Pathophysiology of vascular tone. Arterial hypertension. Prof. Olha V. Denefil

Increased blood pressure is found in 15-30 % of the adult population in the world. There are significant differences in this indicator over the world: from 6 % - in Africa to 30-35 % - in the Scandinavian countries, in the USA is 23-31 %, in Ukraine nearly 40 %.

Arterial hypertension is a major risk factor of many pathological conditions and diseases of the cardiovascular system:atherosclerosisleft ventricular hypertrophy and heart insufficiency,ischemic heart disease (myocardial infarction)cerebrovascular disease (ischemic and hemorrhagic brain stroke)renal insufficiency

RULE of HALFAbout 50% of people do not know about an increase of their blood pressure!!!Of those who know50% of untreated!!!Thus, only about 25 % of patients taking medications to lower blood pressure

Effective antihypertensive therapy have only 12-13 % of patients

REGULATORY SYSTEM,THAT PROVIDESTABILITY OF BLOOD PRESSURE Haemodynamic systems Systems of control Stable Arterial Pressure

Regulation of arterial pressure (P)

Systems of AP controlSYSTEMof BRIEFACTIONSYSTEMof LONG TERMACTIONBaroreceptors andchemoreceptors of aortic arch and sinocarotid zones renin -angiotensin II -arteriolesangiotensin IIaldosterone

Regulative systems of AP

Regulative systems of AP

Regulative systems of AP

ClassificationArterial hypotensionArterial hypertensionAcute(collapse)Chronic(hypotonic disease, symptomatically) Secondary (symptomatically)AP above 139/89 mm HgPrimary(essential)AP less than 100/60 mm Hg

ClassificationPrimary AH (essential, hypertonic disease)80 % of all increase of APSecondary AH (that is happened in 5 - 10 % cases).Its a symptom of some disease course

Etiology of AH

Etiology of primary AH Reason is unknown (AH is polyetiological disease).AH arises on the ground of genetically peculiarities of metabolism. That is possible to have genetically defect of the systems, which control relaxation of the smooth muscle cells of the arterioles.It is possible to:1. Hereditary defect of Ca-ATPase (myocyte relaxation of arterioles involves the movement of Ca in the sarcoplasmic reticulum against the concentration gradient)2. Genetically caused sodium retention in the body3. The variability of the gene that controls the synthesis of receptors for angiotensin 24. Genetically caused by increased activity of ACE5. Lack of endothelial nitric oxide synthesis

Theories of primary hypertension1. Recognized the leading role of the nervous system

Essence: disorders of the nervous regulation of vascular tone

against failure mechanisms of hormonal regulation of arteriolar tone carried over earlier kidney disease, age-related changes in blood vessels, endocrine disorders during menopause2. Recognized the leading role of the kidneys

Essence: imbalance pressor and depressor functions

Increased vascular tone occurs on the background of exhaustiondepressor of kidneys

Contributing factorsFamily historyAge-related changes in blood pressureHigh salt intakeStressHyperinsulinemia: causes high activity sympathetic link of ANS and its effect on cardiac output, peripheral vascular resistance and renal sodium retention; stimulates sodium and calcium transport across the cell membrane of vascular smooth muscle, thereby sensitizing blood vessels to vasopressor stimuliObesity (hyperinsulinemia)Excess alcohol consumption (mechanism in unclear)Race (for example: AH isnt only more prevalent in African Americans than whites, it is also more severe). Possible explanation: due to evolutionary adaptation to the severe environment (western Africa and Western hemisphere) in condition of salt and water deprivation survival is possible due to retention of sodium and water in organism. That leads to conserve sodium. There is little information about other racial groups

1. Increased blood volumePathogenesis

Causes NaCl (use of more than 5 g per day) - mountain population of Japan, the Ukrainian Carpathian and Crimean often suffer from hypertension disease due to the use of water that contains a lot of NaCl Reduced of Na+ excretion by the kidneys(kidney disease)Genetically caused decrease Na excretion by the kidneys

