Cardiovascular Diseases & Rational Drug Design 2002
(3 Lectures: Dr Illingworth)
Basic cardiovascular physiology and pathology: what you need to know and
where to find information on the control of heart rate, cardiac output,
blood pressure, blood volume, ionic composition, renin / angiotensin system,
vascular endothelium, regulation of tissue perfusion, hypertension,
dislipidaemias, atherosclerosis, blood clotting, ischaemic heart disease,
cardiomyopathies, cardiac arrhythmias and cardiac failure.
Cardiovascular drugs: inotropic agents, b
blockers, calcium antagonists, organic nitrates, anti-arrhythmics, ACE
inhibitors, ATII (=AT1) antagonists, diuretics, cholesterol
lowering drugs, clot-busters, anti-coagulants, anti-platelet drugs.
Examples and opportunities for rational drug design in relation to renin,
angiotensin, aldosterone, cytokines, vasoactive peptides and other
cardiovascular targets.
Basic Cardiovascular Physiology
- The right side of the heart (pumping blood to the lungs) is a low
pressure pump, while the left side of the heart (serving the rest of the
body) operates at a much higher blood pressure. This is reflected in the
chamber dimensions and wall thickness.
- The Starling mechanism. If the heart chambers are distended with
blood, the ensuing beat is much more forceful than if the chambers were
initially empty. It is essential that hearts should respond in this way,
since otherwise Laplace's Law would make cardiac pumping impossible if the
ventricles ever became overfull. The molecular explanation is that calcium
ion release from the sarcoplasmic reticulum is much greater when the SR is
mechanically stretched. This should be considered in conjunction with the
next point.
- About 70% of the blood volume resides in the great veins, which have
muscular walls. Contraction of venous smooth muscle, or an expansion in
blood volume, raises central venous pressures and transfers some of this
reserve blood supply into the heart chambers, stretching the heart and
greatly increasing the cardiac output. Ventricular filling is often decribed
as the PRELOAD applied to the heart.
- Most of the resistance to blood flow arises from smooth muscle
compressing the walls of the arterial tree. The main effects are in the
small arterioles, and in the pre-capillary sphincters which ration blood
flow into the capillary beds. The aortic pressure depends on the cardiac
output and the peripheral vascular resistance, and is often called the
AFTERLOAD applied to the heart.
- Local control of blood flow relies mainly on nitric oxide and
endothelin produced by vascular endothelial cells and adenosine
released by ischaemic tissues. Capillary loops seem to be folded back on
themselves so as to bring the inflow and outflow vessels into close
juxtaposition, and thereby facilitate this local signalling.
- Local blood flow regulation helps to keep the cellular oxygen
concentration low. Oxygen is a very toxic substance, and cells are
easily damaged by high concentrations. Local regulation directs the limited
cardiac output to the areas where it is most needed.
- Blood osmolarity is monitored by osmoreceptor cells in the hypothalamus
which control overall water balance through the pituitary peptide
vasopressin (= anti-diuretic hormone, or ADH). These sensors are also
connected to the behavioural systems controlling thirst and salt craving.
Stretch receptors in the right atrium and the arterial tree monitor total
blood volume, and this neurally transmitted information is also used to
modulate ADH release.
- There is interaction between the control of blood volume and blood
osmolarity. Stretching the right atrium stimulates the release of atrial
natriuretic peptide (ANP) from the atrium, which promotes sodium
excretion by the kidney, ultimately reducing blood volume and salt content.
Ventricles produce brain natriuretic peptide or BNP. Conversely, low salt
concentration in the distal convoluted tubule, or inadequate perfusion of
the kidney, both stimulate release of renin into the bloodstream.
This short half-life protease cleaves circulating angiotensinogen producing
angiotensin I. Subsequent proteolysis by the lung endothelium yields
angiotensin II which has a powerful vasoconstrictor effect on arteriolar
smooth muscle. This raises systemic blood pressure, restores kidney
perfusion, and stimulates release of the salt-retaining hormone
aldosterone from the adrenal cortex, which promotes renal sodium
retention and potassium loss.
- In many tissues there is a local angiotensin metabolism superimposed on
the whole body mechanisms described above. Angiotensin is also concerned
with tissue growth.
