Cardiovascular system

Nervous Control of Blood Vessel Diameter:

Blood vessels receive sympathetic

innervation

The neurotransmitter involved is

There is always some tonic activity

At baseline, there is a certain frequency of the impulses which maintains

If you increase the nerve traffic then you can constrict the vessel If you decrease the nerve traffic then you can dilate the vessel

Cardiac innervation:

We change the heart rate by dual innervation - sympathetic and parasympathetic

The sinoatrial nodal cells receive sympathetic and parasympathetic innervation

Normal resting heart rate is around

Parasympathetic slows heart rate down because

decreases the gradient of the pacemaker potential - this means that the potential takes longer to reach threshold and fire

Sympathetic increases heart rate because

and noradrenaline increases the gradient of the pacemaker potential so threshold is reached more quickly

If we cut the sympathetic nerves we lose the ability to increase heart rate so heart rate falls

Controlling Force of Contraction:

Force of contraction can be increased by Starling's Law.Sympathetic activity will also increase the force of contraction

Noradrenaline binds to Adrenoreceptors which increases the amount of

which activates PKA which phosphorylates the L-type calcium channels and the SR calcium release channel and SERCA

So you get more calcium influx and more calcium taken back up into the stores

Action of noradrenaline on beta-1-receptors in the heart will

contraction. So we can alter heart rate and strength of contraction by sympathetic activity. Strength of contraction

be changed by parasympathetic activity

Controlling Stroke Volume:

Stroke volume can be increased by: increased

activity and plasma adrenaline

Intrinsic control of stroke volume: venous return which sets the end-diastolic volume (stretch) which increases the force of contraction We can get more blood back to the heart (increase venous return) if we increase respiratory movements - decreasing intrathoracic pressure helps the filling of the heart

We can get rapid changes in respiratory movement, plasma adrenaline and sympathetic activity in the response known as

Providing Feedback - Baroreceptors:

Baroreceptors are in the aortic arch and in the

Baroreceptors in the carotid bodies feedback to the vasomotor centre via the glossopharyngeal nerve

The aortic arch baroreceptors feedback to the vasomotor centre via the

Baroreceptor Activity:

Carotid sinus baroreceptors respond to pressure between 60 and 80 mmHg Baroreceptor reflex is most sensitive around

Reciprocal Innervation:

When the receptor sees an increase in pressure it fires more - the nerve activity is increased which fires directly to the synapse and mediates an increase in parasympathetic nerve activity

Increase in baroreceptor firing = Increase in

activity

The sympathetic nerves are connected via a series of inhibitory interneurones which slows down the tonic activity

Increase in baroreceptor firing = Decrease in

activity

Parasympathetic stimulation of the heart occurs via the vagus nerve which causes a decrease in heart rate

There is a decrease in sympathetic stimulation to the heart which causes decreased heart rate and stroke volume

Decreased sympathetic stimulation to the blood vessels causes

Reflexes controlled by carotid sinus nerve activity:

Nerve activity from the baroreceptors reflects a rise or fall in pressure

Increased Blood Pressure = huge increase in firing activity throughout from the baroreceptor

The increase in baroreceptor firing is fed back to the

which triggers increased traffic in the vagus nerve

parasympathetic activity reflects exactly what happens in terms of baroreceptor activity

Increase in parasympathetic activity causes an increase in

production in the SAN which decreases the gradient of the pacemaker potential and causes a decrease in heart rate

Increase in baroreceptor activity also decreases the sympathetic nerve traffic which also brings about a decrease in heart rate

Sympathetic cardiac nerves also have an effect on the force of contraction - so less innervation from sympathetic nerves leads to a decrease in the force of contraction

Decrease in sympathetic activity also leads to an increase in vessel

Microcirculation: the circulation for every individual tissue/organ in the body

Consists of: o 1st order arterioles o Terminal arterioles o Capillary o Pericytic (post-capillary) venule o Venule

Surrounded by large amounts of

Blood Flow:

The overall aim of the cardiovascular system is to achieve adequate blood flow through the capillaries

Blood flow rate: volume of blood passing through a vessel per unit time

F = ΔP / R where ΔP =

and R=

The pressure at the beginning of arterioles vs. Pressure at the beginning of capillaries determines blood flow rate through tissues

R = vascular resistance -Hindrance to blood flow due to

between moving fluid and stationary vascular walls

Influencing factors:  Blood viscosity – is relatively constant though  Vessel length – increased length, increased resistance (although length is relatively constant)  Vessel radius – variable (R α 1/r4, therefore if the radius is halved, the resistance is increased 16x)

Microvessels - Arterioles:

Major resistance vessels, mean arteriole pressure (MAP) is

F organ = MAP/ R organ

Vasoconstriction/Vasodilation:

The state of

of the arterioles within that tissue also determine flow:

Vasoconstriction- decreases radius, increases vascular resistance therefore decreases flow rate

Vasodilation- increases the radius, decreases the resistance therefore increases flow rate

