PATHOPHYSIOLOGY OF VASCULAR TONE. ARTERIAL HYPERTENSION.
The level blood pressure in the healthy people it is
the very stable value. The stability of blood pressure is supported complicated
complex by regulative systems. Hayton (1974) has divided them into two groups – hemodinamic system and regulating system.
The hemodinamic systems are represented by two parameters:
– cardiac output (minute volume of blood, that is amount
of blood, which heart throws out in circulation for 1 minutes);
· PR – peripheral
resistance, that is resistance arterial vessels, mainly – arterioles, movement
· The level arterial pressure is determined on the basis of equation Puazel:
AP = ÑO õ PR, that is it directly proportional
to an cardiac output and peripheral resistance.
In the healthy person both these values – cardiac output and peripheral resistance – stay in inversive relation. If in the certain conditions
the cardiac output is increased,
the peripheral resistance accordingly decreases. Owing to opposite shifts of
both values average hemodinamicpressure
remains within the limits of physiological boundaries. In case of decrease of
an cardiac output the peripheral resistance increases,
and average hemodinamic pressure is again saved normal.
The regulating systems two varieties regulative mechanisms –
system of short-term operation and system of durablis action belong. The system of
short-term action is represented by two mechanisms. The first from them it is baroreceptors and chemorecerptors of
aortas arc and sinucarotid zones, which, devices react to acute increasing or
lowering blood pressure. The impulses from receptors achieve vasomotorial
centre in medulla oblongata and reticular formation.
From aorta arc they go to depressor nerve of Ludvig-Cion, from sinucarotid zones the excitation gets brain through ramus sinus caroticus (nerve Hering). From brain efferent signals through cholinergic and adrenergic fibres get to
periphery and regulate lumen of arterioles, frequency
and force of beat veins capacity. So the correction of arterial pressure is
carried out. The second outline
system of short-term operation consists of three components: renin –angiotensin ²² – arterioles. It counteracts to acute hypothension. The system of durablis operation is represented of two final effectors substances –angiotensin ²² and aldosteron.
Regulation of arterial blood pressure. The
kinds of arterial hypertension.
In the healthy
people arterial pressure is within the limits of
100/60-139/89 mm Hg. Despite
of difficult complex regulation, in many cases arterial pressure is increased
or decreased. High arterial
pressure is called hypertension, low – hypotension.
Arterial hypertension is constant and prolonged increase arterial pressure. It is
selecting two stages arterial
hypertension: boundary hypertension and fixed (stable) hypertension. Boundary
hypertension is called such state, when the pressure
periodically achieves values of 140/90-159/94 mm Hg or constantly stays in this range.
If arterial pressure achieves level of 160/95 mm Hg or exceeds these digits, it
is regarded as stable, fixed hypertension.
Arterial hypertension divide on two groups – primary
and secondary. Primary arterial hypertension is called still essential hypertension,
or hypertonic illness. It is separate nosological unit. Its consist above 80 per cent all arterial
hypertensions. The second group consist secondary hypertension. On them it is about 20 per cent of hypertensions. It is
not separate nosological unit, and only symptoms of some
diseases (from this one more name – symptomatic
Etiology and pathogenesis of hypertonic disease
To problem the disease hypertonic to approach easiest on the basis of the analysis already
formula, known for us: AP = ÑO õ PR.
All influences, which are capable to increase cardiac output or peripheral resistance, it is
possible to consider as etiological factors
of hypertonic disease. To major etiologicalfactors belong the following: increase of plasma volume, increase cardiac output, increase activity of sympathetic
nervous system, alteration of
kidneys functions, increase peripheral resistance,
plasma volume is connected with accumulation of the salt in organism. It is
possible in consumption plenties of salt, or in insufficient selection
it by kidneys (for example, kidney insufficiency). It is considered, that the
long consumption 5 g of salt per day can
cause hypertension in the people, which have hereditary predisposition.
The following scientific observations testify to a
role NaCl in occurrence arterial hypertension.
The Japanese population, which lives on sea coast, every day consumes salt in increased amount with water and food. Among this
population is observed very high morbility by hypertension (40 % of the adult
population the after 40 years). At the same time among the population, which
lives in mountainous district and consumes less salt, the level of morbility
from hypertonic disease does
not exceed 2 %, that is in 20 times is lower. On the other hand, that lower-salt diet influences positive medical effect at the
Salt promotes some mechanisms. Owing to accumulation of sodium, volume of extracellular
liquid (including – circulatting blood)
is increased, follow the cardiac output increases
and as a result is increased arterial pressure. Compensator response on increase of plasmas volume is the
limitation blood circulation through the organs, and it is achieved by increase
resistance of peripheral vessels and increase
pressure. The accumulation sodium
and water in walls of vessels is results of thickening the walls and decrease
lumen of vessels. Finally, the
accumulation of sodium in walls of vessels is results of increase sensitivity
myocytes to pressor agents, in particular to
of cardiac output. The increase volume of plasma
increases cardiac output secondaryly. However there are factors, which are capable
directly to increase cardiac output. Among them – emotional
stress, hyperthyroidism. All
these states are accompanied by activation sympathetic nervous system.
