L19 CVS Physiology 10 Integration

Overview

This lecture pulls the vascular and cardiac physiology of the module together into whole-system responses. It starts with the reflex machinery that holds arterial pressure near normal, in particular the arterial baroreceptor reflex, and then applies that machinery to three integrated challenges: standing up (posture and orthostatic hypotension), exercise, and haemorrhage. In each case the same equation, $M A P = C O \times T P R$ , and the same reflex loop are used to explain how cardiac output and peripheral resistance are adjusted, with additional non-reflex mechanisms (the skeletal muscle pump, metabolic vasodilatation, fluid shifts and renal salt and water handling) filling the gaps the reflex alone cannot. The lecture closes with a recap of the key points from the vascular physiology lectures.

Reflex mechanisms that maintain arterial pressure

Key points:

Multiple subconscious special nervous control mechanisms operate all the time to maintain arterial pressure at or near normal.
Almost all of these are negative feedback reflex mechanisms.
The four types named are:
- Arterial baroreceptors
- Carotid and aortic chemoreceptors
- Cardiopulmonary baroreceptors, located in the atria, ventricles and pulmonary vessels, also called “low pressure receptors”
- Central chemoreceptors, located in the medulla

The arterial baroreceptor reflex: anatomy of the loop

This is the short-term control system for mean arterial blood pressure.

Sensors: the aortic and carotid sinus baroreceptors (the carotid sinus sits at the origin of the internal carotid artery from the common carotid, next to the carotid body).
Afferents: travel via the vagus nerve (CN X) and the glossopharyngeal nerve (CN IX, through the carotid sinus nerve) to the cardiovascular centres in the brainstem, terminating in the nucleus tractus solitarius (NTS) in the medulla.
Central connections: the brainstem circuit involves the NTS, RVLM, CVLM, NA and IML, linked by excitatory synapses and inhibitory (GABAergic) synapses.
Efferents: the cardiac control centre and vasomotor centre in the medulla send output through the cardiac nerve and the sympathetic chain to the heart and to the smooth muscle of blood vessel walls, with parasympathetic output to the heart via the vagus.

Tonic activity and the receptor operating curve

There is tonic (ongoing) activity in both the afferent nerves from the baroreceptors and in the efferent parasympathetic and sympathetic nerves.
Because the baseline is not zero, activity can be increased or decreased, so the system can respond readily to either a fall or a rise in arterial pressure.
Baroreceptor action potential frequency rises sigmoidally with mean arterial pressure across roughly 0 to 160 mmHg, with the normal resting value marked at the mid-point of the curve.
Recordings of afferent firing at mean pressures of 50, 75, 100, 125 and 200 mmHg show firing rate and density increasing as mean arterial pressure increases, with the discharge phasic (following the pulse).

Response to a rise in arterial pressure

Ordered steps:

Arterial pressure rises.
Firing in the arterial baroreceptor afferents increases.
Via the reflex through the medullary cardiovascular centre, parasympathetic outflow to the heart increases and sympathetic outflow to the heart, arterioles and veins decreases.
Heart rate falls, cardiac contractility falls, total peripheral resistance falls, and venodilation occurs.
Venodilation reduces the filling pressure of the heart, which with the fall in rate and contractility reduces cardiac output.
Since $M A P = C O \times T P R$ , the fall in both cardiac output and total peripheral resistance brings mean arterial pressure back down.

Experimental demonstration: electrically stimulating the carotid sinus nerve mimics a raised blood pressure signal. During stimulation the trace shows blood pressure falling (a depressor reflex), heart rate slowing (bradycardia, seen as widening spacing between beats), and pulse pressure and therefore stroke volume falling. A reduction of peripheral vascular tone also lowers total peripheral resistance.

Baroreceptors as a pressure buffer

With baroreceptors intact, arterial pressure in the dog fluctuates only narrowly around 100 mmHg over a recording period, giving a tall narrow peak on the frequency distribution curve.
After the baroreceptor nerves are denervated, pressure swings widely (roughly 50 to 190 mmHg) and the frequency distribution becomes short and broadly spread.
The reflex therefore does not set the mean level so much as buffer the moment-to-moment variation, keeping the operating range narrow.