The radii of arterioles are adjusted independently to accomplish two functions: o Match blood flow to the metabolic needs of specific tissues – regulated by local

controls

Help regulate arterial blood pressure – regulated by

controls

1. Matching blood flow to the metabolic needs of specific tissues (depending on the body’s momentary needs)

Chemical response: Active

Increase metabolism therefore increase glucose requirement and oxygen consumption

Physical response:

E.g. Reduced blood temperature on superficial structures, e.g. the skin

Sensed locally, then in order to decrease blood flow to tissue

vasoconstriction occurs to divert blood from the tissue

E.g. 2. Physical stretch

response to physical stretch of arterioles

2. Help regulate arterial blood pressure

Apply F= ΔP / R to the entire circulation, F is

ΔP is

R is TPR

Neural Control:

Cardiovascular Control Center (CCC) in the Medulla (part of brain stem) sends a profound

signal. This can be used after significant blood loss, as it preserves the MAP but is not a good long term system, as it leads to dysfunction and infarction

α receptors within the periphery and β receptors within the heart respond to this neural signal o β receptors especially important as they can result in an increase in heart rate

Hormonal Control:

Vasoconstrictors: o Vasopressin – Posterior Pituitary Gland o Angiotensin II – Lungs

Hormones which act on α and β receptors to increase sympathetic activity o Adrenaline o Noradrenaline – both from adrenal glands

Microvessels – Capillaries:

Capillary exchange – delivery of metabolic substrate to the cells of the organism

Design is specific – accentuates function: Cell wall is

Diameter of lumen (7 micrometers), Extensive branching increases

Therefore capillaries are ideally suited to enhance diffusion (via FICK’S LAW): o Minimise diffusion distance o Maximum diffusion time o Maximise surface area

Capillary Network depends on: Highly metabolically active tissues – denser capillary networks

Structure: Continuous-

Most common – continuous flattened endothelial cells with

-filled gap junctions

As blood flows through the capillary: o Nutrients diffuse across junctions o LIPO molecules diffuse across cells o Transport proteins present to transport larger molecules into tissues

Fenestrated-

Circular fenestrae- circular holes about

nm large allow slightly larger molecules to leave the blood and enter the tissues

E.g in the

Discontinuous-

Very large gap junctions, therefore large molecules i.e. White blood cells can leave blood and enter tissues (and vice versa) e.g.

When a volume of protein free plasma filters out of the capillary, mixes with the surrounding interstitial fluid (IF) and is reabsorbed-

Two important forces affect the bulk flow: the

forces-

pressure– derived from the heart, and drives fluid into surrounding tissues

pressure-derived from the fact there is an increased concentration of plasma proteins in the blood, but not in the surrounding IF. This generates an osmotic force pulling water back into the capillaries

Starling’s Hypothesis: there must be a balance between the hydrostatic pressure of the blood in the capillaries and the osmotic attraction of the blood for the surrounding fluids.

and whereas capillary pressure determines transudation, the osmotic pressure of the proteins of the serum determines

The oncotic pressure along the capillary remains relatively constant, but there are changes in the hydrostatic pressure:

The hydrostatic pressure at the venous end of the capillary is

than the arterial end

When the pressure inside the capillary > in the IF, there is a net loss of fluid into the surrounding tissues (Hydrostatic pressure > Oncotic pressure) – This is known as

When the oncotic pressure > hydrostatic pressure, there is a net reabsorption of fluid back into the capillary. This occurs at the venous end. This is known as

There is a net loss of fluid from the capillaries, as the oncotic pressure is never great enough to reabsorb all the fluid lost by ultrafiltration

Therefore a mechanism is required for the return of this loss of fluid to the capillaries – this is the role of the

system

The Lymphatic System:

Initial Lymphatics- Lymphatic

are interwoven with capillaries

These are blind-ended, therefore do not form complete loop therefore fluid which enters cannot leave

The excess fluid in the capillaries is then drained back into the blood. All excess fluid is eventually drained into the blood by the lymphatic system

Lymph Nodes:

Important for immune

Filled with immune cells; excess fluid passes through the lymph nodes before draining into the blood

The organ which acts as a giant lymph node is the

Lymph Flow:

No heart – relies on skeletal muscle contraction etc

Areas where lymphatic system returns fluid, i.e. drainage ducts: o Right lymphatic duct o Thoracic duct o Right & left subclavian veins

If the rate of production of fluid > rate of return, this leads to

Parasitic blockage of lymph nodes may also lead to Oedema, e.g.

the biochemical process that enables both the specific and regulated cessation of bleeding in response to vascular insult

Role–

Prevent

Enable tissue

modulate inflammation

Important clinical applications –

Diagnosis of bleeding disorders o Treatment of bleeding disorders o Identification of risks for thrombotic disease o Treatment of thrombotic disease o Monitoring of anticoagulant drugs

Haemostatic plug formation:

The response to injury to

cell lining. Consists of 4 stages:

Vessel

Primary haemostasis – formation of an unstable

plug

Secondary haemostasis – stabilisation of the plug with

Vessel repair and dissolution of clot

Vessel Constriction:

Vascular smooth muscle cells contract locally, limiting blood flow to the injured vessels

This is a local contractile response to injury, and is mainly important in small blood vessels

A normal vessel wall consists of:

A layer of endothelial cells –

barrier, which again consists of anticoagulant proteins:

 GAGs – glycosaminoglycan  TFPI - tissue factor pathway inhibitor  TM - thrombomodulin  EPCR - endothelial protein C receptor

Subendothelium which is

and consists of:  Elastin  Collagen  VSMC (tissue factor) – vascular smooth muscle cells  Fibroblasts (tissue factor)

Other vital components of haemostasis circulate in the blood, in a quiescent state: o Platelets o Clotting factors o Plasma proteins

Within a few seconds of injury, these components endeavour to minimise blood loss via

Primary haemostasis – formation of an unstable platelet plug

Platelets -

Circulate in the blood and are derived from

in the bone marrow

Have a granulated cytoplasm, and are highly specialised

plasma cells

Many different ultrastructural features

Formation of the plug consists of: Platelet

-recruitment of platelets from flowing blood to site of injury

Platelet

– formation of the plug

Adhesion:

Within the blood, there are circulating platelets and VWF-

These do not interact, as the VWF are in a

conformation therefore their binding sites are hidden from the platelets – binding sites are called Gp1b

Vascular injury damages the endothelium and exposes the sub-endothelial matrix which consists of

The sub-endothelial collagen then binds to VWF, recruiting them to the endothelial surface  The rheological (flowing force) shear forces of flowing blood through the vessel then unravels the VWF on the endothelial surface

Unravelled VWF has exposed binding site (Gp1b) therefore the

bind. The platelets can also bind directly to the exposed collaged via Gp1a, but this is only under

shear forces.

Activation

-Conversion from a passive to an interactive functional cell

Change shape (spreads and flattens), change membrane composition

Present new

on their surface

The platelets bound to the collagen or VWF release ADP and thromboxane – these activate the platelets

Aggregation- Activated platelets bind more tightly to the collagen and

via GpIIb/IIIa which also binds

which develops the platelet plug

The platelet plug helps slow bleeding and provides a surface for coagulation

Secondary haemostasis – stabilisation of the plug with fibrin

Also known as blood

Stops blood loss

Complex biochemical process

Components involved from: o Liver – most plasma

proteins

o Endothelial cells – VWF. TM, TFPI o Megakaryocytes – VWF, FV

These clotting factors circulate as inactive precursors -

then activated by specific proteolysis (to form either as serine protease zymogens or cofactors)

Look at notes on this and tissue factor pathway

Consists of two pathways; intrinsic and extrinsic:

Intrinsic pathway – initiated when

is activated (not biologically as important)

FVIIIa is the only

all other activated clotting factors are serine proteases

Extrinsic pathway – primary driver of clotting cascade. Steps include:

1) Initiated when TF on surface of cells (which normally do not come into contact with blood) are exposed to plasma clotting factors

TF + FVIITF-FVIIa complex , 2) TF-FVIIa then activates FIX and

FXa activates

inefficiently leading to the generation of trace amounts of thrombin

Thrombin can then activate FVIII and

which function as non-enzymatic cofactors for FIXa and FXa, respectively.

FIXa-FVIIIa catalyses the conversion of increased quantities of

FXa-FVa catalyse enhanced generation of thrombin (more efficient by bypassing initial step)

Thrombin at the site of vessel damage converts fibrinogen (Fbg) to

which is the molecular scaffold of a clot.

Inhibitory coagulation mechanisms help keep clotting to the site of vessel injury, therefore deficiencies in these mechanisms are

TFPI (Tissue Factor Pathway Inhibitor)-

Targets initial tissue factor of

pathway, as well as FXa

This leads to the formation of a TF/FVIIa/Xa/TFPI complex

This shuts down the coagulation pathway

The Protein C anticoagulant pathway (Activated Protein C/APC & Protein S)

APC --> Protein

which targets FVIIIa and FVa

Generated thrombin then binds to

of endothelial cells, which shuts down any further thrombin generation

Antithrombin:

SERPIN (serine protease inhibitor)

Inhibits FIXa, FXa and

Fibrinolysis:

Restores vessel integrity because

binds to the fibrin clot, and via TPA (tissue plasminogen activator) is converted to plasmin

Plasmin then cleaves and degrades the fibrin clot into soluble fragments known as FDP (fibrin degradation products), which are then cleared by the

FDP is elevated in DIC (disseminated intravascular coagulation)

tPA and a bacterial activator-

are used in therapeutic thrombolysis for Myocardial Infarction, ischaemic stroke etc. these are known as

Abnormal Bleeding – the result of a(n)

in fibrinolytic factors and anticoagulant proteins, and a(n)

in coagulation factors and platelets

Characteristics:

• Spontaneous • Out of proportion to the trauma/injury • Unduly prolonged • Restarts after appearing to stop

Examples:

Epistaxis not stopped by 10 mins

or requiring medical attention/transfusion.

