Medical University of Varna
Postgraduate Programme in Internal Medicine
“Pathophysiology of Cardiovascular System”
PATHOPHYSIOLOGY OF HYPERTENSION
Apostolos I. Hatzitolios
Assistant Professor of Internal Medicine
1st Propedeutic Medical Department
Aristotle University of Thessaloniki
Department of Hypertension and Vascular Disease
AHEPA Hospital
PREVALENCE AND DEFINITION OF ARTERIAL HYPERTENSION
Pathophysiology of Arterial Hypertension
Structural hypertrophy of the heart and vessels sustains hypertension and creates
a vicious circle of further increase through kidney damage
MECHANISMS OF HYPERTENSION
CARDIAC OUTPUT/PERIPHERAL VESSEL RESISTANCE
CARDIAC HYPERTROPHY
Although considered compensatory mechanism to an increased vascular
resistance ,it could also reflect a primary response to repeated neural stimulation and
thereby could be an initiating mechanism of hypertension by increasing cardiac output.
INCREASED FLUID VOLUME
Increased preload could induce hypertension by increasing cardiac output in
pre- and mild hypertension, since in most studies subjects with high blood pressure
(increased peripheral vessel resistance) have lower blood volume (and total
exchangeable sodium).
RELATION OF BLOOD VOLUME TO BLOOD PRESSURE
The redistribution of blood volume because of peripheral vessel constriction causes
increase in venous come-back, cardiopneumonal circulation and cardiac output.
AUTOREGULATION MODEL
The initial high cardiac output gives way to increased peripheral vessel resistance
(intrinsic property of the vascular bed to regulate the blood flow depending on the
metabolic need of tissues through constriction and structural thickening ).
Julius proposes an other model: structural changes decrease the cardiac responses to
nervous and hormonal stimuli but enhance the vascular responses causing vascular
hypertrophy and altering the wall-to-lumen ratio.
EXCESS SODIUM INTAKE
Epidemiologic evidence
Primitive people who do not eat sodium have no hypertension. In groups of
people with the same way of life hypertension depends on sodium intake.
Experimental evidence
When hypertensives are sodium-restricted their BP falls. Increased NaCl intake
increases BP by activating mechanisms like increasing intravascular volume and
intracellular sodium and calcium, causing vasoconstriction, insulin resistance, and
increased catecholamines .
Sensitivity to Sodium
Although increased sodium intake is the common issue in industrialized
societies, the fact that only 20-50% develop hypertension suggests a variable degree of
BP sensitivity to sodium ( that is increased reabsorption in renal tubules), in which both
heredity and interaction with environmental exposures are involved.
Mechanisms interpreting sensitivity to sodium
•
Increased activity of the sodium-hydrogen exchanger in the proximal tubule
• Increased sodium reabsorption because of decreased renin-aldosterone
suppressed production
• Increased calcium input in vessel smooth muscles
• Increased sympathetic nervous system activity
• Endothelial dysfunction related to decreased nitric oxide response to sodium
loads
• Inherited, especially maternal (polymorphism 2 of ACE gene)
• Increased Angiotensin II and decreased bradykinin receptors.
RENAL SODIUM RETENTION
Apart from sodium sensitivity, for BP development a possible defect in the
pressure-natriuresis mechanism could be responsible, which blocks BP return to normal
( Guyton 1992 ) , by affecting natriuresis curve (through preglomerular vasoconstriction
and increase sodium reabsorption in the tubules).
Ouabain (endogenous glycoside ) , peptide produced in adrenal gland cortex, could
be responsible for hypertension with increased blood flow. Apart from that, since
ouabain is an inhibitor of Na-K ATPase pump causes increase of intracellular sodium
and calcium in vessel smooth muscles, increasing thus the resistance.
It is also mentioned from experimental data that ouabain causes hypertension
through increased endothelin production.
NATRIURESIS CURVE : ITS SHIFT TO THE WRIGHT IS A MECHANISM
CAUSING HYPERTENSION.
NEPHRON HETEROGENEITY
Sealey theory: a subpopulation that is ischemic from either afferent arteriolar
vasoconstriction or from an intrinsic narrowing of the lumen causes increased renin
secretion from this population . This renin secretion interferes with the compensatory
capacity of normal nephrons to adaptively excrete sodium and ,consequently, perturbs
overall blood pressure homeostasis.
REDUCED NEPHRON NUMBER
Brener et al in1988 υproposed that hypertension may arise from congenital
reduction in the number of nephrons limiting the ability to excrete sodium raising BP
and setting of a vicious circle whereby systemic hypertension causes glomerular
hypertension.