Stimulation of cardiac activity is carried out through
β-adrenoreceptors of myocard on adrenaline acts. It increases stroke volume. In combination with
increase cardiac rate it lead to signiticant increase of cardiac output.
Increase sympathetic tonus. One of the factors responsible for development essential hypertension,
can be increase of activity sympathetic nervous system. This hyperactivity has
effect for functions of some organs, which can be considered as a targe sympathetic influences. To this group
belong heart, arteries, veins and kidney. Heart changes the activity on the
already stated above mechanism: the frequency of cardiac rate is increased, stroke volume of blood is increased and in a result the cardiacoutput is increased.
In pathogenesis of arterial hypertension the special
place belongs small-sized arteries-arterioles. They are named vessels of resistance or taps of vascular system. The most
characteristic property of these vessels is the very high resistance to blood
circulation, for want to it is supported the proper level of
The high resistance to blood circulation in arterioles
is provided with some structural and functional features them, named: à)
a small lumen – 15-70 microns; b) a thick layer
smooth ring muscle; c) the wall of arterioles stays in a state continuous
Regulation of peripheral resistance and arterial
pressure – main function of resistance vessels.
The influence of sympathetic nerves to arterioles is carried out by two
ways –direct and mediated. From the terminations sympathetic nerves is selected noradrenaline. It acts to α1-adrenoreceptors of vessels
and narrows them. In such a way it increases peripheral resistance, and
consists in activation of adrenal gland medullar layer, where are synthesized
catecholamins – adrenaline and noradrenaline.
The level of blood pressure will depend from issue them simultaneous and of
different direct action of both hormones to cardio-vascular system: à) noradrenaline through α1-adrenoreceptors
of resistance vessels increases them tonus, peripheral resistance and arterial
pressure; b) adrenaline excites β-adrenoreceptors
of myocard, increases cardiac
output and in such way increases blood pressure; c) simultaneously
adrenaline acts to β-adrenoreceptors vessels dilatates throught them
and decrease blood pressure.
The development of arterial hypertension is possible
only by following ratio to effects of noradrenaline and adrenaline: increase of pressure
by stimulation vessels β-adrenoreceptors by noradrenaline plus increase
of pressure, stimulated β-adrenoreceptors of myocard by adrenaline, in the sum should
exceed decrease pressure connected to action adrenaline to vessels β-adrenoreceptors. But such situation develops only at 20 percent of the
patients with hypertonic disease.
Noradrenaline increases tonus not only the arteries, but
also the veins. In their walls is present smooth muscle too. The narrowing of
veins causes redistribution of blood from venous vessels
to arterial. The volume of circulatting blood is increased, the cardiac output is increased and the peripheral
resistance is increased.
Kidneys functions disturbance. Long spasm of arterioles includes the renals factor of progressive and
stabilization hypertonic disease. The narrowing of arterioles is results of
pressure falling in renals capillaries. In the answer the synthesis and
selection in blood of proteolytic
enzyme rennin is increased.
Renin is synthesized by juxtaglomerular apparatus, which consists of three structures (parts):
à) endothelium of afferent arterioles of renals glomerule; b) epithelioids
cells near glomerules,
which surround afferent arteriole; c) the dense stain (macula densa) – epithelial cells of a segment distal convoluted renal tubules, which
envelop afferent arteriole
Active renin represents proteolytic enzym with molecular weight 42 KDa. It influences on α2-globulin
(angiotensinogen), which is synthesized in a liver. Renin breaks off leicin-leicinous connection in a molecule of angiotensin and transforms it in angiotensin ²(decaprotein). Angiotensin ² is not active absolutly. It influences angiotensin converting enzyme, which
is located, mainly, in lung. This enzyme separate from angiotensin ² histidilleicin also transforms it in angiotensin ²² (octaprotein).
Angiotensin ²² – very powerful pressor agent. In blood it is not stable.
Under influence enzyme of angiotensinases it loses asparagin acid and turns in angiotensin ²²² (hectaprotein). It occurs mainly in
kidneys. The function of angiotensinases is executed by many proteolytic enzymes – tripsin, hemotripsin, pepsin, aminopeptidase. The activity of angiotensin ²²² makes 30-50 percent activity
The action of angiotensin ²² is very diverse. It includes set of
mechanisms, which increase blood pressure and stabilize arterial hypertension.
Major of them: à) direct action to specific receptors of vessels smooth muscles; b) mediated
action through the central nervous system – some sites of brain trunk are sensitized to angiotensin ²², they stimulate vasomotorial centre; c) through peripheral
sympathetic nervous system – angiotensin ²² is stimulates secretion of
noradenalin from presynaptic endings;
d) through medulla layer of adrenal glands – angiotensin ²² stimulates libering of catecholamins; e) through kidneys – by active reabsorbtion of sodium and delay of water irrespective
of aldosterone mechanism.
Dependent from activity of renin hypertonic disease divide on three
· normoreninemal – 55-60 %
of all cases, · hyporeninemal – 25-30 %, · hyperreninemal - 10-20 %.
Thus, and on this parameter hypertonic disease is not
It was clarified further , that the kidneys select not only renin,
which eventually results in increase of blood pressure and stabilization
arterial hypertansion. They have
also depressor function. The kidneys select following depresor substances: phospholipid inhibitor of renin,antihypertension neutral lipids medullar layer of kidneys, prostaglandins, angiotensinase, alkalized ethers phosphatidilholin.