Posture: the problem gravity creates

Veins are not rigid, so gravity is a determinant of the pressure within them.
Supine: most vessels are close to heart level; venous pressure is about 10 mmHg at the head and at the feet, and central venous pressure at the heart is about 3 mmHg.
Standing: central venous pressure falls to about 0 mmHg, blood pools in the peripheral veins with venous “pooling” of about +500 ml in the legs, and transmural pressure in the leg veins rises by about 90 mmHg.

Orthostatic hypotension: the sequence

Central venous pressure falls.
By the Starling law of the heart, right stroke volume falls.
Left ventricular filling pressure falls.
Left stroke volume falls.
Arterial pressure falls.
Cerebral blood flow falls, producing O2 lack.
Symptoms of cerebral underperfusion appear: dizziness and visual fade.

The reflex response to preserve cerebral perfusion

The mirror image of the response to a pressure rise:

Arterial pressure falls.
Firing by the arterial baroreceptors decreases.
Via the medullary cardiovascular centre, sympathetic outflow to the heart, arterioles and veins increases and parasympathetic outflow to the heart decreases.

Measured during head-up tilt (supine, tilt, supine), with sympathetic activation labelled as the cause of the heart rate and resistance changes:

Heart rate rises.
Relative stroke volume falls.
Relative cardiac output falls.
Blood pressure shows a transient hypotensive dip at the start of tilt, then partial recovery.
Relative total peripheral resistance rises.

The skeletal muscle pump

If moving, even just a little, muscle pumps compress the veins and prevent accumulation of blood in the legs. The three phases with their pressures:

Passive upright rest: arterial-side inflow about 120 mmHg against a venous column of about 200 mmHg, giving a driving pressure $Δ P$ of about 80 mmHg.
Muscle contraction: the muscle compresses the vein and drives flow upward past the valves, venous inflow pressure still about 200 mmHg.
Immediate post-contraction: venous pressure in the emptied segment is driven toward 0 or negative, while venous inflow remains about 200 mmHg, so $Δ P ≅ 200$ mmHg and refilling flow is large.

Exercise: what the cardiovascular system must achieve

Demand on the CVS	How it is met
1. Increase lung O2 uptake	Increased right ventricular output; increased concentration difference in gas
2. Increase O2 transport around the body	Increased left ventricular output
3. Direct the increased O2 supply specifically to the exercising muscle	Increased O2 extraction from muscle blood; decreased vascular resistance in exercising muscle by metabolic vasodilatation
4. Stabilisation of blood pressure	Vasoconstriction in non-exercising tissues

Raising cardiac output in exercise

Increased pulmonary blood flow equals increased cardiac output, and $C O = H R \times S V$ .

Heart rate rises through three mechanisms: withdrawal of vagal inhibition on the SA node (the pacemaker); stimulation of muscle group III mechanoreceptors; sympathetic drive to the pacemaker cells.
Stroke volume rises because venous return increases, raising right ventricular filling pressure and end-diastolic volume. Venous return is increased by the skeletal muscle pump and by venoconstriction.
If venous return does not increase during exercise, the rise in heart rate shortens filling time, so end-diastolic volume falls and stroke volume falls with it.

Directing flow to the exercising muscle

Cardiac output can increase from 5 L/min to 35 L/min, and most of the increase goes to the exercising muscles.
Vasodilatation is due to: local metabolic factors in skeletal and cardiac muscle; release of vasodilators by contracting skeletal muscle; and a decrease in sympathetic vasoconstrictor activity in skin.
Active hyperaemia as an ordered chain: increased metabolic activity of the organ, then decreased O2 and increased metabolites in the organ’s interstitial fluid, then arteriolar dilation in the organ, then increased blood flow to the organ.
Vasoconstriction occurs in the abdominal organs, kidneys and other non-exercising muscles, due to increased sympathetic tone. This is the mechanism that stabilises blood pressure.