These investigators point out that as many as 40% of individuals younger than 30
years have fewer than 600.000nephrons/kidney and speculate that those individuals
whose congenital nephron number fall in the lower range are susceptible to the
development of essential hypertension.
LOW BIRTH WEIGHT
Large studies showed that BP in adulthood is reversely analogous to birth weight
possibly due to congenital oligonephropathy (less nephrons) because of intrauterine
growth retardation.
Causes of low birth weight.
Increased number of pregnancies in adolescence
Small intervals between pregnancies
Inadequate nutrition
RELATION BETWEEN BIRTH WEIGHT AND HYPERTENSION
RENIN-ANGIOTENSIN SYSTEM
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
(RAAS)
Tanin
Cathepsin G
Tissue
plasminogen
angiotensin I
activator
bradykinin Alternative
ways
ACE (kininase)
angiotensinogen
kidneys
renin
Increased BP
negative
feedback
inactive
peptides
Sodium retention
angiotensin II
receptors ΑΤ1,ΑΤ2
aldosterone
AT1 receptors
in adrenal glands
AT1
Vessel
receptors
reverse
AT1
action
VASOCONSTRICTION
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS)
The main mechanism through RAAS contributes to hypertension is a negative
feedback in the axon renin-angiotensin-aldosterone in kidneys and adrenal glands.
Furthermore angiotensin II causes reduced production and action of nitric oxide by
altering arachidonic acid metabolism, thus increasing vasoconstrictive prostaglandines
and increased endothelin production.
• Although low renin is expected in essential hypertension, most patients have
normal or even high rates.
Possible mechanisms:
Nephron heterogeneity
Defect in negative feedback
Increased SNS activity
• IN hypertensive patients with high renin activity, the main mechanism is
vasoconstriction due to increased angiotensin II.
• In hypertensive patients with normal renin activity, the main mechanism is
increased intravascular volume.
HYPERTENSION AND NERVOUS SYSTEM
• Increased SNS activity in central nervous system (SNS and hypothalamus) and
peripheral nervous system (adrenergic ending, α1, α2 και β-vessel receptors) .
• Contribution of SNS in hypertension development through interaction with reninangiotensin-aldosteron axis.
• S tress causes SNS activation and increased sodium retain, insulin resistance (
increased tissues metabolism)
• Baroreceptor malfunction: Normally, baroreceptors are activated from increased BP
and central venous pressure, leading to vagus stimulation, SNS inhibition and BP
decrease. In hypertensives this respond decreases because of structural and functional
receptor changes.
• Stress reaction : Normotensives with high risk for hypertension development show
a greater SNS and cardiovascular stress respond. Production of vasodilators is reduced
and smooth muscle multiplication is increased.
Role of increased SNS activity in essential hypertension
PERIPHERAL RESISTANCE (PR)
Hypertension is maintained by increased PR due to decreased arterial lumen size or
radius in small resistance arteries or arterioles. According to Poiseuille’s law vascular
resistance is inversely related to the radius of the fourth power (decreased lumen size in
vasocontraction or hypertrophy→increased PR)
In studies of small resistance vessels from subcutaneous tissue of hypertensive
subjects compares to normotensives, increases in the ratio of media thickness to internal
diameter of 26-62% have been recorded.
Mechanisms of vessel remodeling
•
Remodeling of smooth muscles around the smaller lumen size.
•
In increased BP (e.g. increased angiotensin II) vessel hypertrophy is caused
due to genetically induced hypertensive reaction of the vessels in growth factors (
PDGF-A , HGF ) .
CELL MEMBRANE ALTERATIONS
Να-Η Countertransport
Increased countertransport in hypertensives, causing increased vascular tone,
cell growth (Na, Ca entry), left ventricular hypertrophy and increase Na reabsorption in
renal proximal tubuls ( possibly related to a polymorphism of a-adukine gene and
change in tropomyocine expression)
Alterations in cell membrane structure
Increased cholesterol/phospholipid ratio leading to increased Na permeability
(increased Να-Η pump activity)
Pathologic Na and Ca transport intracellularly, causes increase PR.
Hypothesis linking abnormal ionic fluxes to increased peripheral resistance.