The largest interest from these substances is
prostaglandins. They are synthesized kidneys. Stimulators synthesis of
prostaglandins in kidneys are considered angiotensin ²², vasopressin, catecholamins, that is those
substances, which cause narrowing renals arterioles
and ischemia of kidneys. Depressor property of prostaglandins will be realized
due to the following mechanisms. Prostaglandins, especially PGE2,
render natriurtic action. They dilatate renals arteries, and also directly oppress return transepithelial transport of sodium chloridum in nefrone.
prevent action of antiuretic on
reabsorbtion of water.
The kidneys start
still one more mechanism of stabilization hypertension - hormonal. Angiotensin ²² and ²²²,
being powerful vasocontrictors,
simultaneously stimulate synthesis of aldosterone in glomerulars zone of adrenal glands cortex. Effect steroids of
them is identical. Aldosterone enhances reabsorbtion of sodium in canaliculus, especially in distaldepartent. Sodium is accumulated
in liquids of an organism and in smooth muscles of vessels.
Increase of vesseles resistance. Irrespective of first reason, in the
patients with hypertonic disease almost always increases peripheral
resistance. It is considered, that the essence hypertonic disease just is
in increase of peripheral vessels tonus. Hyperkinetic phase, which is connected
to increase of cardiac output, happens only at early stages of disease and not in all
The hereditary predisposition has concrete confirmation: à)
in separate families the disease meets in some times more often, than in
population; b) high percent concordans monozygotes twins on hypertonic disease is
installed; c) it is
established, that if one of the parents suffered by hypertonic disease, for
them children the risk of disease six times is higher, than for children from
family not burdened by that disease.
In a basis of hereditary predisposition to essential hypertension the lay
disturbances transmembran transport of ions. In the
particular, in such patients in cytozole of vessels wall myocyte is
accumulated calcium because of deficiency Ca2+ -ATP-ase. Calcium can not be
deleted from myocytes in intracellular environment. The accumulation increases it contractive
ability of vessels wall myocytes and due
to stable increase of peripheral
resistance. Once more possible mechanism – generical conditioned oppression systems endotheliocytes of enzymal,
which make internal vasodilatators (oxid of nitrogen, prostacyclin).
represent symptoms of such diseases. 1. Diseases of kidneys: glomerulonephritis (14 %), pielonephritis, interstitial nephritis due to abusing analgetics, hereditary
nephritis (syndrome Alport’s), polycytosis kidney. 2. Stenosis of renal
artery (1 %).
Hypertension arises not in each stenosis. The most often reason of stenosis, caused atheroscleroticplatelits(at
70-80 of %), which damage usually proximal third of renal artery on the one
hand. Other reason of stenosis with hypertension itsfibromuscular hyperplasia of an average third of
renal artery. It, as a rule, double-side and more often happens at the women.
The mechanism of hypertension in stenosis of renal artery – hyperproduction of renin.
3. Primary aldosteronism (Cînn syndrome) – in 1 % of cases. The
reasons – unilateral adenoma glomerular zone adrenal glands or double-side
diffuse hyperplasia of adrenal glands. 4. Paraganglioma (1 %) –tumour from chromaffin
cells of medullar layer adrenal
glands or sympathetic nerves, as a rule – benighn.
Inparaganglioma is increased both
cardiac output, and peripheral resistance. 5. Coarctation of the aorta is an anatomic defect, in which aorta in pectoral or abdominal
department is narrowed to such extend, that it represents serious barrier for
blood circulation. In all vessels, which depart from the aorta proximal of
narrowing, the resistance increases and is increased arterial pressure.
Experimental models of arterial hypertension
Models confirming a role of the nervous factor in
increase of arterial pressure:
1. Arterial hypertension owing to an irritation of
hypothalamus nucleuses. The irritation of a back nucleus
frequently results to hypertension, connected with increase
of cardiac output. The irritation of a central nucleus causes hypertension due to of peripheral resistance increase. Electricity
stimulation ventro-medial nucleus
gives hypertension, which depends from simultaneously increase of cardiac output and
2. Arterial hypertension from double-side damage
nucleus tractus solitarii
to medulla oblongata of rats,
where are located primary synapsis of sinuaorticus
baroreceptors. Arterial pressure is increased
immediately without change of frequency of cardiac rate. The reason of
hypertension is the sharp increase of peripheral resistance
3. Reflexogenic hypertension,
in dogs and rabbits affter section depressor nerve Ludvig-Cion or sinus nerves Hering.
Models, which confirm participation renals factor in occurrence and stabilization
of arterial hypertension:
1. Vasorenal hypertension, which is caused by narrowing renals arteries. Conditions of reproduction: à)
arteries should be narrowed only partially, instead of are blocked completely;
b) the narrowing should be double-side; c) the variant is possible(probable):
narrowing arteries of one kidney plus removal of the other kidney.
2. Renoprival hypertension it arises after removel both kidneys and spending of animal on dialysis.
Models confirming a role of adrenal glands in fixing
1. Mineral-corticoids hypertension – in the case of long introduction of aldosteron with
simultaneously purpose of
solution NaClinstead of water.