Cutaneous haemorrhage or bruising without apparent trauma (esp. multiple/large).

Prolonged (>15 mins) bleeding from trivial wounds, or in oral cavity or recurring spontaneously in 7 days after wound. Spontaneous GI bleeding leading to

Menorrhagia requiring treatment or leading to anaemia, not due to structural lesions of the uterus.

Heavy, prolonged or recurrent bleeding after surgery or dental extractions.

Defects of Primary Haemostasis (the formation of an unstable platelet plug):

Patterns of bleeding-

Easy

Nosebleeds, Gum bleeding, Menorrhagia, bleeding after

Petechiae (specific for thrombocytopenia)

o Typical of thrombocytopenia (decreased platelets) –

Defects of secondary haemostasis (fibrin mesh formation/coagulation):

Definition: Deficiency or defect of coagulation factors I-

Common examples include:

Haemophilia: FVIII or

(hereditary due to genetic defect)

Liver disease (acquired – most coagulation factors are made in the liver)

Drugs-

-inhibits formation

Dilution

Consumption (DIC – disseminated intravascular coagulation) (acquired)

Acquired coagulation disorders – DIC:

Generalised activation of coagulation –

Haemostasis then takes place

blood vessels, and throughout the general circulation

Associated with sepsis, major tissue damage, inflammation

Consumes and depletes coagulation factors &

Activation of fibrinolysis depletes

Consequences: o Widespread bleeding - from iv lines, bruising, internal o Organ failure – due to deposition of fibrin in vessels

Patterns of bleeding:

Often delayed (after primary haemostasis)

Deeper: joints and

Not from small cuts

Nosebleeds are

Bleeding after trauma/surgery

Easy bruising which is known as

Spontaneous bleeding into joints is known as

-Hallmark of haemophilia, increases pressure in joints and very painful and damaging

Defects of clot stability – excess fibrinolysis:

Can be used in therapy to break down clots after MI (but this must be done carefully as can lead to haemorrhage)

Due to either: o Excess

components – plasma, tPA  Can occur with some tumours

Deficient

components – antiplasmin  Can have a genetic antiplasmin deficiency

Thrombosis – result of a(n)

in fibrinolytic factors and anticoagulant proteins, with a(n)

in coagulation factors and platelets

What is thrombosis?

Intravascular

Effects of thrombosis:

Obstructed flow of blood

Embolism

Venous Thrombo-embolism:

Deep Vein Thrombosis (DVT) – venous return of blood is obstructed

Causes painful, swollen

Pulmonary embolism – causes shortness of breath, chest pain, may lead to sudden death

Prevalence- 1 in

per annum (with incidence doubling each decade)

However is cause of 10% of hospital deaths, and is a preventable cause of death

Consequences:

Death- VT mortality is

Recurrence - 20% in first 2 years and 4%pa thereafter

Severe TPS in 23% at 2 years is known as

syndrome

Why do some people get thrombosis? • Genetic constitution • Effect of age and previous events, illnesses, medication • Acute stimulus

The 3 contibutory factors to thrombosis is known as

and they are blood, vessel wall and

Blood- dominant in

thrombosis

Deficiency of anticoagulant proteins – antithrombin, protein C, protein S

Increased coagulant proteins & activity –  Factor VIII , Factor II &others

Factor V Leiden (increased activity due to activated protein C resistance) and thrombocytosis which is increased

vessel wall - dominant in

thrombosis

Many proteins active in coagulation are expressed on the surface of endothelial cells and their expression altered in inflammation  Thrombomodulin  Tissue factor  Tissue factor pathway inhibitor

Flow - complex, contributes to both

Reduced flow which is known as

increases the risk of venous thrombosis. This can occur due to:

surgery,  fracture,  long haul flight and bed rest

- increased risk of thrombosis

Clinical: o Thrombosis at young age o ‘idiopathic thrombosis’ o Multiple thromboses o Thrombosis whilst anticoagulated

Laboratory: o Identifiable cause of increased risk  AT deficiency  Factor V Leiden  global measures of coagulation activity.

Acquired risks for thrombosis:

Numerous conditions will alter blood coagulation, vessel wall and/or flow to precipitate thrombosis or make it more likely: The

pregnancy, malignancy, surgery and inflammatory response

Therapy and venous thrombosis:

Treatment- clot

Limit recurrence/extension- Increase anticoagulant activity - e.g:

Lower Procoagulant factors – e.g.