- The whole ensemble is monitored and regulated by the autonomic nervous
system. There are blood pressure receptors (baroreceptors ) in the
great veins and in the aorta and the arterial tree. The baroreceptor signals
are integrated with information on body position from the system controlling
voluntary movements, and with information from chemical sensors, ultimately
regulating renin production, cardiac contractility and arterial and venous
smooth muscle tone. The physical position of the body is important, because
the hydrostatic pressures associated with an upright posture are greater
than arterial blood pressures, and very much greater than the pressure in
the veins.
The cardiac cycle: Each beat is initiated by
spontaneous depolarisation of pacemaker cells in the sino-atrial
(SA) node. These cells trigger the neighbouring atrial cells by direct
electrical contacts and a wave of depolarisation spreads out over the atria,
eventually exciting the atrio-ventricular (AV) node. Contraction of the
atria precedes the ventricles, forcing extra blood into the ventricles and
eliciting the Starling response. The electrical signal from the AV node is
carried to the ventricles by specialised conducting tissue (Purkinje fibres)
in the interventricular septum, formed from modified cardiac muscle cells. The
heart does not require innervation in order to beat, but the autonomic nerve
supply can vary the force and frequency of cardiac contraction.
Control of cardiac output: Aortic output varies over a
twenty-fold range between sleeping and vigorous exercise, and is also increased
during pregnancy. The Starling mechanism is very important, but in addition
circulating adrenalin, and noradrenalin released by cardiac nerve terminals,
have inotropic effects, enhancing cardiac contractility via cyclic
AMP and protein kinase A. Increased contractility means that the same peak
systolic pressure can be achieved with a lower end diastolic pressure, i.e. with
a lower degree of ventricular stretch. Increased contractility does not
necessarily produce a rise in arterial pressure, but may produce a fall in the
central venous pressure. Ion channel phosphorylation increases calcium entry
during the action potential, calcium release from the SR during systole
(contraction), and calcium uptake by the SR during diastole (relaxation).
[Direct electrical connections between adjacent cardiac muscle cells preclude
the progressive fibre recruitment seen in voluntary muscles: in the heart every
muscle cell depolarises every beat.] Catecholamines from the sympathetic nerves
acting on cardiac b1 adrenoceptors make
the beats more rapid and forceful, while acetylcholine from the parasympathetic
nerves acting on muscarinic M2 receptors has the opposite effect.
Congestive heart failure (CHF): This term is often
misunderstood. It does NOT mean the heart has stopped beating, it means that
output is insufficient to meet the needs of the body. The autonomic nervous
system detects the inadequate tissue perfusion, and reacts as though the blood
volume were too low. It leads to vasoconstriction, salt and water retention,
reduced parasympathetic activity, increased sympathetic activity and cytokine
production. The low inherent cardiac contractility requires excessive venous
pressures to maintain ventricular output through the Starling mechanism.
Permanently high venous pressures are a serious problem: if the systemic venous
pressures are high (right side failure) it may cause disabling lower limb oedema,
while if the pulmonary venous pressures are raised (left side failure) it will
cause lung congestion (fluid accumulation) breathlessness (dyspnoea) and
coughing. Both sides of the heart may be affected at the same time.
The haemodynamic improvements sought during therapy are:
decreased pulmonary capillary wedge pressure, decreased systemic vascular
resistance, decreased mean right atrial pressure and decreased pulmonary artery
pressure, while improving cardiac index, stroke volume and classical heart
failure symptoms such as dyspnoea (breathlessness) and swollen ankles. [The
cardiac index is the output in litres/minute divided by the body surface area in
square metres.]
Traditional therapy was based on diuretics, vasodilators and
inotropic agents, which relieved symptoms and improved cardiovascular status,
without improving overall mortality! The later introduction of loop diuretics (frusemide),
potassium-sparing diuretics (amiloride) aldosterone antagonists (spironolactone),
b-blockers, and particularly ACE inhibitors
and angiotensin receptor antagonists has greatly reduced the morbidity
and mortality associated with CHF.
Angina: This is a pain in the chest caused by
insufficient blood flow through the coronary arteries, leading to cardiac
ischaemia. It may be a chronic condition persisting for many years, and often
exacerbated by excitement, smoking and over-eating. Reduced coronary blood flow
sometimes results from coronary artery spasm, but most commonly follows
atherosclerotic damage to the blood vessel endothelial lining. This inflammatory
process leads to blood clot formation and obstruction of the vessel lumen. See
Staels (2002) Nature 417, 699 - 701 for a recent brief review. Angina
may be associated with other manifestations of atherosclerosis, such as strokes
and intermittent claudication in skeletal muscle. Prolonged or severe angina may
progress to necrosis of cardiac cells, release of the cell contents into the
bloodstream and myocardial infarction (MI).