2. Salty hypertension. Sodium chlorids in a fair quantity even without
additional hormonal effects is capable to cause hypertension.
Model confirming role of the hereditary factor in
etiology of hypertonic disease.
Exists genetic (spontaneous) hypertension in rats. In
the animal with spontaneous hypertension is revealed higher, than in normal
animals, permeability ions channels in membranes smoothmuscle cells of arteries. These membrane defects
can have some significance in increase of arteries tonus and regulation of volume
extracellular liquid. They can be considered as one of the factors pathogenesis
Hypertension (HTN) or high
blood pressure, sometimes called arterial
hypertension, is a chronic medical
condition in which the blood pressurein the arteries is elevated. This requires the heart to work harder than normal to
circulate blood through the blood vessels. Blood pressure is summarised by two measurements, systolic and
diastolic, which depend on whether the heart muscle is contracting (systole) or
relaxed between beats (diastole). Normal blood pressure at rest is within the
range of 100-140mmHg systolic (top reading) and 60-90mmHg diastolic (bottom
reading). High blood pressure is said to be present if it is persistently at or
above 140/90 mmHg.
Hypertension is classified as either primary (essential) hypertension or secondary hypertension; about 90–95% of cases are categorized as "primary hypertension"
which means high blood pressure with no obvious underlying medical cause. The
remaining 5–10% of cases (secondary hypertension) are caused by other
conditions that affect the kidneys, arteries, heart or endocrine system.
Hypertension is a major risk
factor for stroke, myocardial
attacks), heart failure, aneurysms of the
arteries (e.g. aortic aneurysm),peripheral arterial disease and
is a cause of chronic
kidney disease. Even moderate elevation of arterial
blood pressure is associated with a shortenedlife expectancy. Dietary and
lifestyle changes can improve blood pressure control and decrease the risk of
associated health complications, although drug treatment is often necessary in
people for whom lifestyle changes prove ineffective or insufficient.
Signs and symptoms. Hypertension is rarely accompanied by any symptoms,
and its identification is usually through screening, or when seeking healthcare
for an unrelated problem. A proportion of people with high blood pressure
report headaches (particularly at the back of the head and in the morning), as
well as ligh the adedness, vertigo, tinnitus (buzzing or hissing in the ears),
altered vision or fainting episodes. These symptoms however are more likely to
be related to associated anxiety than the high blood pressure itself.
On physical examination, hypertension may be suspected on the basis of
the presence of hypertensive retinopathy detected by examination of the optic
fundus found in the back of the eye using ophthalmoscopy. Classically, the
severity of the hypertensive retinopathy changes is graded from grade I–IV,
although the milder types may be difficult to distinguish from each other.
Ophthalmoscopy findings may also give some indication as to how long a person
has been hypertensive.
Secondary hypertension. Some additional signs and symptoms may suggest
secondary hypertension, i.e. hypertension due to an identifiable cause such as
kidney diseases or endocrine diseases. For example, truncal obesity, glucose
intolerance, moon facies, a "buffalo hump" and purple striae suggest
Cushing's syndrome. Thyroid disease and acromegaly can also cause hypertension
and have characteristic symptoms and signs. An abdominal bruit may be an
indicator of renal artery stenosis (a narrowing of the arteries supplying the kidneys),
while decreased blood pressure in the lower extremities and/or delayed or
absent femoral arterial pulses may indicate aortic coarctation (a narrowing of
the aorta shortly after it leaves the heart). Labile or paroxysmal hypertension
accompanied by headache, palpitations, pallor, and perspiration should prompt
suspicions of pheochromocytoma. A proportion of resistant hypertension appears
to be the result of chronic high activity of the autonomic nervous system; this
concept is known as "neurogenic hypertension".
Primary hypertension (essential) is the most common form of hypertension,
accounting for 90–95% of all cases of hypertension. In almost all contemporary
societies, blood pressure rises with aging and the risk of becoming
hypertensive in later life is considerable. Hypertension results from a complex
interaction of genes and environmental factors. Numerous common genetic
variants with small effects on blood pressure have been identified as well as
some rare genetic variants with large effects on blood pressure but the genetic
basis of hypertension is still poorly understood. Several environmental factors
influence blood pressure. Lifestyle factors that lower blood pressure include
reduced dietary salt intake, increased consumption of fruits and low fat
products (Dietary Approaches to Stop Hypertension (DASH diet)), exercise,
weight loss and reduced alcohol intake. Stress appears to play a minor role
with specific relaxation techniques not supported by the evidence. The possible
role of other factors such as caffeine consumption, and vitamin D deficiency
are less clear cut. Insulin resistance, which is common in obesity and is a
component of syndrome X (or the metabolic syndrome), is also thought to
contribute to hypertension. Recent studies have also implicated events in early
life (for example low birth weight, maternal smoking and lack of breast
feeding) as risk factors for adult essential hypertension, although the
mechanisms linking these exposures to adult hypertension remain obscure.
Secondary hypertension. Pathophysiology.