Etiologysecondary HRenal (resulted from kidney pathology)GlomerulonephritisKidney damage at collagenosisKidney amiloidosisGlomerulosclerosis because diabetes mellitusNephropathy of the pregnantHereditary defect of renal vesselsRenal vessels atherosclerosis, embolism or thrombosisKidney tumorUri stone disease

Etiologysecondary H3. Angiogene(is caused by vessels pathology) 2. Renoprive (arises after kidney remove)Aorta damageArteries carotids damage

Etiologysecondary H4. Endocrinopathy (develops in the result of endocrine glands pathology)

Cushing's disease (Adrenocorticotropin over production by the pituitary gland anterior part)

Acromegaly (Somatotropin over production by the pituitary gland anterior part)

Hyperaldosteronism (aldosteron over excretion by suprarenal glands)Menopause(age-depended decrease of female gonads activity estrogens excretion decrease)Possible mechanism deficit of NO synthesis by endotheliocytes

Etiologysecondary H5. Neurogene (is accompanying to nerves system pathology)Brain hemorrhageEncephalitisBrain tumorBrain traumaBrain ischemia

Etiologysecondary H7. Drug-induced6. Cardiac Heart failureHeart defectDrugs, which cause vessels spasm (influent on kidney), hormonal contraceptives

Emotional excitement (SNS activation)Increase of circulative blood volume (CBV)Cardiac output (C) increaseKidney functions violationPeripheral vessels resistance increasePathogenesis

Increase of circulative blood volume (CBV)Pathogenesis

Reasons NaCl (intake more 5 g/day)Decrease Na excretion by kidney (kidney diseases)

1. CBV increaseNa+ retention in bloodBlood osmotic pressure increaseHypervolemiaCardiac output increaseAP elevationNa accumulation in vessels smooth muscle wall and increase of its osmotic pressure Vessels wall edemaVessels narrowingPeripheral vessels resistance increaseVessels smooth muscle sensitivity to vasoconstrictive influences increase (noradrenalin, adrenalin, endotheline, angiotensin)Formula: P = CO PRPathogenesisVessels spasm

2. Cardiac output increase (CO)Reasons Circulative blood volume increase (CBV)physical (overload) stress Emotional stress HyperthyreosisPathogenesis

2. Cardiac output increaseSAS activationAdrenalin excretionIncrease of cardiac contractility forceIncrease of cardiac outputIncrease of heart beats AP elevationPathogenesisFormula: P = CO PR

3. SAS activationInteraction adrenalin and alpha-adrenoreceptorsArterioles smooth muscles spasmSuprarenal glands activationVenues and veins smooth muscles spasmIncrease of circulative blood in big blood circle adrenoreceptors of heartdrenalinNoradrenalinIncrease of CBVCO increaseArterioles vasoconstrictionalpha-adrenoreceptors of vesselsCO increaseAP increaseSAS activation

Arterioles vasoconstriction PR increasePathogenesisFormula: P = CO PRProduction of catecholamine

4. Kidney functions violationLong time spasm of kidneys arteriesAP increaseAP decrease in renal capillariesActivation of JGARenin excretionAngiotensin 2 synthesis Angiotensin 2 effects

Smooth muscles contraction in the vesselsStimulation of the vasoactive center in brainNoradrenalin excretion increaseAdrenalin excretion increase from suprarenal glandsAldosteron excretion increase from suprarenal glands (Na retention due to kidney)Activation of Na and water reabsorption in the kidney without aldosteronePathogenesis

Formsof hypertensivediseaseDecrease concentration of rennin in blood (25-30%)Increase concentration of rennin in blood (10-20 %)Norm concentration of rennin in blood(55-60 %)

Depressive function of kidney synthesis of the substances for AP reducePG 2Phospholipids Renin InhibitorAngiotensinasePhosphatydilcholin alkali ethers

! ! !Exhaustion of kidney depressive function leads to arterial hypertension stabilizationdilates renal arteries, reduces renin synthesis and reduces Na reabsorbing in kidney

