Download Microcirculation and coronary circulation 2011

PATHOPHYSIOLOGY OF CORONARY
CIRCULATION
and
MICROCIRCULATION
Akos Koller
DEPARTMENT OF
PATHOPHYSIOLOGY AND GERONTOLGY
FACULTY OF MEDICINE
UNIVERSITY OF PÉCS
2009
Angina pectoris
ISCHEMIC HEART DISEASES
myocardial ischemia, infarction
• Develops due to (absolute or relative) tissue hypoperfusion
• Reduced myocardial oxygen supply
• Increased oxygen demand
• Accumulation of tissue metabolites
imbalance between oxygen demand and supply
MYOCARDIAL INFARCTION
Myocardial infarction is an irreversible
damage/necrosis of a given region of the
myocardium due to the long-term critical
reduction of the coronary blood flow.
CAUSES OF REDUCED
MYOCARDIAL OXYGEN SUPPLY
Partial or complete intraluminal occlusion of
coronary vessels:
• atherosclerotic plaque
• thrombus
• aggregation of platelets
• coronary embolism
• coronary aneurysm
• arteritis (polyarteritis nodosa)
Possible triggers of MI
unknown
CLINICAL FORMS OF ISCHEMIC
HEART DISEASE
•
•
•
•
•
•
•
•
•
stable pectoral angina (effort angina):
silent ischemia
acute coronary syndromes
unstable pectoral angina
myocardial infarction
non-Q myocardial infarction
infarction with ST-elevation
acute heart failure of ischemic origin
sudden cardiac death of ischemic origin
STABLE PECTORAL ANGINA
SYNDROME
Caused by reversible myocardial ischemia.
A clinical syndrome associated with blunt chest pain, sweating,
dyspnoe (breathlessness), fear of death, ECG abnormalities
(ST,T). Initiated by:
• physical stress
• emotional stress
• at rest may also develop
• last no longer than 15 minutes
• ceases upon rest or nitroglycerin (nitrate) treatment
STABLE PECTORAL ANGINA
SYNDROME
Caused by reversible myocardial ischemia.
A clinical syndrome associated with blunt chest pain, sweating,
dyspnoe (breathlessness), fear of death, ECG abnormalities
(ST,T). Initiated by:
• physical stress
• emotional stress
• at rest may also develop
• last no longer than 15 minutes
• ceases upon rest or nitroglycerin (nitrate) treatment
!!
Evaluation of the risk of patients
suffering from coronary dysfunction
physical examination
ECG
laboratory tests
functional examinations
exercise test (ergometry)
thallium heart scan
exercise echocardiography
coronarography
ST-segment depression
Causes of dysfunction of coronary
circulation
atherosclerosis, thrombus, platelets
physical obstruction
(large vessels)
Angiogram of
a narrowing
coronary
artery.
(plaque disruption)
Davies, Heart 83:361
(2000)
Atherosclerosis
funtional constriction
reduced diameter
(resistance vessels)
Q=
4
r
Going toward the capillaries:
• the total cross-section of vessels increases
• the range of change in diameter increases
(2-5% to 60-80%)
The metabolism of tissue depends on the blood
(oxygen ) supply, thus the healthy structure
and function of microvessels (microcirculation)
are utmost important
If the blood supply is not sufficient the pumping function
of the heart become reduced (heart failure)
TREATMENT OF STABLE
ANGINA PECTORIS
•
•
•
•
•
•
•
Aspirin (inhibits platelet aggregation)
Beta-receptor blockers
Nitrites and nitrates
Calcium antagonists
Statins (inhibit cholesterol build up)
ACE - inhibitors
Other drugs
Mechanisms determining coronary
circulation
THE SPECIAL FUNCTION OF THE HEART IS
ENSURED BY ITS SPECIAL CIRCULATION
The pump function requires energy.
This energy derives from the metabolism of the
heart muscle.
This metabolism primarily depends on the O2
supply and therefore on the coronary
microcirculation.
The blood supply of the heart, nutrition and
oxygen needs
The heart is an obligate aerobic organ
The number of mitochondria in the cardiac muscle fibers is
significantly greater as compared to other types of muscles.