In most people with established essential (primary) hypertension,
increased resistance to blood flow (total peripheral resistance) accounting for
the high pressure while cardiac output remains normal. There is evidence that
some younger people withprehypertension or 'borderline hypertension' have high
cardiac output, an elevated heart rate and normal peripheral resistance, termed
hyperkinetic borderline hypertension. These individuals develop the typical
features of established essential hypertension in later life as their cardiac
output falls and peripheral resistance rises with age. Whether this pattern is
typical of all people who ultimately develop hypertension is disputed. The
increased peripheral resistance in established hypertension is mainly
attributable to structural narrowing of small arteries and arterioles, although
a reduction in the number or density of capillaries may also contribute.
Hypertension is also associated with decreased peripheral venous compliance which
may increase venous return, increase cardiac
preload and, ultimately, cause diastolic dysfunction. Whether
increased active vasoconstriction plays
a role in established essential hypertension is unclear.
Pulse pressure (the difference between systolic and diastolic blood
pressure) is frequently increased in older people with hypertension. This can
mean that systolic pressure is abnormally high, but diastolic pressure may be
normal or low – a condition termed isolated systolic hypertension. The high pulse
pressure in elderly people with hypertension or isolated systolic hypertension
is explained by increased arterial stiffness, which typically accompanies aging
and may be exacerbated by high blood pressure.
Many mechanisms have been proposed to account for the rise in peripheral
resistance in hypertension. Most evidence implicates either disturbances in
renal salt and water handling (particularly abnormalities in the intrarenal
renin-angiotensin system) and/or abnormalities of the sympathetic nervous system. These mechanisms are not mutually exclusive
and it is likely that both contribute to some extent in most cases of essential
hypertension. It has also been suggested that endothelial dysfunction and
vascular inflammation may also contribute to increased peripheral resistance
and vascular damage in hypertension.
Diagnosis. Typical tests performed. Renal System - Tests - Microscopic
urinalysis, proteinuria, BUN and/or creatinine; Endocrine – Serum sodium,
potassium, calcium, TSH; Metabolic - Fasting blood glucose, HDL, LDL, and total
cholesterol, triglycerides; Other - Hematocrit, electrocardiogram, and chest
radiograph (Sources: Harrison's principles of internal medicine others).
Hypertension is diagnosed on the basis of a persistently high blood pressure.
Traditionally, this requires three separate sphygmomanometer measurements at
one monthly intervals. Initial assessment of the hypertensive people should
include a complete history and physical examination. With the availability of
24-hour ambulatory blood pressure monitors and home blood pressure machines,
the importance of not wrongly diagnosing those who have white coat hypertension
has led to a change in protocols. In the United Kingdom, current best practice
is to follow up a single raised clinic reading with ambulatory measurement, or
less ideally with home blood pressure monitoring over the course of 7 days.
Pseudohypertension in the elderly or noncompressibility artery syndrome may
also require consideration. This condition is believed to be due to
calcification of the arteries resulting an abnormally high blood pressure
readings with a blood pressure cuff while intra arterial measurements of blood
pressure are normal.
DISORDER OF LIPOPROTEIN
Plasma lipoproteins are synthesized and excreted by two types of cells:
liver parenchyma cells and small intestine epithelial cells. There is a lipid
drop inside (nucleus), containing triglycerides and cholesterol ethers.
Membrane covers the nucleus; it consists of protein (apolipoprotein, or apo-),
phospholipids and non-aetherificated cholesterol.
All lipids are in blood plasma in protein-binded form. Non-aetherificated
fat acids are binded with albumin, others – with a- and b-globulins and make
lipoprotein complexes. General amount of all lipids in blood plasma of healthy
adults can changes between 4-8 g/l. Generally the lipoprotein particle is
soluble in water and is transport form of lipids in blood. There are four main
classes of lipoprotein: chilomicrones, very low density lipoproteins,
low-density lipoproteins, high-density lipoproteins.
The richest in triglycerides are the particles (table), which are formed
in the intestinal wall during absorption of exogenous triglycerides and
cholesterol. At first chilomicrones go into thoracic lymphatic duct, and then –
into the common blood flow (their components are 90 % of alimentary
trigycerides, 4-5 % of cholesterol, 4-5 % of phospholipids, 1 % of albumin –
apoprotein A, B, C, E). Very low-density lipoproteins (VLDL) are produced in
the liver, and less –in bowels wall. They are basic transport form of
endogenoustriglycerides. They contain 10 % ofapoprotein B, C, E, 90 % of
lipids, main components of which – 60 % triglycerides, synthesized in organism,
15 % cholesterol, 15% phospholipids. Low-density lipoproteins (LDLP) contain
about 25 % of apoprotein B, E and 75% of lipids. Lipids contain mostly cholesterol (about 50 %, major of it ischolesterol
ethers), phospholipids – about 30 %, triglycerides – about 8-10 %. Low-density
lipoproteins are mostly rich in cholesterol and are the most atherogenous. In
healthy people two of third of all cholesterol of blood plasma is found in
low-density lipoproteins, so they are the basic transport form of cholesterol
in human organism. Low-density lipoproteins
are generated partially or fully due to very low-density lipoproteins
disintegration in blood plasma owing to lipoproteidlipase, which are activated
by heparin. High-density lipoproteins (HDLP) about 30 % of phospholipids, about
20 % of cholesterol ether and very little of triglycerides. Part of them
synthesizes in liver and in the thin bowels wall, and another part forms in
blood plasma from chilomicrones and very low-density lipoproteins degradation
products, which were formed due to lipoproteidlipase.
