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72 Chapter 4 Haemostasis and thromboembolic disorders
7) How are the two processes of coagulation and platelet plug formation integrated?
8a) List three chemical mediators involved in platelet recruitment during thrombus formation.
8b) Which receptor on platelets plays the most prominent and final role in platelet aggregation?
9a) What are the main differences in formation and content between arterial and venous thrombi?
9b) What are the consequences of these differences for choosing first-line drugs to treat
thromboembolic disorders?
Sunita and Dr Brown also mention thrombin and antithrombin.
10) Identify and list four roles that are played by thrombin (factor IIa) in the coagulation which has led to
Monique’s DVT formation.
The pharmacist on call is asked to supply some more heparin for the infusion. She introduces
herself as Jo.
Jo talks to Monique about heparin. She tells Monique that her body itself produces some
heparin to prevent uncontrolled clotting.
11a) List three chemicals in Monique’s blood that are involved in preventing uncontrolled coagulation.
11b) Describe how they interact.
When Monique asks how heparin works, the nurse tries to explain.
12) Which substances in Monique’s blood does unfractionated heparin interact with in order to be
effective? How does this reduce coagulation? (Figure 4.4)
Monique is moved to ward 17. This is awkward, involving the movement of the drip stand down
the long corridor.
Monique asks Sunita why heparin was not given to her in tablet form, or as a quick injection.
13a) Why has Monique been given unfractionated heparin as a continuous infusion and not as an
intravenous, or subcutaneous injection (Section 4.2.1)?
Note:
Intravenous infusion = a solution of a drug administered directly into a vein continuously over more
than 8–10min.
Intravenous injection = a solution of a drug administered into a vein by injection over a short
period.
Subcutaneous injection = a solution of a drug administered under the skin.
Hint: What is the half-life of unfractionated heparin? How long after subcutaneous injection is the
effect of unfractionated heparin evident?
WORKBOOK 1 Thromboembolic disorders 73
13b) Could Monique have been given heparin orally? Explain your answer.
Moniqueisalsofedupbecauseevery6hoursthenursecomesroundandtakesbloodtocheck
what they refer to as her aPTT.
14) What does aPTT stand for and what does it measure?
After Monique becomes stable and does not require oxygen, Jo suggests that the
unfractionated heparin is changed to low molecular weight heparin (LMWH).
The doctor agrees to do this, and LMWH is started as a subcutaneous injection to be given
once a day only.
15) What is the difference in action of unfractionated heparin and LMWH?
16) Why is the pharmacokinetic profile of unfractionated heparin less predictable than that of LMWH?
17) List two advantages of LMWH over unfractionated heparin.
Monique could actually name one!
18) List one advantage of unfractionated heparin over LMWH.
Hint: What drug is used to reverse bleeding with heparin?
19) Why was unfractionated heparin given first, rather than administering LMWH from the outset?
Much later the consultant on call stops to see Monique during his rounds. He checks her INR to
decide how to proceed with the warfarin dosing. The student nurse asks whether the heparin
can be stopped as the aPTT is in range.
The consultant explains that warfarin and heparin should be given simultaneously for at least 5
days, and that Monique’s target INR must be maintained for at least 24 hours.
The next day Monique is surprised when Andreas, her boss, comes to visit her in hospital. She
has secretly liked him since he started at the pharmaceutical company where she works.
They chat about work and then Monique’s illness.
Andreas says his dad has been taking warfarin since he was diagnosed with pulmonary
embolism after a second DVT two years ago. He and Sunita, who is also visiting, start to
discuss warfarin and clotting factors.
They explain to Monique that warfarin affects several of the factors involved in blood clotting.
20) Explain how these clotting factors are involved in the mechanism of action of warfarin. Refer in
particular to the role of vitamin K.
Jo, the pharmacist, drops by and explains why the consultant had insisted that Monique should
still be given LMWH injections during the first few days of taking warfarin tablets.
74 Chapter 4 Haemostasis and thromboembolic disorders
21) What does Jo say is the reason for giving LMWH and warfarin simultaneously?