OBESITY AND HYPERTENSION
Obesity causes hypertension through:
Increased cardiac output and volume expansion
•
•
•
•
•
Increased Leptin, causing :
Increased SNS activity
Increased NO decomposition
Increased Na reabsorption
Shift to the right of the natriuresis curve
Increased renin activity
Fatty infiltration of the kidney causing increased glomerular pressure
and thus their damage
Increased insulin resistance and hyperinsulinemia
MECHANISMS THROUGH WHICH INCREASED INSULIN RESISTANCE
AND HYPERINSOULINEMIA CAUSE HYPERTENSION
MECHANISM
•Increased sodium-aqua reabsorption
•Increased sensitivity in sodium consumption
n
(Gupta et al 1992)
(Sharma et al 1993)
•Increased response of BP and aldosterone to angiotensin II (Rocchini et al 1990)
•Alterations in transmembran ion exchange
n
n
Increase of intracellular sodium
(Barbagallo et al 1993)
Decreased Na/K ATPase activity
(Pontremoli et al 1991)
Increased Na/H pump activity
(Aviv 1992)
Increased intracellular calcium
(Aviv 1992)
•Growth factors activation especially in vessel smooth muscles (Bornfelt et al 1992)
•Increased SNS activity
•Decreased vasodilator prostaglandines
•Impaired vasodilation
•Increased endothelin production
(Lembo et al 1992)
(Axelrod 1991)
(Baron et al 1993)
(Hu et al 1993)
METABOLIC SYNDROME Χ
CENTRAL
ADIPOSITY
HYPERINSULINEMIA
IGT
CORONARY
DISEASE
INSULIN
RESISTANCE
HYPERTENS
SYNDROME
DYSLIPIDEMIA
MICROHYPERURICEMIA
ALBUMINOURIA
VASOACTIVE FACTORS –REGULATION OF VESSEL TONE
Vasoconstrictive:
TXA2, PGH2, O2, A II
Vasodilative: NO, GGI2 ,EDHF
Blood vessel
Growth inhibitors:
NO
Growth inductors:
Endothelin- 1, TXA2,O2,A II
ENDOTHELIAl DYSFUNCTION
(surface of 400m2, 1.200.000.000 cells: the largest endocrine gland)
Decreased synthesis (endothelial synthase, e-NOs acts in the basic aminoacid Larginine), possibly through decreased response to acetylcholine ( dilation through
muscarine receptors in intact endothelial cells , contraction through muscarine receptors
of smooth muscle cells in damaged endothelium) or increased NO decomposition
or/and increased endothelin production
NO reaches smooth muscle cells, stimulates guanylcyclase and production of 3,5
cyclic monophosphoric guanocin (cGMP). Ach, bradykinin, P substance and others, by
acting in receptors on endothelial cells increase Ca++ entry and activate e-NOs. NO
apart from vasodilation inhibits smooth muscle cells’ multiplication (hypertrophy) and
ET-1 production.
NO system in essential hypertension pathogenesis
Decreased NO production under normal circumstances and stimulation
Decreased vasodilation as response to Ach
Increased vascular resistance
Essential hypertension
Vasodilation
Neurotransmiters as histamine,bradykinin, or hormones like argininevasopressine (AVP) and norepinephrine (ΝΕ) acting in certain endothelial
receptors or mechanic powers (shear stress) control ΝΟ production and circulation
(EDRF) as long as other vasodilator substances like prostacyclin and endothelial
dependent hyperpolarizator factor (EDΗF)
histamine
endothelium
Smooth muscles
bradykinin
bradykinin
dilation
Vasoconstriction
Situations like growing old, BP, DM, atherosclerosis and menopause, can lead to the
production and circulation of contractive factors from endothelial cells, like
prostanoids, ΤΧΑ2, PGH2, free Ο2 radicals, that neutralize the vasodilative NO and
PGI2 action .
activation
endothelium
activation
Smooth muscles
contraction
OTHER FACTORS CAUSING ARTERIAL HYPERTENSION
Inherited factors
Polymorphism 2 of ACE gene : salt sensitivity
Polymorphism of a-adukine gene :increased Na-H countertransport.
gene metalaxis
phenotype
Glucocorticoid receptors
Increased Glucocorticoid
angiotensinogen
Increased angiotensinogen
SA gene
unknown
Lipoprotein lipase
Insulin resistance
Rare metalaxis
Aldosteronism susceptible to glucocorticoid
Increased 18-hydroxy-steroids
phenomenal mineralocorticoid excess
Decreased cortisol/cortison ratio
Inherited adrenal gland hyperplasia
Increased precursor cortisol forms
Polycystic kidneys syndrome
Renal cysts
Liddle, Gitelman syndromes
Low plasma K
Smoking : through insulin resistance, increased endothelin and decreased dilation of
vessel endothelium.
Alcohol : through increased SNS activity, increased insulin resistance, thus
hyperinsulinemia and alterations in cell membrane leading to increased intracellular
calcium.