Healthy people plasma, taken before meals, contains 0,8-1,5 g/l of very
low-density lipoproteins, 3,2-4,5 g/l of low-density lipoproteins and 2,7-4,3
g/l of high-density lipoproteins. Women’s plasma contains more high-density
lipoproteins than men’s plasma. From the chemical point of view is fatty
alcohol. Natural waxy cholesterol properties allow it to execute functions of
the cell “skeleton” in human and animal organism. Each cell of our body
contains cholesterol. Being a point of the cell, cholesterol together
withphospolipids and proteins provide the selective cell perspicacity for
substances, which enter and leave. Cholesterol is source of formation of sexual
and steroid hormones, and also of cholic acids. It’s indispensable for organism
growth and cell division.
The low-density lipoproteins is the main transport form of cholesterol in
the human organism, they carry cholesterol from liver into membranes of
different cells. How dolow-density lipoproteins particles bring cholesterol
into the cell? Organs and tissues cells contain specific apo-B and
apo-Å-receptors for binding low-density lipoproteins particleson the surface of
plasmatic and intracellular membranes. General number of receptors can go up to
ten thousand per one cell. One apo-B or apo-Å-receptors binds up one
apoprotein-B or apoprotein-E particle of low-density lipoproteins. This is the
receptor-mediated endocytosis. This way of lipoproteins transportation is
directed only to supply the internal cells’ needs in cholesterol and does not
lead to lipoprotein-particles entrance into arteries’ intimae of cholesterol
changes or its metabolites
in plasma and cells, they govern the cells interchange including the
liver. When entering the cell endocytosis vesicles that contain lipoproteins particles
come into contact with lysosoms where lipoproteins are slitted. The exempted
cholesterol is used for own needs (for example, for membranes synthesis). This
way is regulated according to the reverse mechanism: if cholesterol
contentsrise in the cell amount of apo-B or apo-Å-receptors on the cell
membranes diminishes, and, as the result, lipoproteins enthrallment take place;
also the intracellular synthesis is being depresses.
(receptor connects one apoprotein B or apoprotein E particle of LDLP, is
depended to Ch needs of the cell)
Another way of cholesterol regulation is its removal from the cellular
membrane. Such removal of the “fulfilled” cholesterol takes place permanently.
It is realized by high-density lipoproteins rich albumen and phospolipids
during their contact with the cell membrane. Cholesterol is etherificated under
the influence of special lecitin-cholesterin-acetiltransferase and is
transported into liver, where is partially oxidized into cholic acids and
excreted out the organism.
Normally these two processes cholesterol in low-density lipoproteins from
liver into cell and in removal from the cell and the reverse transportation to
the liver are balanced. A thin balance between the delivery and the removal of
cholesterol and other fats into the cell and from it determines vessels’ wall
destiny: whether fats are accumulated in it or the wall remains normal. The
process regulation in considerably depends on lipoproteins concentration and
correlation in blood plasma. 10-15 % of
population has got hereditary molecular deviations in cholesterol or
lipoprotein metabolism: 1) some one has the heightened synthesis of
cholesterol, of atherogenous lipoproteins synthesis in liver and thin bowels;
2) others have violations of atherogenous lipoproteins removal in blood flow.
Examples of hereditary lipoproteins metabolism defects: à) tanjer’s illness –
almost full absence of high density lipoproteins in blood, such patients,
despite the very low content of general cholesterol in blood (30-125 mg/dl),
have the signs of atherosclerosis in earlyage, b) family hyperlypoproteinaemia.
This pathology the lack of apo-B and apo-E-receptors on cell surface of
parenchymatose and connective type is genetically conditioned. Low density
lipoproteins blood plasma don’t enter the cell, or enter it in considerably
diminished amount, this is the reason the accumulation of low density
lipoproteins to the blood and, as the consequence, to development of
atherosclerosis in already early age.
There is another way – the unregulable (or non- receptor) endocytosis.
Plasma low-density lipoproteins and very in endocytosevesicles penetrate via
undamaged endothelial cells. These vesicles transport low-density lipoproteins
from the plasmatic membrane to the basal one by means of endocytosis into the
vessels’ intimae. It is assumed, that the unregulable endocytosis low-density
lipoproteins enthrallment wins the main role in atherosclerosis development.
Namely word “atherosclerosis” consists of two Greek words: “atheros”
–porridge, “sclerosis” – bulge. Atherosclerosis is characterized by the focal
bulge and the consolidation of the vessel wall in the result of deposit of the
porridge-like mass in it, that masscontaining lipids (cholesterol), complicated
carbohydrates, blood elements and calcium salts. Atherosclerosis is the variable combination
of changes in arteries’ intimae, which consists of focal lipids accumulation,
complicated carbohydrates, blood substances of fibrous tissue and of calcium
salts accumulation, which is associated with changes in media. Precipitation
takes place in intimae of big and middle caliber arteries with well-developed
elastic layer (aorta, coronary vessels, cerebral arteries), that accumulation
of lipids is called lipoidosis.