How long does it take before the effect of warfarin is experienced? What is warfarin’s effect on
protein C?
22) What is the name of the test used to monitor warfarin? Explain what this test measures.
Refer back to the biochemistry section of clinical clerking.
Onday5postadmission,Monique’sINRis2.5andhasbeenbetween2and3for2days.The
LMWH is discontinued, and it is decided to discharge her in 2 days if her INR is maintained at
this level.
But Monique develops a chest infection, and because she is allergic to penicillin antibiotics, she
is started on the non-penicillin antibiotic erythromycin.
Her INR result 2 days later is 5.5, and she has had several nosebleeds.
Vitamin K is given orally.
23) What could have caused Monique’s nosebleeds?
Warfarin is metabolized by hepatic microsomal enzymes (P450/CYP enzymes) that are affected by
many drugs. The interaction of drugs with these enzymes can either increase or decrease the rate
of metabolism of warfarin, to alter its anticoagulant effect.
24) How will the vitamin K that Monique is given influence her INR? Explain the mechanism.
Vitamin K, found in some green vegetables, counteracts the effect of warfarin.
25) List four other drugs that could increase the activity of warfarin. (See for example, warfarin in
Appendix 1 of the British National Formulary.)
Andreas had been told that warfarin was better than aspirin for his dad. He wonders, though, if
aspirin could be an option to treat Monique’s DVT, and asks Jo the pharmacist when she comes
round.
26) Which of the two drugs do you think Jo would recommend for Monique’s DVT?
Andreas tells Monique that his father has to avoid certain foods and drinks. He asks if anyone
has talked to her about this.
27) Referring back to Monique’s social history, what do you think Jo will tell her when she counsels her
about warfarin and her lifestyle?
Monique’sINRnormalizesafter5days,anditisdecidedthatshecanbedischarged.
Sheistoldthatsheshouldcontinuetotakewarfarinfor6months.Shewillhavetoattenda
clinic regularly for blood tests, after which her dose of warfarin could be modified.
She is given a warfarin booklet with more information about the drug. Jo explains the content
and recommends that she carries the booklet around with her, and that she always tells any
healthcare professional attending to her that she takes warfarin.
WORKBOOK 1 Thromboembolic disorders 75
28) List six other things which patients on warfarin must be educated about.
Andreas insists on taking Monique home. She is concerned that the clot in her leg is still there,
as she wasn’t given drugs to get rid of it, only ones to stop more clotting.
29) What has happened to the thrombus in Monique’s vein?
30) How do thrombolytic drugs act?
31) Why was Monique not given a thrombolytic drug?
Before they leave, Monique wants to say goodbye to Mrs Goodfellow, a retired GP who had
been in the bed next to Monique for 2 days. She was moved to intensive care after a nasty
reaction to heparin. The nurses told Monique that the name of the reaction is type II HIT.
32a) What does HIT mean? How does it manifest itself?
32b) What is the difference between type I HIT and type II HIT in terms of mechanism and severity?
Monique is pleased to see an improvement in Mrs Goodfellow, who is waiting to be taken back
to the ward. Because she knows how interested Monique is in the medication, she tells her that
the heparin was replaced with argatroban.
33) What is argatroban and how does it differ from heparin and warfarin?
34) Why was Mrs Goodfellow not given a low molecular weight heparin instead of argatroban?
Mrs Goodfellow tells Monique that the doctors had considered dabigatran as an alternative to
argatroban.
Dabigatran can be taken by mouth and is an example of a novel oral anticoagulant (NOAC).
35) List two other NOACs and explain how they differ from dabigatran.
Monique promises Mrs Goodfellow she will come back and visit her in a couple of days. She
leaves the hospital with Andreas. She completes her six-month course of warfarin with no
further problems.
Chapter 5
Hypertension
Useful terms for this topic
Afterload: Pressure inside the aorta, against which
the left ventricle has to pump.
Cardiac output: Volume of blood being pumped by
the heart per minute.
Chronotropy: Affecting heart rate—chronotropic
effects can be either positive or negative.
Diastole: Phase in the cardiac cycle when ventricles
relax and rell.