Capillary recruitment

Recruitment of capillaries in the exercising muscle:

Increases the total surface area available for diffusion.
Shortens the diffusion distance, because the perfused capillaries are more evenly spaced and closer to every cell.

Skin blood flow and core temperature

Increased skin blood flow occurs in response to increased core temperature (exercise, fever), through vasodilatation and sweating. It is caused by:

Increased sympathetic cholinergic fibre activity to skin resistance vessels.
Decreased sympathetic vasoconstrictor drive to the arteriovenous anastomoses (AVAs) in the extremities.

Measured during leg exercise, forearm blood flow stays low and flat at about 2 to 3 ml/min/100 ml until core temperature exceeds about 37.5 °C, then rises steeply.

Haemodynamic changes during exercise

With $P_{A O} = C O \times T P R$ , the recorded changes from rest to exercise are:

Skeletal muscle blood flow: large increase.
Mean, systolic and diastolic arterial pressure: all rise slightly.
Total peripheral resistance: falls, due to the vasodilation in skeletal muscle and skin.
Cardiac output: rises.
Heart rate: rises, due to decreased parasympathetic and increased sympathetic activity to the SA node.
Stroke volume: rises, with contractility increased by increased sympathetic activity and by increased filling.
End-diastolic ventricular volume: rises.

Haemorrhage: how much loss matters

Blood volume is tightly regulated (5 to 6 L, 70 ml/kg) for optimal cardiovascular function, and changes in blood volume can have profound effects on blood pressure.
10% blood loss, the volume of a standard blood donation: no significant threat.
20 to 30% blood loss: clinical shock; cardiac output falls, followed by a reduction in arterial pressure.
More than 40% blood loss: may cause severe and sometimes irreversible shock, with reduced cerebral and coronary perfusion.
Plotted against percentage of total blood removed, cardiac output and arterial pressure are both well maintained up to about 10 to 20% loss, then decline, cardiac output falling somewhat earlier and faster than arterial pressure, both approaching zero near 45 to 50% loss.

The uncompensated causal chain: haemorrhage, then decreased blood volume, decreased venous pressure, decreased venous return, decreased atrial pressure, decreased ventricular end-diastolic volume, decreased stroke volume, decreased cardiac output, decreased arterial blood pressure.

The three time-scales of the response to haemorrhage

Rapid, within seconds: the baroreceptor reflex.
Intermediate, within minutes: fluid reabsorption.
Long-term, hours to days: the kidneys.

Restoring blood volume itself has two components: the transfer of fluid from the interstitial space into the circulation to restore circulating volume, and replacement of the lost volume (salt and water), which is renal.

Immediate response: the baroreceptor reflex

Haemorrhage lowers arterial pressure, which decreases firing by the arterial baroreceptors. Four reflex arms follow:

Decreased parasympathetic discharge to the heart, so the SA node increases heart rate.
Increased sympathetic discharge to the heart, so cardiac muscle increases stroke volume toward normal.
Increased sympathetic discharge to the veins, so veins constrict, venous pressure rises toward normal, venous return rises toward normal, end-diastolic volume rises toward normal, and this also increases stroke volume.
Increased sympathetic discharge to the arterioles, so arterioles constrict and total peripheral resistance rises.

The heart rate and stroke volume arms combine into increased cardiac output toward normal; this together with the increased total peripheral resistance raises arterial pressure toward normal.

Intermediate response: autotransfusion

Haemorrhage, then decreased blood volume, then decreased capillary hydrostatic pressure, then absorption of fluid from the interstitial fluid. In full:

Arterial pressure falls.
Reflex arteriolar constriction occurs.
Capillary hydrostatic pressure falls.
Fluid absorption from the interstitial compartment increases.
Plasma volume increases.
Arterial pressure is restored toward normal.