Prevention (NICE Guidelines 2010):

Assess individual risk and circumstantial risk, All patients admitted should have VTE risk assessment o Give prophylactic antithrombotic therapy o E.g. heparin for in-patients o TED stockings

Design of the Circulation

The cardiovascular system consists of two pumps and circuits (systemic and pulmonary) that are connected in series . Both circulations are very similar - there are elastic arteries, resistance vessels and exchange manoeuvres

Structure of the Systemic Circulation:

Initially when blood leaves the heart it is carried by large, thick-walled, elastic arteries which act as dampening vessels

Then you move into smaller arteries and arterioles which have extensive

muscle in their walls which regulates their diameter and produces a resistance to blood flow

A lot of the pressure drop in the arteries takes place in the small arteries and arterioles

The veins are very stretchy and highly compliant so they act as a

for blood volume

In terms of cross-sectional area, the

make up the largest cross-sectional area in the CVS - this is because it has an exchange function

Much of the blood at any one point rests in the veins and venules - this is why they are considered a reservoir for blood volume

You can load up the vessels with blood under normal (rest) conditions, but if you need to exercise you get

meaning that you decrease the amount of stored blood and move more blood back to the heart

By shifting the blood from the reservoir to the heart you produce more venous return and more cardiac output

The Fluid Circuit is similar to an Electric Circuit: Electrical circuit V=IR Fluid circuit- P=QR (Darcy's law) where P is

Q is

R is resistance

Pressure Difference can be estimated as being mean arterial blood pressure

Physiologically, the regulation of flow is achieved by variation in

while blood pressure remains relatively constant (relies on mechanisms to detect blood pressure and feedback to keep it constant)

We can direct the blood by specific contraction and relaxation of the blood vessels that serve the particular vascular bed that we're interested in

Pressure throughout the circulation :

Pressure falls across the circuit due to

pressure losses

Small arteries and arterioles present

resistance to flow

On the right side, the pulmonary artery presents a resistance to flow as well

The resistance to blood flow depends on THREE variables:

Fluid

- not fixed but in most physiological conditions this remains more or less constant

Length of Tube - fixed - the lengths of the blood vessels remains constant

Inner Radius of Tube - variable

The main determinant of resistance is

Distribution of Blood Flow to Organs:

When exercising, we can boost our cardiac output up to

L/min. By changing the radius of various vessels we can increase the blood flow to the working skeletal muscle - by constricting some vessels and dilating others to direct the blood to the place that needs it most

What sort of flow occurs in vessels?

It is known as

flow.

Blood generally flows in stream lines which don't tend to interfere with one another - it is laminated flow and hence laminar flow. It

be heard. When you measure blood pressure, you pump the cuff up to obstruct blood flow and when you start to release the cuff slowly, the blood will start pushing through the cuff producing

flow which you can hear -sounds of

When you partially occlude the vessel and blood starts to flow through in a turbulent manner, you hear a soft tapping sound

When you further drop the pressure in the blood pressure cuff, you won't hear anything at all because the vessel is no longer occluded and the blood starts to flow in a laminar fashion which you can’t hear

Turbulence is characterised by whirlpool like regions and the velocity of the fluid

constant in turbulent flow whereas it is constant in laminar flow

You need to be able to differentiate between laminar and turbulent flow because turbulent flow could bring about pathophysiological changes

Flow, Viscosity and Shear:

Blood flows quickest in the

This is because there are adhesive forces which attach the blood to the vessel walls

The velocity gradient that is established - the difference between the highest velocity blood in the middle of the lumen and the lowest velocity blood that adheres to the blood vessel walls - The

When shear rate is multiplied by viscosity you get

This disturbs endothelial function which is important for laminar flow and the production of various transmitter substances which give rise to vessel dilation and constriction

When shear stress is

it promotes endothelial cell survival so the endothelial cells line up and produce substances normally

If you have low, disturbed or changed shear stress (turbulent flow), endothelial

is stimulated which has a bearing on vasoconstriction, coagulation, platelet aggregation and atheroma formation

More on Shear Stress and Endothelial Function:

Shear stress is important because it determines how happy the endothelial cells are and determines their function

Measuring Blood Pressure:

You measure the changes in

You put a cuff around the upper arm and you increase the pressure until the cuff pressure exceeds arterial pressure

You place the stethoscope distal to the cuff - initially you won't hear anything because the blood flow is occluded

As you let the cuff down, you eventually get to a point where the pressure in the cuff is just overcome by the pressure in the artery

At this point, blood starts to squirt through the occlusion and sets up

flow - you hear a light tapping sound

If you continue to reduce the pressure in the cuff, you reach a point where you have no occlusion in the artery and so blood will start to flow in a laminar fashion again which you can not hear - this is the

blood pressure

Summary: Sounds APPEARS = Systolic Blood Pressure Sound DISAPPEARS = Diastolic Blood Pressure

The difference between systolic and diastolic blood pressure =

Mean Blood Pressure = Diastolic + 1/3 of pulse pressure

Why do ventricular and aortic pressure differ?