Close to one third of the total cardiac mass is mitochondrion.
The usable glycogen storage in the heart is minimal
The O2 bond to the myoglobin can provide O2 only for short
period of time
Therefore, the functioning heart
needs continuous blood supply
OXYGEN CONSUMPTION (mVO2) OF THE HEART
At “rest” the mVO2 is 8-10 mL/100g/min.
(for left ventricle )
The weight of heart in adult man is 300 g, thus
mVO2 at “rest” is 25-30 mL, which is 12 % of the
total (250 ml) mVO2 of the organism.
RELATIONSHIP BETWEEN O2 CONSUMPTION
AND FUNCTION OF THE HEART
• Contraction of the heart generates pressure
and kinetic energy.
•The major part of mVO2 is utilized to
generate pressure and to a lesser degree
kinetic energy
Wall stress!
O2 CONSUMPTION OF THE HEART CAN
INCREASE MULTIPLE TIMES
to physical activity, but also in response to emotional excitements
In trained athletes it can rich 65-70 mL/100g/min (from 1520%)
At maximal physical activity the O2 consumption can increase
to 7 times of resting condition (for short time)
Positive inotropes (e.g. cathecolamines) increase the energy
demand of the heart, even if the mechanical efficiency do not
increase
O2 CONSUMPTION OF THE HEART CAN
INCREASE MULTIPLE TIMES
In resting conditions cardiac O2 extraction (AVdO2) is larger
than other organs have.
Coronary venous O2 saturation: ~ 25%
25 (from 95-100%)
The venous pO2 ~20-Hgmm (vs. 95-100%),
Thus O2 extraction can increase just a little bit !
Thus in case of increased O2 demand:
CORONARY BLOOD FLOW MUST INCREASE!!
CORONARY BLOOD FLOW (CBF)
At rest:
180-240
ml/min
At maximum:
900-1200
ml/min
The resistance segments of the coronary circulation:
small arteries, arterioles, precapillary sphincters(?)
have substantial basal tone
The dilation of small vessels reduces the vascular resistance
to 1/5-1/7!
The coronary blood flow is phasic!
Systole: no coronary blood flow! (or „negative flow”)
Diastole: coronary flow is high
Systole:
0,3 s
Diastole:
0,5 s
IF THE HR INCREASES FROM 70/MIN TO 180/MIN
the diastolic perfusion time
decreases from 35 s to 24 s in a minute
The transmural pressure in the
coronary wall is determined by:
THE INTRALUMINAL AND THE
EXTRALUMINAL PRESSURES!
(it is different in the right and left ventricle!)
NUTRIENTS AND OXYGEN CONSUMPTION
The nutrients of cardiac muscle:
glucose
free fatty acid
lactic acid
ketone bodies
aminoacids
The use of nutrients depends on
their concentrations in the blood
THE GREAT O2 DEMAND OF THE CARDIAC
MUSCULAR FIBRES IS ENSURED BY
THE RICH VASCULAR SYSTEM
OF THE CARDIAC MUSCLE
AORTA
Anatomy of the coronary circulation
The right and left coronaries originate
behind the sac after the aortic valve
There is a huge individual variability in the
ramification and the supplied area
Anatomy of the coronary circulation
arteries two main branches (circumflex,
descendens), then additional superficial arterial
branches, then intramural arteries
arterioles intramural, subepi-, subendocapillaries (1 muscular fibre/1 capillary:
O2-diffusion)
venules
veins
Characteristics of the coronary circulation
The circulatory transit time in the
coronaries (the time needed for the red
blood cells to get from the arterial side to
the venous side) is 6-8 sec at rest.
The transit time during physical activity
is much less.
Despite of the rich vascular system of the
heart muscle, there are
no collaterals (in humans)
between the large coronary branches and
the smaller arteries, arterioles.
Clinical significance:
In humans, the continuous blood flow is always
endangered. The leading cause of death:
failure of the left ventricle’s blood flow supply.
