood pressures and act to rapidly regulate blood pressure on a beat to beat basis.
Upon activation, baroreceptors can influence the PNS and SNS systems.
Skeletal muscle afferents
Mechanoreceptors/ metabaroreceptors
located in muscle and sense mechanical or metabolic signals associated with muscle contraction.
Upon activation, these receptors primarily influence the SNS system to increase blood pressure and HR.
These receptors contribute to the central control of blood flow.
What type of control do vasoconstrictor hormones have on arteriolar diameter? What are these hormones?
Extrinsic regulation
Norepinephrine
Epinephrine
Angiotensin II
Vasopressin
Serotonin and thomboxane A2
Where are norepinephrine and epinephrine secreted from? Role?
Potent vasoconstrictors released from the adrenal medullae directly into the blood
Promote systemic vasoconstriction and increased blood pressure.
Angiotensin II role
Acts to increase total peripheral resistance and therefore blood pressure.
At the local level, angiotensin II can severely limit blood flow by promoting severe vasoconstriction.
Pathological role of angiotensin II
Contributes to the development of hypertension in many pathological cardiovascular conditions.
Vasopressin role, formation and storage?
(also called antidiuretic hormone)
even more potent vasoconstrictor than Angiotensin II
Formed in nerve cells in the hypothalamus and is stored in the posterior pituitary gland.
When secreted into the blood, it can influence blood pressure regulation during severe hemorrhage.
However, it is not clear if vasopressin has a role in the regulation of blood pressure during physiological conditions.
When are serotonin and thromboxane A2 released?
released from platelets during vascular injury.
What are the vasodilator hormones? What type of regulation do they exert on arteriolar diameter?
Bradykinin
Histamine
Extrinsic regulation
What is bradykinin?
lasts only for a few minutes in the circulation
causes powerful dilation and increased capillary permeability.
What is histamine? Where does it come from?
local chemical modulator that causes vasodilation of arteriolar smooth muscle
usually only released upon mechanical damage to tissues or during an allergic reaction
histamine arises from connective tissue cells or circulating white blood cells.
What is the role of intrinsic control of arteriolar diameter?
Match blood flow to a specific tissue’s metabolic needs
Important for adjusting cardiac output to the organ’s needs (fraction of cardiac output for each organ is altered depending on metabolic requirements)
Nature of local controls of arteriolar diameter
Chemical or physical
Chemical intrinsic regulators of arteriolar diameter
High O2 tension (low CO2) = vasocontriction
High CO2 tension (low O2) = vasodilation
Other metabolites
Prostaglandins
Prostacyclin
EDRF
EDHF
Endothelin
What is active hyperaemia?
Oxygen is required for oxidative phosphorylation (ATP production)
ATP is required for smooth muscle contraction
When metabolic demands increase, O2 is depleted and muscle tension cannot be maintained, vessel dilates and flow to tissue increases
Products of actively metabolizing tissues in arteriolar diameter regulation
Intrinsic control
Produce CO2, acids (H+ and lactate, which lower pH), K+ (due to increased number of action potentials) and adenosine (from the breakdown of high energy phosphates
all of these substances are vasodilators
How are metabolic products removed from vessels?
They cause vasodilation, which increases blood flow and washes away substances
Role of prostaglandins in arteriolar diameter? Produced by? Antagonized by?
Chemical intrinsic regulator
Vasodilation
Produced by many cell types, often as part of inflammatory response
Antagonized by many pain killers and anti-inflammatories
Role of prostacyclin in arteriolar diameter? produced by?
Chemical intrinsic regulator
Maintain normal flow
Produced by endothelial cells
Vasoactive substances produced by endothelial cells
Chemical, intrinsic regulators
EDRF
EDHF
Endothelin
Released by endothelial cells but act on vascular smooth muscle
EDRF - role, identity
Chemical, intrinsic
endothelial-derived relaxing factor
potent vasodilator that has been identified as the soluble gas nitric oxide (NO).
NO diffuses to neighboring smooth muscle and induces relaxation.
What is impaired EDRF (NO) production associated with?
hypertensive disorders.
EDHF - role, identity
Chemical, intrinsic
endothelial-derived hyperpolarizing factor
vasodilator substance (or phenomenon) that to date remains unidentified.
may play a key anti-hypertensive role specifically in females
its identity may vary depending on the specific vascular bed.
Endothelin - structure, role
Chemical, intrinsic
21 amino acid peptide
Present in endothelial cells of most blood vessels
Can be released in response to vascular damage caused by physical trauma.
Stimulates severe vasoconstriction to help prevent extensive bleeding from arteries larger than 5 mm in diameter that may have been torn open.
Histology of arterioles
See figure
How NO release from endothelial cells is stimulated
As red blood cells bump into the epithelial cells, they cause the epithelial cells to deform, which triggers the release of nitric oxide.
Nitric oxide then signals the VSMC to relax, thereby enhancing local blood flow.
Nitric oxide also enhances the dilation of upstream terminal and primary arterioles to further increase local blood flow.
See figure
Synthesis of NO
Synthesized from L-arginine by endothelial nitric oxide synthase (eNOS)
What happens to NO in diseased states?
nitric oxide bioavailability is reduced due to an accumulation of oxidative stress
Excess oxygen free radicals combine with NO to create ONOO which damages cellular proteins
Less NO available, so impaired VSMC relaxation
= Vasodilation is impaired
See figure
What is nitric oxide bioavailability?
the total amount of nitric oxide that is biologically active
the difference (mathematical function) between the total production of nitric oxide minus the total amount of nitric oxide destroyed by other processes
Examples of pathological conditions that reduce NO bioavailability
Hypercholestrolemia
Atherosclerosis
Peripheral artery disease
Coronary artery disease
What factors may enhance endothelial function and promote increase in NO bioavailability?