1st period functional violations (heart hypertrophy) 2d periodPathological changes in arteries and arterioles (dystrophy):Arterioles sclerosisArterioles wall infiltration by plasma (leads to dystrophy)Arterioles necrosis (hypertonic crisis arises in clinic)Veins wall thickeningArterial hypertension after-effects

3d period Secondary changes in organs and systemsKidney (nephrosclerosis and chronic kidney insufficiency)CNS brain hypoxia neurons destruction apoplexy (because vessels destruction and rupture leads to brain hemorrhages and brain destruction)HeartDecompensate heart failureOrgans of visionretinopathy (retinas vessels injury)hemorrhages and separation (exfoliation) of retina, that leads to blindnessEndocrine systemGlands atrophy and sclerosisArterial hypertension after-effects

Pathogenetic principles of treatment 1. Decrease of consumption and increased excretion of fluid and Na+ - decrease of CBV and vascular sensitivity to pressor effects2. Decrease of emotional and physical stress - decrease CNS activity (including sympathoadrenal activity)3. Block of adrenoreceptors - reduce the effects of catecholamine in the heart, i.e. CO4. Block of adrenoreceptors - reduce the effects of catecholamines in the arterioles, i.e. reducing vasomotor arteriolar tone5. Block of ACE - reduce the formation of angiotensin 2 - decrease basal arteriolar tone6. Decrease the effects of angiotensin 2 - blocking receptors for angiotensin 2 - decrease basal arteriolar tone7. Decrease admission of Ca in myocytes of arterioles - decrease basal arteriolar tone8. Increase of depressor kidney function - decrease basal arteriolar tone9. Increase of vasodilator function of blood vessels involving nitric oxide - reducing basal arteriolar tone

Plasma lipoproteins are produced and secreted by the liver parenchymal cells and epithelial cells of the small intestine.

General structure of lipoprotein.There is a lipid drop inside (nucleus), which contains triglycerides (TG) and cholesterol esters (ACh). Membrane covers the nucleus and consists of protein (apoprotein, or apo-), phospholipids (PhL) and non-ester cholesterol (NACh).The outer membrane of lipoprotein is hydrophilic and inner core is hydrophobic.Lipoproteins are soluble in water, it is a transport form of lipids in the blood.

In plasma of healthy people is4-8 g/l - total lipids0.8-1.5 g/l - VLD3,2-4,5 g/l - LDL2,7-4,3 g / l - HDL3,9-6,5 mmol/l -general chylomicrons

The value of cholesterol1. Necessary for maintaining of cell shape2. Together with PL and proteins provides selective permeability of cells to different substances3. Source of sex and steroid hormones 4. Source of bile acids5. Necessary for growth of the organism and cell division

Balance of cholesterolOne day in the human body450 mg of cholesterol oxidized to bile acids450 mg of cholesterol excreted with faeces100 mg of cholesterol excreted with dermal fat

300 mg of cholesterol derived from food700 mg of cholesterol is synthesized from acetyl-CoA in the cells of various organs, the highest in the liver and small intestine

In adult is about 140 grams of cholesterol (93% is in the cells, 7% is transported in the form of LP mainly LDL in plasma).

Role of LP in Cholesterol transport inside the cell. That is due to receptor-mediated mechanism.It was discovered by American scientists M.Brown and J.Goldstein in 1973-1975 (Nobel Prize in 1985)p--receptorp--receptor(receptor connects the LDL, depends on Cholesterol needs of the cell)

Receptor-mediated endocytosis

Regulation of cholesterol contentsExcept the receptor-mediated cholesterol admission into the cell to regulate the content exists by removing cholesterol from the cell membrane surface. This is done by HDL. In blood this cholesterol undergoes etherification under influence of lecithin-cholesterol-acetyltransferase, is transported to the liver, where partially oxidized to bile acids.

Normally, these two processes are balanced.