End diastolic volume: Volume of blood in ventricle
just before systole.
Essential hypertension: High blood pressure of no
known cause.
Heart rate: Number of heart beats per minute.
Inotropy: Force of heart muscle contraction—
inotropic effects can be either positive or negative.
Pacemaker/sinoatrial node: Patch of tissue in upper
segment of right atrium, origin of electrical excitation
of heart.
Pre-capillary arterioles: Narrowest blood vessels
with smooth muscle in walls; their diameter is the
main determinant of total peripheral resistance.
Preload: Degree of stretch of ventricle walls just
before they contract in systole.
Stroke volume: Volume of blood pumped from the left
ventricle per heart beat.
Systole: Phase in the cardiac cycle when the
ventricles contract and blood is ejected from the
heart.
Total peripheral resistance: Resistance to ow of
blood offered by the blood vessels.
Ventricular/cardiac myocytes: Heart muscle cells.
Imagine you feel perfectly well, you go to your doctor for a
routine check, and are told you must start taking drugs
every day for the rest of your life for a condition with no
symptoms. Furthermore, you could be told that as time
goes by you may need to increase the number of dierent
drugs you take, perhaps to four a day, despite no
perceptible increase in your wellbeing. Millions of people
worldwide have experienced such a situation, having
been diagnosed with high blood pressure or
hypertension. If asked by the patient about the criteria
used to decide whether they should receive treatment,
the doctor may, in the spirit of openness, advance the
view that the dividing line between who is, and who is
not, to be treated for hypertension is arbitrary.
e consequences of hypertension, if left untreated, are
profound, with a greater probability of major
cardiovascular and kidney disease, and consequently a
shorter lifespan (see Table 5.1). e potentially disastrous
cardiovascular events referred to are familiar ones; they
include atherosclerotic disease (‘clogged-up’ arteries,
Chapter 6), stroke (Chapter 17), ischaemic heart disease
in the form of angina and myocardial infarction (heart
attack, Chapter 6), arrhythmias, and heart failure
(Chapter 7). Treatment that lowers blood pressure
Table 5.1 Hypertension is a risk factor for various
conditions
Primary condition Secondary consequence
Atherosclerosis of
coronary arteries
Myocardial infarct Heart failure
Kidney disease
Hypertension
Retinal disease
Diabetes
a
Kidney disease can be caused by hypertension, but can itself be a cause
of hypertension.
a
a
Angina
Myocardial infarct
Stroke (ischaemic or haemorrhagic)
Arrhythmias
Hypertension
Kidney disease
a
a
Chapter 5 Hypertension 77
Table 5.2 Two schemes for designating blood pressure ranges (note their uses in different parts of the world)
A. Version 1. Used in Europe (including UK)
Systolic (mmHg) Diastolic (mmHg)
Optimal
Normal 121–129 80–84
High normal 130–139 85–89
Hypertension Grade 1 140–159 90–99
Hypertension Grade 2 160–179 100–109
Hypertension Grade 3
B. Version 2. Used in USA
Normal
Pre-hypertension 121–139 80–89
Stage I 140–159 90–99
Stage II
<120 <80
>180 >110
Systolic (mmHg) Diastolic (mmHg)
<120 <80
>160 >100
therefore aims to reduce the risk of suering such
conditions, and this explains why the patient may not be
directly aware of the benets of such therapy. is lack of
perceived benet can in turn lead to problems with
compliance; patient education is therefore paramount
and requires a solid understanding of the biological basis
of hypertension and its consequences, and of how it is
modied by the profusion of drugs available.
e objective of this chapter is to provide the healthcare
professional with this secure foundation. is
understanding can then be applied to planning
individualized therapeutic strategies, and to advising
patients on their drug usage.
Hypertension is an extremely common condition,
aecting about 25% of the total population, with a higher
prevalence in people of African origin. Other risk factors
include family history, ageing, lifestyle (e.g. stress, diet,
alcohol), and obesity. In the vast majority of cases, the
cause is unknown (so-called essential hypertension). In
other rare cases there is an identiable cause (secondary
hypertension), such as renal disease or a tumour of the
catecholamine-secreting cells of the adrenal medulla
(phaeochromocytoma).