Once the aortic valve closes, ventricular pressure falls

but aortic pressure falls

This is explained by the

of the aorta which buffers changes in pressure and so it doesn't drop to zero like the ventricular pressure - the pressure is maintained by the elasticity of the vessel

Dichrotic Notch - when blood enters the aorta faster than it leaves the aorta, about 40% of the stroke volume is stored by the elastic arteries

When the aortic valve closes, the ejection of blood stops but there is a

because the arteries and the aorta are very elastic which produces the dichrotic notch Pressure falls slowly downstream of the aorta hence showing that the elasticity allows it to act as a

This damping effect is sometimes called the

effect. If arterial compliance decreases (e.g. with age) the damping effect of the Windkessel is reduced and the pulse pressure will

The effect of pressure on the walls of vessels:

The pressure inside the vessel-

pressure- determines the distension of the vessel wall The relationship between transmural pressure and wall tension is determined by the law of

T=PxR

Circumferential stress also depends on vessel wall thickness

The relationship between the transmural pressure and vessel volume is called the

Compliance is dependent on vessel elasticity

Aneurysm:

Over a prolonged period, the vessel walls can weaken causing a balloon like distension. Aneurysms form as a result of Laplace's law

If an aneurysm forms in the blood vessel, this means that for the same internal pressure, the inward force exerted by the muscular wall must also increase

However, if the muscle fibre is weakened and the compliance isn't great, the force needed to withstand the internal pressure cannot be produced and so the aneurysm will continue to expand

Summary of Laplace's Law: The larger the vessel radius, the greater the wall tension required to withstand a given internal fluid pressure

Compliance Properties of Arteries and Veins:

Relatively small changes in venous pressure distends veins and increases the volume of blood stored in them

For the same pressure, veins can hold a

volume of blood

Venous compliance is about 10 to 20 times greater than arterial compliance

When you change the nervous supply to the smooth muscle causing contraction, you decrease the venous volume and increase venous pressure

When you stand up quickly, gravity makes the blood pool in the legs which is due to the venous

When it pools in the legs, this reduces venous return to the heart which means that cardiac output

and you get less blood going to the brain

A mechanism to compensate for the postural hypotension is that you get venous

which means that more blood is returned to the heart and cardiac output is increased

Gravity and Blood Pressure across the Circulation:

At any particular location, the gradient of pressure from large artery to capillary is

so flow always occurs the normal way. The major effect of gravity is on the distensible veins in the

Why we don't faint when we're standing:

Standing causes activation of the

nervous system which stiffens and constricts veins

The arteries are constricted to increase total peripheral resistance and maintain blood pressure

Also, when you stand up there may be a slight increase in heart rate and an increase in the force of contraction which allows more blood to return to the brain

Failure of these mechanisms can lead to fainting known as

The failure of the mechanisms could lead to

Muscle and Respiratory Pumps:

Skeletal Pump - the contraction of the muscle squeezes blood back through the veins to the heart This assists the movement of blood back to the heart and

venous capacitance

Respiratory Pump - as we breathe in, we expand our chest and our intrathoracic pressure decreases which allows blood to come back to the right atrium and increase venous return These two simple mechanisms allow us to be able to stand up for long periods of time without fainting

Problems with Standing:

If you have incompetent valves, this could lead to

veins

The autonomic nervous system: Consists of the parasympathetic and sympathetic nervous systems

Sympathetic nervous system is organised around the thoracic and

spinal cord

Cardiovascular control:

Baroreceptors in carotid sinus and aortic arch sensitive to

Increased frequency of impulsesreduced inhibition of sympathetic activity from solitary tract nucleus increased blood pressure through increased vasoconstriction

α1 receptors at end of pre-ganglionic neurone, α2 receptors in

β2 receptors in heart via vagus nerve

Effector nerves: Sympathetic outflow-

Paravertebral sympthatic chain ganglion – neurotransmitter is acetylcholine therefore is a

receptor

Post-ganglionic fibre contains lots of

vesicles which are released on depolarisation, binding to the adrenergic receptor on the effect organ.

The NA is then either taken up by the neurone and repackages, or taken up by the effector organ and broken down by

Parasympathetic outflow-

Parasympathetic ganglia are in or near effector organ, and involve

Effector organ also has cholinergic receptor, which binds to the acetylcholine released by the postganglionic neurone. This acetylcholine is then recycled

Catecholamines: Noradrenaline and adrenaline are synthesised in the terminal

They are then removed from the neuroeffector junctional synapse via uptake systems:

Neuronal reuptake and recycling, or degradation into deaminated metabolites by MAO. Extraneuronal uptake into effector organ and degradation by COMT or MAO

Adrenoceptors:

Two groups of effects: Excitatory effects on smooth muscle (constriction). Mediated by

-adrenoceptors

lead to an increase in intracellular

Relaxant effects on smooth muscle, stimulatory effects on heart

-adrenoceptor mediated

lead to an increase in cyclic AMP, which causes an increase in Ca2+ in the heart but a decrease in smooth muscle

β- receptors:

β1 adrenoceptors located on: Cardiac muscle and smooth muscle of the

β2 adrenoceptors located on: bronchial, vascular and uterine smooth muscle

β3 adrenoceptors located on: smooth muscle of GI tract and

α- receptors: α1-adrenoceptors: located post-synaptically i.e. predominantly on effector cells

important in mediating constriction of resistance vessels

α2 -adrenoceptors: located on

nerve terminal membrane

their activation by released transmitter causes negative feedback inhibition of further transmitter release. Some are post-synaptic on vascular smooth muscle