10% of the population have congenital molecular abnormalities in cholesterol metabolism or LP:

1) increased synthesis of cholesterol, atherogenic LP in the liver and small intestine

2) the prevalence of violations outlet of atherogenic LP in the bloodstream by help of HDLViolation of regulating processes of cholesterol metabolism

Inherited defects in exchange of LP (cause early atherosclerosis and coronary artery disease)1) Tangier disease - (also known as "Familial alpha-lipoprotein deficiency") orHypoalphalipoproteinemiais a rare inherited disorder characterized by a severe reduction in the amount ofhigh density lipoprotein(HDL), often referred to as "goodcholesterol," in the bloodstream. 2) familial hypercholesterolemia - genetically caused by the absence or deficiency of receptors on the surface of parenchymatous and connective tissue-type cells

Receptor-mediated and nonreceptor (unregulated) endocytosis (basis of atherosclerosis development)

Atherosclerosis is the variable combination of changes in arteries intimae, which consists of focal accumulation of lipids, complicated carbohydrates, blood substances, fibrous tissue and calcium, and associated with changes in media (WHO definition)

First experimental model of atherosclerosis was created on rabbits in 1913. Every day within 3-4 months A.Anichkov added 10 g of Cholesterol in rabbits ration.

Atherosclerosis is impossible without cholesterol. .N.nichkov

Ways of LDL transport in the arterial wall1. Nonspecific unregulated endocytosis2. Through the intercellular channels of endothelial monolayer (action of adrenaline, noradrenaline, serotonin, angiotensin II, histamine)3. Through the damaged endothelial monolayer (nicotine, autoimmune complexes, high blood pressure, turbulent blood flow, push of pulse wave, the tension shift)

HIOLOGYCholesterol metabolism violation

1. Hypercholesterolemia

2. Dislipoproteinemia

) LDL concentration

b) Kch = (LDL+VLDL)/HDL (high coefficient correlates to higher probability of atherosclerosis)Endothelium damage 1. Action of Hemodynamic factors) arterial pressure stroke volume blood push endotheliocytes displacement and damage b) Turbulent moving of blood(arch of aorta, bifurcation of arteries, branching of arteries, winding section - in these places often formed plaques)2. Damage by immune complexes

Modified LDLPeculiarities Are produced- in blood- extra cellular space- in arterial wall

Properties1. They do not interact with p- and p-receptors 2. They interact with scavenger receptors . Entrance of LDL inside the cell results from the gradient concentration (uncontrolled ndocytosis)3. Supply cholesterol in cells and stimulate put-off of cholesterol in artery wallsPeroxides modified LDL LDL+GlucoseLDL+proteinLDL+IgLDL+glycosaminoglycanTheir accumulation promotes the forming of foam cells

There are persons who have normal concentration of LDL, but suffer from atherosclerosis!

Reducing of HDL concentration is importantAnti atherosclerosis role of HDL1. Very easy penetration inside the intimae (due to approtein-) and take out cholesterol 2. Reduce coming up of LDL inside endotheliocytes3. Retention of LDL damage by free radicals4. Increase prostacyclin synthesis and and decrease thrombocytes aggregation5. Decrease proliferation of the smooth muscle cells, which is induced by LDL6. Decrease synthesis of glycosaminoglycans by smooth muscle cells

In the occurrence of atherosclerosis there are 4 defining mechanisms:1. Hereditary factors (lipid metabolism associated with mutation of genes, which encoding receptor of cells to low-density lipoprotein: decreasing the quantity of receptors for LDL on the surface of hepatocytes or they are absent; hereditary hyperlipoproteinemy; deficiency of lipoprotein lipase, enzymes of -oxidation of fatty acids; defects of NO-synthase genes, polymorphisms of genes encoding of angiotensinogen, angiotensin receptors, angiotensin-converting enzyme, and endothelin receptors to them, growth factor of platelets and fibroblasts).2. Lipid metabolism disorders (increase level of total cholesterol above 5.2 mmol/l; serum cholesterol LDL above 4 mmol/l; decrease serum level of high density lipoprotein cholesterol below 0.9 mmol/l).3. Changes in the vascular wall of arteries.4. Violation receptors of cells (E.I. Chazov, 1998).