1. Minimum arterial pressure (diastolic) during the
cardiac cycle corresponds to the phase of ventricular
relaxation and relling (diastole).
2. Peak arterial pressure (systolic) corresponds to the
phase in the cardiac cycle when the ventricles contract
and blood is ejected.
Readings are conventionally presented as systolic/
diastolic.
e clinical denition of hypertension is based on data
which relate elevated blood pressures to increased risk of
cardiovascular disease (CVD). For example, a 55-year-old
non-smoking man with normal blood lipids (see Chapter
1
6) and a systolic blood pressure of 120 mmHg
has a 1 in
10 chance of CVD within 10 years. However, this risk rises
to over 1 in 5 if his systolic blood pressure is over 160
mmHg. Table 5.2 sets out two schemes for dening
optimal to high blood pressure readings which are used
in dierent geographical regions. In both, sustained
blood pressures over 140 mmHg systolic and 90 mmHg
diastolic are diagnostic of hypertension, and the patient
should therefore be considered for drug treatment. In
practice, the decision to treat is based not only on these
blood pressure schemes, but also on other factors (e.g.
Blood pressure is measured in the aortic side of the
vasculature, and while pulmonary hypertension is a
recognized condition, here we are concerned only with
hypertension of the systemic circulation. Blood pressure
readings comprise two values.
1 e universal unit for recording blood pressure is millimetres of
mercury (mmHg) in a mercury column. is reects the use of the
mercury sphygmomanometer as the rst choice for blood pressure
measurements for many decades. Alternative mercury-free devices
are now in routine use, but readings are still given as mmHg.
78 Chapter 5 Hypertension
=×
=×
=××
coexisting conditions) and potential benet from lifestyle
changes.
It should also be noted that patients with extremely high
blood pressures, such as Andreas the ctional patient in
Workbook 2, may be classied as having a hypertensive
crisis, requiring a more urgent and separate approach to
treatment.
Later in this chapter and in Workbook 2 we will
consider how decisions and choices in the drug
treatment of individual patients are made. Before that,
however, we must review how arterial blood pressure is
generated and controlled, and then examine the
fundamental mechanisms by which antihypertensive
drugs act.
5.1 The physiological control of arterial blood pressure
Antihypertensive drugs can only be understood by
reference to the mechanisms that regulate and set our
blood pressures. ese mechanisms have their basis in
the blood vessels and heart, and are inuenced by both
the nervous system (the brain acting via the sympathetic
and parasympathetic branches of the autonomic nervous
system) and the endocrine system (acting via the release
of hormones into the blood). Drugs in common use for
hypertension act at all these levels of control.
5.1.1 What determines our blood pressure:
heart and blood vessels
Arterial blood pressure is largely determined by only two
factors, cardiac output (determined by the heart) and
total peripheral resistance (a function of blood vessels).
Contraction of the ventricles in the heart provides most of
the driving force for pumping blood around the body.
Cardiac output (CO), then, is a measure of how much
blood is being pumped by each ventricle per minute, and
is the product of two factors: heart rate (HR; the number
of beats per minute) and stroke volume (SV; the volume
of blood pumped out of each ventricle per heart beat).
Arterial blood pressure is determined by both cardiac
output and the resistance to the ow of blood oered by
the blood vessels, called the total peripheral resistance
(TPR). is resistance is dependent on the degree of
contraction of the smooth muscle in the walls of the
pre-capillary arterioles. ese are the narrowest blood
vessels which contain smooth muscle in their walls,
unlike capillaries. eir diameter can be regulated
through contraction or relaxation of this muscle to
inuence the ow of blood through them (see Section
5.1.4):
CO HR SV (5.1)
BP CO TPR (5.2)
Combining equations (5.1) and (5.2), we see that arterial
blood pressure has three components—heart rate, stroke
volume, and total peripheral resistance:
BP HR SV TPR
We shall consider the aspects of these three parameters
which enable us to devise an individual drug treatment
plan for a patient with hypertension.