Pathogenesis study of this illness has started from experiments
N.N.Anichkov and S.S.Khalatov, which showed that feeding of rabbits with clean
cholesterol brought on the formation of atherosclerotic plaques in aorta wall.
Thus a first experimental model of this illness was created. The cholesterol atherosclerosis model for
more then 90 years has being the object of numerous scientific researches
because changes in animals’ arteries are principally identical to atherosclerotic
changes in human being. Anichkov created the infiltrative atherosclerosis
theory. The following expression belongs
to him: “There is no atherosclerosis without cholesterol”. But other scientists
proved that atherosclerosis could be without the hypercholesterinaemia and,
even, hypercholesterinaemia without atherosclerosis. It was shown, that
hypercholesterinaemia can appear not only by alimentaryway, because two of
third of cholesterol in man organism is synthesized from albumens, fats, and
carbohydrates via acetyl-Co-A.
The great role was given to the disorder of lipoproteins metabolism, to
the disorder of low-density lipoproteins and high-density lipoproteins
fractions correlation, dyslypoproteinemias, and also to the state of the
vascular wall. It was shown, that neither cholesterol, nor other lipids do not
penetrate independently into arterial wall (only in lowdensity lipoproteins
storage). Besides receptor-mediated endocytosis Klimov describes such
lipoproteins transport ways into the arterial wall, as unspecific unregulable
The capture of lipoproteins particles by endothelial cells with their
following transportation into subendothelial space (intimae). This way starts
to function actively when the low-density lipoproteins level in blood rises and
at the same time their cholesterol saturation rises. There are the next
mechanisms: via intercellular channels of endothelium, through damaged gaps of
endothelium monolayer. Damage of endothelium takes place permanently and during
all life. Endothelium can be damaged by some chemical substances, for example
by tobacco nicotine, and by autoimmune complexes.
Obesity, diabetes, smoking, hypokinesia and other risk factors influence
arteries’ wall. One of damage causes is action of hemodynamic blood factors.
There are hypertension, pulse wave blow and blood stream turbulence. These
factors are mostly active in those arteries areas of big or middle caliber,
where convexity, bifurcation, offshoot, constriction and outside squeezing of
vessels are present. These are those places, where the glycocalics-supraendothelial
layer is first impaired, which defends the endothelium, and then the
endothelium itself is empired. In people who have hypertension, the
atherosclerosis develops in 3-4 times quickly, than in people with normal blood
The second important hemodynamic factor is the so-called displacement
tension, which is mostly strongly displayed on the outside side of the bend and
of the arteries ramifications. There in first turn starts the formation of
atherosclerotic injuries. Heart contractions induce pushing arteries’
displacement, and in the result of that, the shift straining effect on
endothelium and intimae becomes stronger, that gives rise to microtearings
formation in these layers of coronal arteries.
The autoimmune complexes, including lipoproteins as antigen, damage the
endothelium. The thrombocytes adhesion takes place. Active thrombocytes excrete
thromboxanum, which assists their adhesion and aggregation and narrows the
vessels; excrete a growth factor, which stimulates proliferation of vascular
wall cells. The delay of lipoproteins passing through intimae can be the result
of thickening of this layer of arterial wall (age hyperplasia, hypertension,
genetic factors, inflammatory processes and other).
During long stay in intimae, lipoproteins undergo different
transformations (modifications – low density lipoproteins). They stimulate
cholesterol precipitation in arteries walls. Modified lipoproteins are actively
captured by intimae cells and primarily by macrophages, as macrophages have not
only apo-B and apo-E-receptors to low-density lipoproteins, which regulate the
mechanism of re-entry tie, but also unregulable intracellular cholesterol
receptors, which provide enthrallment of different modification lipoproteins.
These are so-called “scavenger-receptors” for modified-lipoproteins, for
lipoproteins glycoseamynoglicanes complex, for very low-density lipoproteins,
receptors for autoimmune complexeslipoproteins-antibody. This leads to piling
up of great amount of cholesterol in macrophages, mainly cholesterol ethers and
to foamy cells formation. Accumulation of modified low density lipoproteins in
intimae is key moment of atherosclerosis, because low density lipoproteins
induce the formation of foamy cells, the destruction of which leads to forming
of atheroma and necrosis of ambient tissues of vascular wall.
The basic cellular source is the monocytes-macrophages, which are
transformed into foamy cells. Unlike other cells, they have many
scavenger-receptors to modified lipoproteins on their surface. The important
condition which lead to monocytes migration into intimae is very low density
lipoproteins in plasma, under influence of which endothelium of big vessels
excretes the monocytes’ chemotaxic factor, which assists the adhesion of
monocytes on endothelium surface. Fixed monocytes excrete interleukin-1, which
changes superficial properties of endothelium, provides adhesion of monocytes
and their active migration into intimae. Scavenger-receptor reaction of
monocytes-macrophages in vascular wall is defensive and adaptive. It is
directed on the removal from intimae of the surplus fixed lipoproteins in it.
But unregulable capture of modified lipoproteins and their in complete
catabolism in cell’s lysosoms lead to the transformation of macrophages into
foamy cells. The capture of immune complexes lipoproteins-antibody by
macrophages hastens the foamy cells formation.