The Starling forces this shifts, at a normal capillary:

Arterial end: $P_{c} = 35$ , $π_{c} = 28$ , $P_{i f} = 0$ , $π_{i f} = 3$ , so net filtration pressure $= 35 + 3 - 0 - 28 = 10$ mmHg, favouring filtration.
Venous end: $P_{c} = 15$ , $π_{c} = 28$ , so net filtration pressure $= 15 + 3 - 0 - 28 = - 10$ mmHg, favouring absorption.

Long-term response: renal fluid replacement

Depending on the volume lost, autotransfusion alone is not enough to replace the lost volume.
Decreased renal perfusion triggers renin and angiotensin II. The chain is: blood loss, decreased arterial pressure, decreased GFR, increased renin release, increased angiotensin II, which increases ADH, aldosterone and thirst, giving water retention, salt retention and water intake respectively.
Angiotensin II is a vasoconstrictor; it reduces renal perfusion so less urine is formed (with ADH); it reduces renal Na loss (via aldosterone); and it stimulates thirst.
Over the next few hours to days the total body water and salt lost are replaced, by increasing intake and reducing losses.

Long-term response: replacing blood constituents

Red blood cells are replaced by the bone marrow, through erythropoiesis: proerythroblast, basophilic erythroblast, polychromatic erythroblast, orthochromatic erythroblast, reticulocyte, erythrocyte.
Albumin is replaced by the liver, whose sinusoids are lined by fenestrated endothelium with Kupffer cells and stellate cells and the space of Disse between endothelium and hepatocytes.
Full replacement takes around 6 weeks.

Recap: vascular physiology key points

Poiseuille’s law. Three factors govern resistance: length of the tube (L), viscosity of the liquid ( $η$ ) and radius of the tube (r), with $R = \frac{8 η L}{π r ^{4}}$ .

Patterns of blood flow. Three patterns: laminar (most arteries, arterioles, venules, veins); turbulent (ventricles, sometimes the aorta, for example in pregnancy, and over atheroma, giving a bruit); bolus (capillaries).

Aorta and large artery function. These vessels reduce the fluctuations in flow and pressure generated by the intermittent ejection of the stroke volume. This is accomplished by their highly elastic walls: during systole energy is stored in the vessel wall as the elastic elements are stretched, and this energy is released during diastole. This prevents large swings in arterial blood pressure between heart beats and results in a more or less steady blood flow into the smaller arteries.

Veins as reservoirs. Because veins have a high compliance at normal operating pressures they can release or store blood in response to small changes in pressure.

Vascular tone regulates arterial blood pressure. $M A B P = C O \times T P R$ , and continuous adjustment of resistance vessel tone helps control blood pressure during standing up and during hypovolaemic emergencies such as haemorrhage.

Determinants of vessel diameter:

Sympathetic activity.
Vasoactive metabolic factors: vasodilators carbon dioxide, lactate, hydrogen ion, adenosine; vasoconstrictor oxygen.
Endothelial secretions: vasoconstrictor endothelin; vasodilators nitric oxide, prostacyclins, adenosine.
Myogenic regulation (autoregulation).
Hormonal factors: vasoconstrictors adrenaline (via $α$ -receptors), angiotensin II, vasopressin (ADH); vasodilators adrenaline (via $β$ -receptors), atrial natriuretic peptide (ANP).

Recap: capillary physiology key points

Capillary structure and numbers. 6% of the total circulating blood is flowing through capillaries, and this fraction performs all the exchange functions (nutrients, metabolic end products and secretions), termed “nutritional blood flow”. An adult has an estimated 25,000 miles of capillaries. Density depends on organ and tissue: skeletal muscle 300 to 1000 capillaries/mm2; myocardium and brain 3000 capillaries/mm2. The wall is a thin endothelium (about 0.1 µm) on a basement membrane, with intercellular junctions and clefts and vesicles.

Diffusion across the capillary wall. 98% of nutrient (or drug) transport is by diffusion, and the transcapillary diffusion gradient exists because of cellular utilization or production of the substance.