5.1.2 What determines the heart rate?
In a healthy heart, the electrical excitation of each
heart beat has its origin in a patch of tissue at the upper
segment of the right atrium called the sinoatrial (SA)
node or pacemaker. From here the wave of excitation (or
depolarization) spreads through the atria. It is then held
up for a moment by the barrier formed between the atria
and the ventricles before it gathers at the atrioventricular
node at the base of the right atrium, from where it passes
down specialized conduction cells to rapidly spread
throughout the ventricles (Figure 5.1).
e cells of the SA node re action potentials on their
own. at is, they do not require a neuronal input to tell
them when to re—they show automaticity. It is the
frequency with which they re action potentials that
determines your heart rate. As seen in Figure 5.2, SA node
cells do not have a steady resting potential, but are slowly
depolarized until a threshold is reached for action
potential generation. is slow depolarization is called
the pacemaker potential. It is apparent from Figure 5.2
that heart rate is determined by the steepness of the
pacemaker slope of the SA node action potentials; if the
slope is steep it takes less time to reach threshold and
action potentials re more frequently, resulting in an
increase in heart rate.
e pacemaker potential is the sum of the activity
through three sets of ion channels for Na+, K+, and Ca2+; it
is some of these proteins, localized in the membrane of
5.1 The physiological control of arterial blood pressure 79
Left and right atria
Sinoatrial
node
Atrioventricular
plane
Atrioventricular
node
Left ventricle
Purkinje bres
Bundle of His
Figure 5.1 The origin and spread of excitation in the
heart.
In a healthy heart, the excitation arises spontaneously as
depolarization in the sinoatrial (SA) node. A wave of
depolarization spreads through the muscle cells of the atria. The
atrioventricular plane is impermeable to depolarization, except at
the atrioventricular (AV) node. From here the excitation is
transmitted along the bundle of His, which divides into left and
right branches, before connecting with Purkinje fibres which
conduct the impulses to the heart muscle cells. The specialized
conducting cells enable extremely rapid spread of the impulse
throughout the ventricles so as to ensure coordinated
contraction. (See also Chapter 7, Box 7.1.)
the SA node cells, which are the molecular target of drugs
that regulate heart rate. e physiological determinants of
heart rate, such as activity in the sympathetic and
parasympathetic branches of the autonomic nervous
system, also act here. In brief, the release of
noradrenaline from the sympathetic nerve terminals (or
adrenaline from the adrenal medulla via the
bloodstream) increases the steepness of the slope, and
therefore increases heart rate (positive chronotropic
eect). Conversely, the release of acetylcholine (ACh)
from the parasympathetic nervous system decreases the
steepness of the slope and so decreases heart rate
(negative chronotropic eect).
Receptors for noradrenaline and adrenaline in the SA
node cells are mainly of the 1-adrenoceptor subtype
(although other subtypes are also found). ese receptors
are Gi-coupled receptors (GPCRs; see Chapter 2, Section
2.2.4), whose activation leads to a stimulation of cyclic
AMP synthesis inside the cell. is ultimately increases
the size of the inward Na+ and Ca2+ currents carried by the
SA node ion channels. is is achieved by various
mechanisms including an increase in their
phosphorylation state. e eects collude to steepen the
pacemaker slope (Figure 5.2).
0
Threshold
–65
Membrane potential (mV)
↑Sympathetic nervous system
Figure 5.2 The sinoatrial node action potential.
The action potentials are characterized by the pacemaker slope which controls the heart rate. The
steepness of the slope may be increased by stimulation from the sympathetic nervous system (red
lines compared with black) to reach threshold more quickly, and so the heart rate rises. Where
parasympathetic stimulation dominates (blue lines) the slope becomes more shallow, and the heart
rate falls. Note also that under the influence of the parasympathetic nervous system the pacemaker
slope starts from a more negative value as the SA node cells are hyperpolarized. The pacemaker
slope is formed by activity at several ion channels, including those carrying the If current (f for funny;
these voltage-gated channels are unusual in that they open when the membrane potential is
negative). These channels are the target of the anti-angina drug, ivabradine (Chapter 6).