Atherosclerosis has four stages: 1) pre-lipid or foamy cells stage
(monocytes-macrophages transformation into foamy cells); 2) lipid blots; 3)
fibrous plaque; 4) complicated stinging (ulceration, calcinosis, thrombosis).
The first stage is characterized by formation of the foamy cells, migration of
smooth muscles cells from media into the intimae due to haemotaxic factors of
macrophages, endoteliocytes and smooth muscles cells proliferation under the
influences of thrombocytes and endotheliocytes growth factors, interleukin 1.
The mechanism of lipid blots formation are as follows: surplus
cholesterol ethers and cholesterol non ethers accumulation in foamy cells leads
to their splitting, in the result of that lipids cholesterol outpour outside,
forming extra cellular lipid pilings.
Lipid blots. The third stage has such mechanisms: cholesterol irritates
ambient tissues, causing the corresponding reaction of connective tissue and
macrophages, which is displayed by the proliferation, and then by development
of fibrous tissue which like capsule surrounds the lipid mass trying to isolate
it fully. A part of capsule turned to vessel clear space side is denser; it
protrudes inside the vessel. Plaques, in which softening phenomena and
disintegration of fatty inclusions prevail, are called atheromas. Clots and
plaques havedimension from pin head to several centimeters in diameter. This stage
3 stage of atherosclerosis
Fourth stage: an ulcerated plaque can be the formation place of wall
thrombus, the cause of atheromatous detritus penetration into the blood and
brain, coronary arteries’ embolia.
The risk factors are causally connected with illness; their influence can
be evaluated in popularistic researches. Besides hypercholesterinemia,
hypertriglyceridemia and hypo-α-lipoproteinemia, the role of which has
already been explained in detail and which also refer to risk factors. It is necessary to mark such factors, as age,
sex (mainly males), arterial hypertension, smoking, broken tolerance to glucose
(diabetes), obesity, overeating, low-movable mode of life, person’s
peculiarities and conduct, heredity, gout, softness of drinking water.
Age. Atherosclerosis develops within long time, sometimes during all human life. It is mostly
expressed in old and senile age. The fighting for continuation of active human
existence of period can be considered as prophylaxis method of atherosclerosis
and its clinical expressions.
Sex. Men considerably more
frequently suffer from atherosclerosis, that's why belonging to masculine
gender can be a risk factor. One of
causes of their raised receptivity to atherosclerosis is lower content of antiatherogenous
high-density lipoproteins. In women the antiatherosclerotic action of woman’s
sexual hormones is found.
Arterial hypertension is the reason of arteries’ endothelial cover damage
and bulge of intimae. In such intimae lipoproteins particles stay and
Smoking. Nicotine raises endothelial cells penetration for lipoproteins,
causes spasms of heart and lower extremities arteries, rises the ability of
thrombocytes to aggregation and, thus, contributes to formation of thrombus in
Diabetes mellitus. Patients have high level of lipoproteins (very
low-density lipoproteins and triglucerides) in blood as the result oflipolysis
activation. High level of blood glucose conduces of the modified lipoproteins
(glucosidated low density lipoproteins) formation.Glucosidated low-density
lipoproteins increase the vassal permeability, macrophages hemotaxis into the
intimae, conduce monocytes and thrombocytes adhesion, stimulate of the smooth
muscle cells proliferation.
Obesity (surplus body mass) conduces to lipoproteins increase in blood,
and frequently to decrease of antiatherogenous high-density lipoproteins.
Low-movable mode of life (hypokinesia). People, who permanently attend to
running, have the raised amount ofantiatherogenous lipoproteins in blood.
Physical work generally contributes to saving the normal body mass, to lowering
the arterial pressure; it prevents the development of diabetes mellitus. And
this, its turn, detains the development of atherosclerosis and ischemic heart
Person’s conduct and peculiarities. Contemporary man, especially in city
conditions, has strained, stowed with stresses and emotions life rhythm. In
response for frequent emotional situations, the adaptable reactions of
cardiac-vascular system are disturbed due to the plenty secretion of
catecholamines into blood. This, on one hand, causes to perspicacity rise of
endothelium for plasma apo-B-lipoproteins, and on another – to lypolysis
process activation in adipose tissue to reinforcement of triglycerides
synthesis and very low-density lipoproteins in liver.
Heredity. Convincing data, that show the meaning of genetic factors in
atherosclerosis pathogen, were received in several countries during the inspection
of families’ members and relative persons of people, suffering with ischemic
heart disease. It was discovered that among relatives of those women, who had
myocardium infarction before 65 the death rate because of coronal insufficiency
(men younger 55, women younger 65) was seven times higher, than in whole
Gout. Patients with atherosclerosis frequently have raised level of
urinary acid in blood. And patients, ill with gout, often have atherosclerosis.
There is correlation between urinary acid level and triglycerides contents in
Water Softness. Regions where people use up soft water with insufficient
microelements contents, atherosclerosis is more frequent and is more difficult,
than in regions with hard water. Vanadium, manganese, magnesium, chrome are
those microelements insufficiency of which contributes to atherosclerosis
All these factors act not
independently, but several together. Knowledge of peculiarities of their action
plays a great role for primaryprophylaxy of atherosclerosis.