Lipid soluble substances, including oxygen and CO2, diffuse easily through the endothelial cells.
Ions and polar molecules are poorly soluble and pass through the water-filled channels in the endothelial lining, the intercellular cleft.
Proteins are usually not allowed to diffuse through the water-filled channels; the liver is an exception.

Four pressures determine the filtration rate. Mean forces tending to move fluid outward: mean capillary pressure 17.3, negative interstitial free fluid pressure 3.0, interstitial fluid colloid osmotic pressure 8.0, total outward force 28.3 mmHg. Mean force tending to move fluid inward: plasma colloid osmotic pressure 28.0, total inward force 28.0 mmHg. Summation: outward 28.3 against inward 28.0, giving a net outward force of 0.3 mmHg. The net filtered fluid is returned via the lymphatic system.

Approach to special circulations

A four-part framework for any special circulation:

Special tasks.
Special features (adaptations): structural and functional.
Regulation.
Special problems.

The lecture closes by placing itself against the module’s guiding questions, of which it specifically addressed how the vascular system provides and controls perfusion, and how the system adapts.

Self-test

List the four reflex mechanisms named as maintaining normal arterial pressure, and state where the cardiopulmonary baroreceptors are located.
Name the sensors, the afferent nerves and the first central relay of the arterial baroreceptor reflex.
Explain why tonic activity in both the afferent and efferent limbs matters for the baroreflex.
Describe how baroreceptor afferent firing varies with mean arterial pressure, and where the normal resting value sits on that relationship.
Describe the steps by which the baroreflex corrects a rise in arterial pressure, ending with the effect on MAP.
Predict what happens to blood pressure, heart rate, pulse pressure and peripheral vascular tone when the carotid sinus nerve is electrically stimulated, and explain why.
Describe what baroreceptor denervation does to the distribution of arterial pressure in the dog, and what this shows about the reflex’s role.
Compare venous pressures and blood distribution supine and standing, giving the values from the lecture.
Describe the sequence of orthostatic hypotension from the fall in central venous pressure through to symptoms.
Describe the reflex response to the fall in arterial pressure on standing.
Describe the changes in heart rate, stroke volume, cardiac output, blood pressure and total peripheral resistance during head-up tilt, and state whether the reflex on its own restores arterial pressure.
Explain how the skeletal muscle pump helps on standing, using the pressures in the three phases.
List the four demands exercise places on the cardiovascular system and how each is met.
List the three mechanisms that raise heart rate in exercise.
Predict what happens to stroke volume in exercise if venous return fails to increase, and explain the mechanism.
State how far cardiac output can rise in exercise and where the increase is directed.
List the causes of vasodilatation in exercising muscle and skin given in the lecture.
Describe the steps of active hyperaemia.
Explain how capillary recruitment improves exchange in exercising muscle.
Describe how forearm blood flow changes with rising core temperature during leg exercise, and name the two autonomic changes responsible.
Explain how arterial pressure is stabilised during exercise despite the fall in total peripheral resistance.
State the direction of change during exercise of muscle blood flow, arterial pressure, total peripheral resistance, cardiac output, heart rate, stroke volume and end-diastolic volume.
State the normal blood volume and the consequences of losing 10%, 20 to 30% and more than 40% of it.
Describe the uncompensated causal chain from blood loss to a fall in arterial blood pressure.
List the three time-scales of the cardiovascular response to haemorrhage and the mechanism operating in each.
Describe the four reflex arms of the immediate baroreceptor response to haemorrhage and how they combine.
Explain autotransfusion, and give the Starling pressures at the arterial and venous ends of a capillary.
Describe the renal response to blood loss and list the actions of angiotensin II.
State what replaces the lost red cells and plasma protein after haemorrhage, and how long this takes.
State Poiseuille’s law and the three factors governing resistance.
Name the three patterns of blood flow and where each is found.
Explain how the aorta and large arteries smooth the intermittent output of the heart.
Explain why veins function as reservoirs.
List the groups of factors controlling vessel diameter, with a dilator and a constrictor example from each where the lecture gives them.
Give the capillary numbers: the fraction of circulating blood in capillaries, and capillary density in skeletal muscle versus myocardium and brain.
Distinguish how lipid soluble solutes and polar solutes cross the capillary wall, and state what proportion of transport is diffusive.
List the four pressures determining filtration rate with their values, and give the net force and its fate.
Give the four-part approach to understanding a special circulation.
Integrative: compare how the same baroreflex loop is deployed in standing, exercise and haemorrhage, and state what each response needs in addition to the reflex.