Cardiac oxygen demand correlates closely with systolic blood
pressure (or more strictly with the area under the ventricular pressure * time
curve), but does not increase so markedly with the volume of blood actually
pumped by the heart. [This is because myosin ATP hydrolysis does not depend on
whether the muscle actually succeeds in shortening.] The treatment is therefore
to reduce the cardiac afterload (the mean aortic pressure) with drugs
which dilate the systemic arterioles. The resulting fall in systemic blood
pressure allows the left ventricle to empty more completely and reduces the
overall cardiac work load. This brings the cardiac oxygen supply and demand into
better balance. The benefit may be less than desired because the treatment
necessarily reduces the coronary perfusion pressure and this may reduce the
coronary blood flow.
Nitroglycerine tablets dissolved under the tongue remain the
classical treatment for anginal attacks. The drug is rapidly absorbed through
the buccal epithelium, and is metabolised in the tissues to nitric oxide, which
has vasodilator and hypotensive effects. [Hypotension was noted many years ago
among workers in munitions factories who absorbed organic nitrates through their
skin.] A variety of polyol nitrates, calcium channel antagonists and
b adrenergic blocking agents may also be used to
achieve the desired effect. A new treatment for unstable angina without
infarction is abciximab - a chimeric mouse-human monoclonal antibody
directed against the platelet glycoprotein IIb/IIIa fibrinogen receptor. This
treatment interferes with blood clotting, and delays the extension of the
arterial plaque.
| medical condition |
angina pectoris |
congestive heart failure |
| physiological problem |
cardiac oxygen demand exceeds supply |
low contractility (more rarely, atrial fibrillation)
causes high venous blood pressure |
| treatment strategy |
reduce cardiac work output, try to improve oxygen
supply |
increase cardiac volume output, reduce cardiac
workload, reduce venous congestion |
| drug 1 |
nitroglycerine causes arterial vasodilation, lowers
afterload |
ACE inhibitors or AT1 blockers produce
arterial vasodilation |
| drug 2 |
b-blocker (e.g. metoprolol)
but care needed in diabetics |
diuretics (e.g. furosemide plus amiloride) remove
excess fluid |
| drug 3 |
calcium channel blocker (e.g. nifedipine or verapamil) |
b-blockers (e.g. carvedilol)
in hemodynamically stable patients |
| drug 4 |
lipid lowering and anti-clotting drugs, aspirin or
clopidogrel |
digitalis (especially for atrial fibrillation, or
severe failure) |
Myocardial infarction: The heart is uniquely sensitive
to lack of oxygen because it operates a highly aerobic, lipid-based metabolism,
with up to 95% arteriovenous oxygen extraction. Many tissues have arterio-venous
shunts in their capillary network and extract only about 30% of the available
oxygen in arterial blood. The high cardiac oxygen extraction may arise because
the capillaries are squeezed during systole, so that blood flow only occurs
during diastole.
If the coronary arteries are partially or completely blocked,
then downstream muscle cells may die, releasing their enzymes into the
extracellular space. The enzymes continue to leak into the bloodstream over
several hours. This release is non-specific but can be useful in the diagnosis
of suspected myocardial infarction from peripheral blood samples. Not all heart
attacks are painful enough to be immediately recognised, although many are.
Other signs of myocardial infarction are changes in the ECG, and under
favourable conditions these can show the precise location of the damage. A
really big transmural infarct carries the risk that the ventricle may eventually
rupture with disastrous results, but normally the most serious risks are
cardiogenic shock and ventricular fibrillation provoked by the
abnormal electrical properties of partially ischaemic cells at the edge of the
infarct. If the patient survives the first few days the damaged area is invaded
by macrophages and fibroblasts. The cells are replaced by scar tissue, leaving
the heart usable, but permanently weakened. Infarcts affecting the cardiac
impulse conducting system may produce partial or complete heart block,
where synchronisation is lost between atria and ventricles. This can be treated
with an artificial pacemaker.
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