0
Steep slope
↑Heart rate
100
Time (msec)
Pacemaker
slopes
200
↑Parasympathetic nervous system
Shallow slope
↓Heart rate
80 Chapter 5 Hypertension
Membrane potential (mV)
Receptors for ACh in the SA node cells are muscarinic
ACh receptors (mAChR) of the M2 subtype. ACh
stimulates these GPCRs, and activation results in a
reduction in cyclic AMP synthesis. is aects ion
channels by reducing phosphorylation, which leads to a
decrease in the Ca2+ current whilst enhancing K+ channel
activity. e increased permeability favours entry of K+
into the cell, which consequently becomes
hyperpolarized. e pacemaker potential therefore starts
from a more negative value, and this, combined with its
decreased slope, means that threshold is reached more
slowly and heart rate falls (Figure 5.2).
Although the parasympathetic inuence on the
pacemaker slope is profound (and unopposed can cause
a very substantial lowering of heart rate), it is noteworthy
that the -adrenoceptors are a more signicant target for
therapeutic agents, for example the antihypertensive
-adrenoceptor antagonists described later.
5.1.3 What determines stroke volume?
e determinants of stroke volume are complex, and here
we will only cover those issues necessary to understand
the action of therapeutic agents. We will divide the factors
aecting stroke volume into two groups: those directly
inuencing the ventricular myocytes (or heart muscle
cells), and those acting via the blood vessels.
Direct inuences on cardiac myocytes mainly involve
changes to their action potentials which drive the
contraction of these cells. In a healthy heart, the
ventricular action potential is characterized by (1) the
absence of a pacemaker slope (depolarization is
dependent on action potentials which originate in the SA
node, and which pass down from the atria) and (2) a Ca2+
plateau (Figure 5.3). Ventricular myocytes have a large
number of L-type voltage-dependent Ca2+ channels
(named L-type because of their long-lasting eect). When
the upsweep of the action potential occurs and the
membrane depolarizes, they open and Ca2+ ows into the
cell. e channels remain open for a prolonged period,
which maintains the depolarization (hence the plateau)
and provides the raised intracellular Ca2+ to stimulate the
muscle contractile mechanism.
Receptors for noradrenaline or adrenaline in the
ventricles are -adrenoceptors: clinically they are
mainly considered to be 1-adrenoceptors (although 2
subtypes are also found and may become more important
in certain pathologies, e.g. heart failure). ese GPCRs are
0
2
Na+ in
–90
Figure 5.3 The action potential of a ventricular myocyte.
Plot of membrane potential (mV) against time. A negative
potential indicates that the cell is electrically negative inside the
membrane compared with outside. Notable points are: (1) the
absence of a pacemaker slope; (2) the rapid rise caused by
opening of fast voltage-sensitive Na+ channels, giving a rapid
depolarizing influx of Na+; (3) the Ca2+ plateau in which
depolarization is maintained by a sustained influx of Ca2+; (4) the
eventual return to a negative potential when the inward Na+ and
Ca2+ currents have both been shut down. At the same time,
increased K+ permeability means that K+ ions leave the cell and
the membrane potential returns to the resting level (5).
1
coupled to a stimulation of cyclic AMP synthesis, which
ultimately leads to enhanced phosphorylation of the
L-type voltage-dependent Ca2+ channels. is
phosphorylation results in an increased probability of the
channels opening and therefore a higher Ca2+ plateau.
is increases the force of contraction of the myocytes
(positive inotropic eect) which means an increase in
stroke volume (more blood is ejected from the ventricles
with each heart beat). Additional inuences on the
myocyte ion channels combine to shorten the overall
length of the action potential. is allows a simultaneous
increased rate of action potential ring which is being
directed by the concurrent inuence of noradrenaline/
adrenaline on the SA node (the positive chronotropic
eect; see previous section). e overall eect, then, of
noradrenaline/adrenaline is increased strength of
contraction combined with increased heart rate; both
eects can be felt in situations where an adrenaline surge
is experienced (ght-or-ight response).
e cardiac -adrenoceptors whose activation underlies
these eects are a major target for drugs.