Theories of atherosclerosis1. Hypothesis response to injury

2. Monoclonal hypothesis

3. Lysosomal theory

Morphological stages of atherosclerosis1) lipid spots 2) fibrous plaques 3) complications: ulceration, calcification, thrombosis

PATHOGENESISMacrophages have main role:They have scavenger-receptors so Cholesterol comes in macrophage only due to concentration gradient 2. They can accumulate a lot of Cholesterol inside the cell (process is controlled by HDL)3. Modified LDL stimulate macrophages activity1 STAGE FOAM CELLS

1 STAGE FOAM CELLS Migration of macrophage in intimaeCapture of LDLDecrease of LDL concentration in intimaeMany macrophages change into foam cells

Role of endotheliocytesThere is no deposit of LDL inside the endotheliocytes!!!!!!!!!) Due to p-,-receptors entrants of LDL is controlled) Using of scavenger receptors stimulates retroendocytosis

But!!!1. At hypercholesterolemia absorption of LDL is activated. That causes endotheliocytes proliferation and accumulation of LDL in intimae.2. Endothelium injury is common uncontrolled penetration of LDL inside the vessel wall.3. On endothelium surface is activated lipoprotein lipase, which controls dissociation of VLDL into LDL and HDL 1 STAGE FOAM CELLS

Role of the smooth muscle cellsDeposit of LDL in intimae causes excretion of hemotaxis factors by endotheliocytes, macrophages and fibroblasts. These substances conduce smooth muscle cell (SMC) hemotaxis into intimae (contractile cells have ability to change in secretory).What do they do ???1. They absorb of LDL (they have p- and p- receptors)2. They proliferate (due to thrombocyte growth factor. Their DNA synthesis activates and mitosis occurs)3. They synthesize collagen, elastin, glycosaminoglucans (connective tissue matrix of plaque)1 STAGE FOAM CELLS

2 stage LIPID SPOTSThey are formed on different parts of arterial system (in elastic and elastic-muscle type of vessels): They have different square in different age:in aorta 10 % in 10 years, 30-50% in 25-30 years

in coronary arteries are appear in 15 years

in cerebral arteries are appear in 35-45 years

Formation mechanismFoam cells overload by cholesterol causes their damage. At this time hydrolytic lisosomal enzymes release, which causes necrosis of surround tissue.There is proved that this stage can be reversible due to prolonged uncholesterol diet2 stage LIPID SPOTSContents of LIPID SPOTS:- Foam cells - nocytes/macrophages- Smooth muscle cells- Lymphocytes- Free cholesterol- Connective tissueMain characteristic dont violate blood flow

3 stage FIBROUS PLAQUECholesterol and lisosomal enzymes irritates intimae (because they are the foreign bodies)Excreation of proliferation factors by macrophages, ndotheliocytes, lymphocytes and thrombocytesSMC migration in intimae and active proliferation collagen and elastin (capsule that isolates place accumulation of cholesterol and damage of blood vessels by lysosomal enzymes)

characteristicContents: Chol, NEChol, leavings of elastin and collagen, foam cells, Chol crystals, necrotic mass

Vessel narrowingStage unalterable

Partial regression (dilipidation) - diet without Cholesterol (150-160mg/dl) during 1,5-2 years3 stage FIBROUS PLAQUE

THROMBOSIS (due to endothelium damage)

2. Ulceration(necrotic disintegration content plaques leads to thinning of its walls)

3. Calcinations(deposit of insoluble calcium salts)4 stage - COMPLICATIONS

4 stage - COMPLICATIONS

Risk factors of atherosclerosis development1. Irreversible (endogenous)Age (men over 40, women over 50 years)Gender (male, anti-sclerotic effect of estrogen, cholesterol in the case of nonatherosclerotic -lipoprotein)Genetic predisposition (sudden death, myocardial infarction or brain stroke in parents: at age before 50 in men and before 55 in women)

2. Inverse (managed)SmokingHypertensionObesity

3. Potential or partially reverseHyperlipidemia - Hypercholesterolemia and / or hypertriglyceridemiaHyperglycemia and diabetes mellitusLow levels of high density lipoprotein

4. Other possible factorsLow physical activityEmotional stress and / or personality typeIntoxication, infection

Thank you for your attention!