Exercise training
Medical treatments
How does exercise increase NO bioavailability?
Increases eNos protein expression
Reduces the amount of ROS made by NADPH oxidase
Lower oxygen radicals lowers amount of -ONOO produced, which lowers cellular damage
May enhance Superoxide dismutase protein expression, which reduces oxidative stress
How does SOD reduce oxidative stress?
Converts oxygen radicals into hydrogen peroxide (H2O2)
Catalase or glutathione peroxidase then converts H2O2 into water
Physical, intrinsic regulators of arteriolar diameter
Heat, cold
Myogenic response
Shear stress
Pressure
How do heat and cold regulate arteriolar diameter?
Physical, intrinsic
Heat increases bloodflow
Cold decreases blood flow (relieves swelling of inflammatory response)
How does the myogenic response to stretch regulate arteriolar diameter?
VSMC responds to being passively stretched by increasing its tone.
Passive stretch is a function of the volume of blood delivered to an organ.
The converse is also true: reduction in blood flow to the tissue reduces passive stretch, resulting in decreased tone.
What intrinsic responses are important in reactive hyperaemia and pressure auto regulation?
Myogenic response to stretch
Effects of metabolites
What is reactive hyperaemia?
physical, intrinsic regulator
when blood flow to a tissue is totally restricted, myogenic relaxation is coupled with a decrease in O2 levels (and increased metabolites) in that tissue.
Result is a large but transient increase in blood flow once the occlusion is removed.
What is shear stress?
physical, intrinsic regulator
a longitudinal force induced by the friction of blood flowing over the endothelial cell surface
As a result, these cells release the potent vasodilator nitric oxide (NO), causing relaxation of underlying smooth muscle.
What is pressure autoregulation during a drop in MAP?
Physical, intrinsic regulator
a drop in MAP (e.g. hemorrhage) reduces blood flow and stretching of the arterioles, and metabolites build up
arterioles dilate to restore blood flow to the tissue, thus maintaining blood flow fairly constant.
What is pressure autoregulation during an increase in MAP?
increased MAP (e.g. hypertension) leads to increased blood flow and increased stretch of arterioles
results in reflex vasoconstriction to restore blood flow back to normal.
Increased NO release due to increased shear force is likely also involved.
Factors limiting maximal blood flow to tissues
1) The heart has a limit for the maximal amount of blood that it can pump each minute (maximal cardiac output).
2) There is a limited amount of total blood volume within the circulatory system that must perfuse a lot of different tissues.
3) There is a limited density of capillaries in each different type of tissue, which directly limits the perfusion of that tissue.
Degree of perfusion of tissues at any given time depends on///
Systemic and local factors
Factors are tuned to different stimuli and drive specific responses (vasoconstriction of vasodilation)
Are tissue metabolic demands static?
No
Can change rapidly
Results in need to quickly alter perfusion, often to many tissues at once.
This occurs automatically as the various systemic and local factors change.
Distribution of cardiac output at rest vs exercise
See figure
Tissue blood flow during exercise
During maximal muscle activity, flow undergoes a 20x increase. Cardiac output only undergoes a 5x increase.
Cardiac output does not dully account for the increased blood flow through the muscles
Second level of blood flow regulation is required. Circulatory system controls blood flow to local tissues as a way to optimize and match tissue perfusion with metabolic demand
Effects of exercise on cardiovascular function
Increased CO (Increased HR, Increased SV)
Increased HR (Decreased PSNS singling - decreased vagal nerve stimulation, Increased SNS signalling)
Increased SV (Increased filling due to venous return, Increased contractility - frank starling)
Increased BP (Increased cardiac output, Increased systemic TPR)
See figure
Vasodilation and vasoconstriction during maximal exercise
BP increases due to increase in TPR across entire system
Vasoconstriction in non-metabolically active tissue limits flow to tissue, allowing more blood to be directed to where the body needs it
Local control factors in metabolically active tissue vasodilator the local arterioles and enhance blood flow to this tissue
Effect of number of capillaries on oxygen delivery
Each capillary supplies oxygen to a cylindrical region of surrounding tissue (Krogh cylinder)
The ability of the circulation to deliver oxygen to the tissue is thus directly related to the capillary density in the tissue.
How can a person increase their capillary density?
Training their muscles
What is involved in long term regulation of flow?
Vascularity
physical growth of new arterioles, capillaries and veins contributes to the long term regulation of blood flow to metabolically active tissue.
Types of muscle fibres and capillary density
Oxidative fibres (Type 1 fibres) have a higher capillary density compared to glycolytic fibres (Type 2 fibres).
Endurance trained people have significantly more capillaries compared to sedentary people.
LACK OF OXYGEN IS MAJOR FACTOR IN THE GROWTH OF NEW CAPILLARIES
Speed of capillary growth depending on situation
begins within days in extremely young animals
In new growth tissue (such as scars and cancerous tissue)
much more slowly in aged people or established tissue.
Vascular growth factors
All are small growth factors
Vascular endothelial growth factor (VEGF)
Fibroblast growth factor (FGF)
Platelet-derived growth factor (PDGF)
Angiogenin
What is reduced oxygen’s effect on gene expression?
Reduced oxygen tension can drive the expression of specific genes via oxygen- responsive transcription factors such as hypoxia-inducible factor 1α (HIF-1α)
What is angiogenesis?
Growth of vessels
source of new cells is endothelial cells of existing vessels.
Grows directly off existing vessel
See figure
What is vasculogenesis
Growth of vessels
source of precursor cells is the undifferentiated cells of the splanchnic mesoderm.
Grows spontaneously near the vessel then hooks onto it