Other mechanisms may increase cyclic AMP and
intracellular Ca2+, leading to increased force of
contraction. For example caeine increases cAMP levels
in cells by inhibiting the phosphodiesterase enzymes
responsible for breaking it down. is then leads to
Ca
3
2+
in
4
+
K
out
5
5.1 The physiological control of arterial blood pressure 81
→↑
Stroke volume
increased force (and rate) of contraction. Agents which
activate other receptors coupled to enhanced cyclic AMP
synthesis include histamine acting at cardiac H2receptors, explaining a direct eect of histamine to
increase cardiac output. Digoxin is a clinically useful drug
(see Chapter 7), which includes in its action an increase in
Ca2+ that is independent of cyclic AMP, and consequently
increases force of contraction of cardiac myocytes.
Receptors for ACh in the ventricles are of the M2
subtype and are coupled to a decrease in cyclic AMP and
reduced force of contraction. However, the direct
End-diastolic volume
inuence of the parasympathetic system on ventricular
stroke volume is weak and may in fact be due to
decreased contraction of the atria.
Indirect inuences on stroke volume are mainly due to
changes in blood vessels. ese aect the heart in a
number of ways—two of them are explored here: changes
Figure 5.4 Ventricular function curve.
The relationship between end-diastolic volume and stroke
volume. When the end-diastolic volume is increased, the walls of
the ventricle are more stretched before the contraction begins,
and so the muscle will contract with greater force, leading to an
increase in stroke volume.
to the venous side, or the arterial side, of the circulation.
Changes to the venous side: the importance of
venous return, preload, and end-diastolic volume
e sympathetic inuence on the large capacitance
vessels2 will cause contraction of smooth muscle, leading
to vasoconstriction. e valves in the large veins ensure
that the blood is forced in one direction only—back to the
heart. So, enhanced sympathetic stimulation gives an
increased ow of blood through the veins back to the
heart, known as venous return. As a result, just before
they contract, the walls of the ventricles will be more
stretched (sometimes referred to as an increase in
preload) and the volume of blood in the ventricles
(end-diastolic volume) will be increased. is has an
eect on stroke volume as explained by Starling’s law,
which states that the more a muscle is stretched before it
begins to contract, the greater the force of the subsequent
contraction (Figure 5.4).
So we can sum up the situation as follows:
sympatheticstimulation of largeveins venous
→↑ →↑
return enddiastolic volume stretching
of theventricle walls forceof
-
→↑
→↑
contractionincreased stroke volume
Preload is also augmented by an overall increase in blood
volume, which explains the involvement of the kidney
2 e large veins in the body contain 60–70% of the total blood volume,
and so are described as capacitance vessels; contraction of these vessels
leads to increases in venous pressure.
and salt-retaining hormones such as aldosterone in the
physiological regulation of cardiovascular function. e
eect of blood volume on preload underlies the
usefulness of drugs crucial to the management of
hypertension, such as the thiazide diuretics used to treat
Andreas in Workbook 2. e enhanced elimination of
water and sodium by diuretics decreases blood volume,
and consequently reduces preload and therefore stroke
volume. However, note that in addition, thiazide diuretics
have an unrelated and benecial vasodilatory eect that
contributes to their blood-pressure-lowering activity (see
below).
Changes to the arterial side: the importance of arterial
blood pressure and afterload
When the left ventricle begins to contract at the start of
systole, the pressure within the ventricle rises rapidly
because the valves which allow the blood to leave remain
closed. ere is therefore a short delay until the blood is
ejected into the aorta. Within a few milliseconds, the
pressure inside the ventricle rises above the pressure in
the aorta, the aortic valve is forced open, and blood is
ejected from the heart. If the arterial blood pressure (i.e.
the pressure inside the aorta) is increased, the ventricular
pressure will have to reach a higher level for blood ow to
begin (Figure 5.5). is is referred to as an increase in
afterload. Similarly, as the contraction phase passes its
peak and the blood ow begins to fall, the aortic valve will
close earlier if aortic pressure is raised. Both of these