Answers

Reveal answers

Arterial baroreceptors; carotid and aortic chemoreceptors; cardiopulmonary baroreceptors; central chemoreceptors. The cardiopulmonary baroreceptors lie in the atria, ventricles and pulmonary vessels and are also called low pressure receptors (the central chemoreceptors are in the medulla).

Sensors are the aortic and carotid sinus baroreceptors; afferents run in the vagus (CN X) and glossopharyngeal (CN IX) nerves; they relay to the cardiovascular centres of the brainstem, in the nucleus tractus solitarius of the medulla.

Both the baroreceptor afferents and the parasympathetic and sympathetic efferents carry ongoing tonic activity, so activity can be either raised or lowered from baseline. This means the system can respond readily to a fall as well as to a rise in arterial pressure.

Action potential frequency rises sigmoidally with mean arterial pressure over roughly 0 to 160 mmHg, with firing rate increasing as mean pressure rises through 50, 75, 100, 125 and 200 mmHg. The normal resting value is marked at the mid-point of the curve.

Arterial pressure rises, baroreceptor firing increases, and via the medullary cardiovascular centre parasympathetic outflow to the heart increases while sympathetic outflow to heart, arterioles and veins decreases. Heart rate, contractility and total peripheral resistance fall and venodilation occurs; venodilation reduces cardiac filling pressure so cardiac output falls. Since MAP = CO x TPR, mean arterial pressure falls.

Stimulation mimics a raised pressure signal, so blood pressure falls (a depressor reflex), heart rate slows (bradycardia), and pulse pressure and therefore stroke volume fall. Peripheral vascular tone is also reduced, lowering total peripheral resistance.

With baroreceptors intact, pressure fluctuates narrowly around 100 mmHg and the frequency distribution is a tall narrow peak. After denervation, pressure swings widely (about 50 to 190 mmHg) and the distribution becomes short and broad. The reflex therefore acts as a pressure buffer, keeping the operating range narrow.

Supine, most vessels are near heart level: venous pressure about 10 mmHg at head and feet, central venous pressure about 3 mmHg. Standing, central venous pressure falls to about 0 mmHg, about 500 ml pools in the leg veins, and leg transmural pressure rises by about 90 mmHg because veins are not rigid and gravity determines the pressure.

Central venous pressure falls, so by the Starling law right stroke volume falls; left ventricular filling pressure then falls, left stroke volume falls, arterial pressure falls and cerebral blood flow falls with O2 lack, producing the symptoms of cerebral underperfusion, dizziness and visual fade.

Arterial pressure falls, firing by the arterial baroreceptors decreases, and via the medullary cardiovascular centre sympathetic outflow to the heart, arterioles and veins increases while parasympathetic outflow to the heart decreases.

During tilt, heart rate rises, relative stroke volume falls, relative cardiac output falls and relative total peripheral resistance rises, the rate and resistance changes being attributed to sympathetic activation. Blood pressure shows a transient hypotensive dip at the start of tilt followed by only partial recovery, so the reflex alone does not fully restore arterial pressure; the skeletal muscle pump is presented as a further requirement to prevent pooling of blood in the legs.

At passive upright rest, arterial-side inflow is about 120 mmHg against a venous column of about 200 mmHg, so the driving pressure is only about 80 mmHg. Muscle contraction compresses the vein and drives blood upward past the valves. Immediately after contraction the emptied venous segment is at about 0 or negative pressure while inflow pressure is still about 200 mmHg, giving a driving pressure of about 200 mmHg. Even a little movement therefore compresses veins and prevents accumulation of blood in the legs.