Receptor coupling:

α1-adrenoceptors- coupled with G-protein linked receptor which activates the phosphlipase C pathway, which leads to an increase in free Ca2+ and activated protein kinases (involving IP3 and DAG)

α2-adrenoceptors- coupled with

activates adenyl cyclase, which converts ATPcyclic AMP leading to a decrease in intracellular

Effects of catecholamines on activation of adrenoceptors:

Natural - Noradrenaline – α1, α2, β1 - Adrenaline – α1, α2, β1, β2 - Dopamine – weak effects at α1, β1, but has own receptors

Synthetic - Isoprenaline - β1, β2 (unselective beta-agonist) - Phenylephrin - α1 (selective alpha-agonist)

Response of major vascular beds:

Skin (alpha receptors): Noradrenaline – constriction, Adrenaline –

Isoprenaline – no effect

Visceral (alpha receptors) o Noradrenaline –

Adrenaline – constriction Isoprenaline – no effect (slight dilation)

Renal (alpha & beta receptors) – constriction, Noradrenaline – constriction, Adrenaline – constriction and Isoprenaline-

Coronary (alpha & beta1 receptors) – dilation

Noradrenaline –

Adrenaline – dilation and Isoprenaline – dilation

Skeletal muscle (alpha & beta2 receptors): Noradrenaline – constriction, Adrenaline – dilation and Isoprenaline –

The Renin-Angiotensin System:

Renin, an enzyme, is secreted by

cells of renal afferent arteriole which converts angiotensinogen to

which is then converted to angiotensin II by

this then enters the zona glomerulosa of the

to form

Stimuli for renin release:

A decrease in the renal perfusion

a decrease of blood pressure in the pre-glomerular vessels, A decrease in arterial blood pressure.

Haemorrhage, salt and water loss, hypotension (low blood pressure). A change in Na+ or

concentration. β1-receptor activation in the kidney (sympathetic nervous system).

NaCl reabsorption at the macula densa -which are a group of cells in the

Pharmacologic manipulation of renin release

Loop diuretics – block NaCl reabsorption at macula densa

NSAIDs – block renin release via inhibition of COX

ACE inhibitors – block the synthesis of

AT1 blockers (Ang II receptor antagonists) – block vasoconstriction and aldosterone synthesis and secretion

Alpha2 and beta1 blockers - block receptor activation in the kidney, inhibiting renin release

AT1/Ang II type I receptors: Are coupled with a

It also couples to phospholipase A2

The AT1 receptors are located in the blood vessels, brain, adrenal glands, the kidneys and the heart.  Activation of the AT1 receptors works to

blood pressure, and stimulate aldosterone secretion

Effects of angiotensin II:

Peripheral resistance- Direct

-There is enhanced action of peripheral

due to increased release and reduced uptake

-increased sympathetic discharge

-release of catecholamines from the adrenal glands.

Renal Function:

-Direct effects to increase

reabsorption in the proximal tubule.

-Synthesis and release of aldosterone from the adrenal cortex.

Altered renal haemodynamics.  Renal vasoconstriction.  Enhanced noradrenaline effects on the kidney.

Cardiovascular structure:

Haemodynamic effects: - Increased preload and afterload. - Increased vascular wall tension.

Non-haemodynamic effects: -Increased expression of

Increased production of growth factors. Increased synthesis of extracellular matrix proteins.

Pharmacology of ACE Inhibition:

ACE is needed to convert

to

which increases blood pressure (by vasoconstriction and stimulation of the SNS).

Therefore inhibition of ACE will prevent angiotensin II production, and so ACE inhibition reduces blood pressure.

At the same time, a local hormone called

is also broken down by ACE.

It is an important local vasodilating hormone.

ACE inhibition therefore stops the bradykinin from being broken down, and so the bradykinin therefore will have vasodilating effects, and so here ACE inhibition further acts to reduce the blood pressure

AT2 ./ Ang II type 2 receptor antagonist actions:

No effects on the bradykinin system.

Selectively blocks the effects of Angiotensin II. o Pressor effects. o Stimulation of the noradrenaline system. o Secretion of aldosterone. o Effects on renal vasculature. o Growth-promoting effects on the cardiac and vascular tissue

Uricosuric effect-increased amount of

in the urine

Aldosterone:

Physiological effects – maintains body content of Na+, water and

Increases Na+ (and hence water) retention

Increases K+ (and H+) excretion

Pathophysiologic effects in CVD:

Myocardial fibrosis and

Inflammation, vascular fibrosis and injury

Prothrombotic effects – impaired

Central hypertensive effects

Endothelial dysfunction, Autonomic dysfunction

Effects of stress:

Increased blood pressure and heart rate

Increased Na+/water

Increased coagulation

Decreased fibrinolysis

Cardiac Position and Borders: The long axis of the heart is at an angle to the long axis (midline) of the body, with the apex (formed by the

part of the left ventricle- the bottom part furthest away from the midline of the body) in the left side of the body (Approx 2/3rds of the heart lies in the left side of the body)

The heart lies between the

and the spine. The sternum is

to the right ventricle. The spine is

to the left atrium

Functionally consists of two pumps separated by a partition. Each pump consists of an atrium, ventricle separated by a valve.