Increase lung O2 uptake, met by increased right ventricular output and an increased concentration difference in gas. Increase O2 transport around the body, met by increased left ventricular output. Direct the increased O2 supply specifically to exercising muscle, met by increased O2 extraction from muscle blood and reduced vascular resistance in exercising muscle through metabolic vasodilatation. Stabilise blood pressure, met by vasoconstriction in non-exercising tissues.

Withdrawal of vagal inhibition on the SA node; stimulation of muscle group III mechanoreceptors; sympathetic drive to the pacemaker cells.

Stroke volume would fall. The rise in heart rate shortens filling time, so end-diastolic volume falls and stroke volume falls with it; normally the skeletal muscle pump and venoconstriction raise venous return and right ventricular filling pressure to prevent this.

Cardiac output can rise from 5 L/min to 35 L/min, and most of the increase goes to the exercising muscles.

Local metabolic factors in skeletal and cardiac muscle; release of vasodilators by contracting skeletal muscle; and a decrease in sympathetic vasoconstrictor activity in the skin.

Metabolic activity of the organ increases; O2 falls and metabolites rise in the organ’s interstitial fluid; arterioles in the organ dilate; blood flow to the organ increases.

Opening more capillaries increases the total surface area available for diffusion and shortens the diffusion distance, because perfused capillaries are then closer together and more evenly spaced.

Forearm blood flow stays low and flat at about 2 to 3 ml/min/100 ml until core temperature exceeds about 37.5 °C, then rises steeply. It is caused by increased sympathetic cholinergic fibre activity to skin resistance vessels and decreased sympathetic vasoconstrictor drive to the arteriovenous anastomoses in the extremities, with vasodilatation and sweating.

Increased sympathetic tone causes vasoconstriction in the abdominal organs, kidneys and non-exercising muscles, which offsets the vasodilatation in exercising muscle and skin; combined with the large rise in cardiac output this keeps mean, systolic and diastolic pressures rising only slightly.

Skeletal muscle blood flow rises markedly; mean, systolic and diastolic arterial pressure rise slightly; total peripheral resistance falls; cardiac output rises; heart rate rises; stroke volume rises; end-diastolic ventricular volume rises.

Blood volume is 5 to 6 L, about 70 ml/kg. A 10% loss, the size of a standard blood donation, is no significant threat. A 20 to 30% loss causes clinical shock, with cardiac output falling followed by a reduction in arterial pressure. A loss of more than 40% may cause severe and sometimes irreversible shock with reduced cerebral and coronary perfusion.

Haemorrhage reduces blood volume, which lowers venous pressure, so venous return falls, atrial pressure falls, ventricular end-diastolic volume falls, stroke volume falls, cardiac output falls, and arterial blood pressure falls.

Rapid, within seconds: the baroreceptor reflex. Intermediate, within minutes: fluid reabsorption from the interstitium. Long-term, hours to days: the kidneys replacing lost salt and water.

The fall in arterial pressure decreases baroreceptor firing, giving: decreased parasympathetic discharge to the heart so the SA node raises heart rate; increased sympathetic discharge to the heart raising stroke volume toward normal; increased sympathetic discharge to veins causing constriction, raising venous pressure, venous return and end-diastolic volume toward normal and so also stroke volume; and increased sympathetic discharge to arterioles causing constriction and raising total peripheral resistance. Heart rate and stroke volume combine to raise cardiac output toward normal, which with the raised resistance raises arterial pressure toward normal.

Autotransfusion is the shift of fluid from the interstitial compartment into the circulation. The fall in arterial pressure and reflex arteriolar constriction lower capillary hydrostatic pressure, so fluid absorption from the interstitium increases, plasma volume rises and arterial pressure is restored toward normal. Normally at the arterial end Pc = 35, pi_c = 28, Pif = 0, pi_if = 3, net filtration pressure 35 + 3 - 0 - 28 = 10 mmHg favouring filtration; at the venous end Pc = 15, giving 15 + 3 - 0 - 28 = -10 mmHg favouring absorption.