The right pump receives

blood and sends it to the

and the left pump receives

blood and sends it to the

The heart can be thought of as having 5 surfaces: Posterior, anterior, left pulmonary, right pulmonary and

The posterior consists of left atrium, small part of

and the

(beginning) parts of the great veins:

Superior vena cava (enters top right atrium- delivering blood from body). Also known as superior caval vein

Inferior vena cava (enters bottom

- delivering blood from body). Also known as inferior caval vein.

Coronary sinus (enters

medial to the inferior vena cava opening delivering deoxygenated blood draining from the coronary veins, i.e. from the heart itself)

Pulmonary veins (enter either side of

- delivering blood from lungs)

There are four pulmonary veins: right upper, right lower, left upper and left lower

The anterior surface consists of:

Mainly the

some of the right atrium and left ventricle

The pulmonary

emerges from the right ventricle, and divided into the left and right pulmonary artery

It has a central position and a spiral relationship with the

which emerges from the left atrium

Cardiac Chambers:

The four chambers of the heart are separated by interatrial, interventricular and atrioventricular septa:

Atrial Chambers-

Right Atrium- Venous Sinus: superior vena cava, inferior vena cava and coronary sinus. The inferior vena cava is guarded by the

and the coronary sinus is also guarded by a valve

The right atrium can be divided into two continuous spaces, divided by the

Characteristic

muscle bundles cover the walls of the atrium on the triangular appendage in the space anterior to the crest, known as the

In the space posterior to the crest has smooth, thin walls and both venae cavae and the coronary sinus empty into this space

Interatrial septum:

The right and left

are separated by the interatrial septum

A depression/infolding rim in the septum (just above the

of the inferior vena cava in the right atrium) is clear – this is the

The oval fossa effectively is a flat valve, which prevents blood flow directly between the atrial chambers

The oval fossa marks a location important for

circulation as it allows oxygenated blood to bypass the non-functioning lungs and enter the right atrium passing directly to the left atrium

when the lungs begin to function, this hole in the septum is supposed to close

Left Atrium:

Posterior half is smooth and receives blood from the four

Anterior half is contiuous with the

and contains pectinate muscles. However in the left atrium, there is no distinct separation (like the terminal crest) between these two halves

The crescent shape of the oval fossa is apparent in the anterior wall of left atrium, and is known as the valve of

(which prevents blood flow from left to right atrium)

However this valve may not completely fuse with the oval fossa in adults, which may leave a passage between the two atrial chambers, leaving a

foramen ovale (effectively a hole in the septum, leading to shunting of blood between the atria)

Ventricular Chambers:

Both ventricular chambers have an inlet, apical and

components, and constant apical

Right Ventricle:

Forms most of the anterior surface of the heart, and a portion of the diaphragmatic surface

Inlet component – the tricuspid valve and the

Apical component – trabecular portion

Outlet component -

It is to the right of the right atrium, and in front of and left of the right atrioventricular orifice. Blood therefore enters the ventricle moving in a horizontal and forward direction

Outflow portion: pulmonary

– leads to the pulmonary trunk – has smooth walls

Inflow portion wall has substantial complex muscle structures called

; these are either attached continuously to the walls forming ridges, or attached at both ends forming bridges

Trabeculations which are only attached at one end to the ventricular surface and the other end are attached to

(fibrous tendon-like chords which connect to the free edges of the tricuspid valve), are also known as

muscles. There are 3 types of papillary muscles in the right ventricle depending on their point of origin

Anterior- arises from the anterior wall and is the

Posterior- arise from the posterior wall

Septal- most inconsistent as either small or absent, but allow chorea tendineae to emerge directly from the interventricular septum

The septomarginal trabecula/ moderator band: single trabecula which forms a bridge between the lower portion of the intraventricular

and the base of the anterior papillary muscle, carrying the right atrioventricular bundle to the anterior wall of the right ventricle during cardiac conduction

Any of the individual muscle structures within the right ventricle have the potential to become atrophied, or necrose following a myocardial infarction

Intraventricular Septum:

The left ventricle is some-what

to the right ventricle, so the interventricular septum forms some of the posterior wall of the right ventricle (and is to the left).

The septum is described as having two parts: muscular and

The muscular part is thick and forms the major part. The membranous part is thin and forms the

part of the septum.

A third part of the septum may be considered to be atrioventricular as its superior location places it between the left ventricle and the right atrium

Left Ventricle:

Contributes to the anterior, diaphragmatic and left pulmonary surfaces of the heart. Forms the