Blood loss lowers arterial pressure and GFR, increasing renin release and so angiotensin II, which raises ADH, aldosterone and thirst, producing water retention, salt retention and water intake. Angiotensin II is a vasoconstrictor, reduces renal perfusion so less urine is formed (with ADH), reduces renal Na loss (via aldosterone) and stimulates thirst. Over hours to days the lost body water and salt are replaced by increasing intake and reducing losses.

Red blood cells are replaced by the bone marrow through erythropoiesis (proerythroblast, basophilic erythroblast, polychromatic erythroblast, orthochromatic erythroblast, reticulocyte, erythrocyte) and albumin by the liver; this takes around 6 weeks.

Resistance is governed by the length of the tube, the viscosity of the liquid and the radius of the tube, with R = 8(eta)L / (pi)r^4, so radius dominates through the fourth power.

Laminar flow in most arteries, arterioles, venules and veins; turbulent flow in the ventricles and sometimes the aorta, for example in pregnancy, and over atheroma where it produces a bruit; bolus flow in capillaries.

Their highly elastic walls store energy during systole as the elastic elements are stretched and release it during diastole, so the fluctuations in flow and pressure caused by intermittent ejection of the stroke volume are reduced, preventing large swings in arterial pressure between beats and giving a more or less steady flow into the smaller arteries.

Because veins have a high compliance at normal operating pressures, they can store or release blood in response to small changes in pressure.

Sympathetic activity; vasoactive metabolic factors (dilators carbon dioxide, lactate, hydrogen ion, adenosine; constrictor oxygen); endothelial secretions (dilators nitric oxide, prostacyclins, adenosine; constrictor endothelin); myogenic regulation or autoregulation; and hormonal factors (constrictors adrenaline at alpha-receptors, angiotensin II, vasopressin; dilators adrenaline at beta-receptors, atrial natriuretic peptide).

6% of the total circulating blood is in capillaries at any time; an adult has an estimated 25,000 miles of capillaries; density is 300 to 1000 capillaries/mm2 in skeletal muscle and 3000 capillaries/mm2 in myocardium and brain.

98% of nutrient or drug transport is by diffusion. Lipid soluble substances, including oxygen and CO2, diffuse easily straight through the endothelial cells, whereas ions and polar molecules are poorly soluble and pass through the water-filled channels of the intercellular cleft; proteins are usually excluded from these channels, the liver being an exception.

Outward: mean capillary pressure 17.3, negative interstitial free fluid pressure 3.0 and interstitial fluid colloid osmotic pressure 8.0, total 28.3 mmHg. Inward: plasma colloid osmotic pressure 28.0 mmHg. Net outward force is 0.3 mmHg, and the filtered fluid is returned via the lymphatic system.

Special tasks; special features or adaptations, both structural and functional; regulation; and special problems.

In all three the arterial baroreceptors sense the change in pressure and the medullary centres reset the balance of sympathetic and parasympathetic outflow to heart, arterioles and veins, altering cardiac output and total peripheral resistance so that MAP = CO x TPR is defended. On standing, firing falls and sympathetic activation raises heart rate and resistance, but recovery of pressure is only partial and the skeletal muscle pump is also needed to stop leg pooling. In exercise the reflex-driven autonomic changes raise heart rate and contractility while local metabolic vasodilatation in muscle lowers resistance, so sympathetic vasoconstriction in non-exercising tissues is needed to stabilise pressure, and the muscle pump and venoconstriction are needed to supply the venous return. In haemorrhage the reflex buys seconds by raising rate, stroke volume and resistance, but volume itself must be restored, first by autotransfusion from the interstitium and then by renal salt and water retention, with cells and albumin replaced over about 6 weeks.

tags	cvs, lecture, physiology
aliases	L19 CVS Physiology 10 Integration

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