Clinical significance:
this may arise from
• restriction of the lumen or total occlusion,
• the decreased vasomotor dilator capacity of the
resistance vessels
Consequence: ischemia and heart muscle injury,
necrosis
the flow of the injured area is only 10 %
of the original in case of acute occlusion:
ischemia, infarction
If the occlusion develops gradually,
there is a chance to develop anastomosis,
therefore the symptoms of the occlusion
are less severe
Intraluminal pressure is different in the right
and left ventricle!
Systolic blood pressure in the right ventricle (and
ventricular wall) is only ~ 25 mmHg therefore it has
only little effect on the transmural pressure and the
diameter of the arteries
Systolic blood pressure in the left ventricle (and
ventricular wall) is ~ 120 mmHg and this pressure
can obstruct the arteries.
Therefore coronary blood flow is determined by the
intraluminal pressure (which is identical to the aortic
pressure) and the pressure generated by the heart muscle
The left ventricle receives its blood flow mainly during
diastole
even negative blood flow can be observed: for a
short time blood flows from the coronaries back to
the aorta
during systole coronary blood flow is minimal in
the left ventricular wall
coronary blood flow is high during diastole
Resting frequency (HR): 70/minute.
systole: 0,3 sec, diastole: 0.5 sec.
Total blood flow of the left ventricle:
60 mL/min (50 mL under diastole)
• If HR increases, the diastolic period of time
decreases limiting the increasing of flow
•If HR exceeds 180/min the phasic flow may
become impaired
Subepicardium:
Capillary system of the myocardium
high density, capillaries are between the
muscle fibers
almost every muscle fiber has its own
capillary
it supplies the fibers with sufficient O2
diffusion, even if the O2 demand of the fibers is
maximal
In case of maximal dilatation: 2500-4000
capillaries/mm3 are open (in working skeletal
muscles: 300-400/mm3)
The highest capillary density is near to the
endocardium of the left ventricle
If the ventricular load chronically rises, the
ventricular wall becomes thicker (ventricular
hypertrophy)
Ventricular hypertrophy: capillary density doesn’t
follow it, capillary/muscle fiber ratio decreases
The O2 and energy supply of the myocardium
decreases
From here
The coronary/peripheral
circulation is regulated by the
integrated effects of
3
mechanisms:
neural
- hormonal
- local
-
The vascular resistance is
determined by the
small arteries and arterioles
Diameter of the
arterioles is
determined by
vasoactive agents
(among others)
Neural regulation
Increased activation of the sympathetic
nervous system leads to the release of
catecholamines,
norepinephrine, epinephrine
Catecholamine-s
(norepinephrine, epinephrine):
Vasoconstriction through α1-receptors.
In case of maximal stimulation constriction can be 30%
if β-receptors are blocked.
Vasodilatation through the direct stimulation of
β2 receptors
If there is a coronary stenosis, maximal sympathetic
stimulation can cause death, because it increases the O2
demand of the myocardium
Catecholamine-s
(norepinephrine, epinephrine):
Vasoconstriction through α1-receptors.
In case of maximal stimulation constriction can be 30%
if β-receptors are blocked.
Vasodilatation through the direct stimulation of
β2 receptors
If there is a coronary stenosis, maximal sympathetic
stimulation can cause death, because it increases the
myocardial O2 demand
NE effects the contractility (HR)
and
the diameter of coronary vessels
Norepinephrine
vs.
α and β receptors
NE (10-7 to 3x10-7 mol/L) elicited dose-dependent dilations of of isolated
human coronary arterioles arterioles (n=39)
Copyright ©2002 American Heart Association
Sun, D. et al. Circulation 2002;106:550-555
Relationship between maximal diameter (passive diameter, PD) and
changes in diameter, as percentages of PD, to NE in individual arteries.
The data show that the percent increase in vessel diameter was not dependent on vessel size. There were no
significant differences in NE-induced dilations between vessels with spontaneous tone and vessels treated with
endothelin. Only 2 vessels (average passive diameter 240 µm) responded with a decrease in diameter to NE. r2
equals 0.005, 0.053, and 0.089 (P=NS) for the following NE concentrations: 10-7 mol/L, 2x 10-7 mol/L, and
3x10- 7 mol/L, respectively.
Copyright ©2002 American Heart Association
Sun, D. et al. Circulation 2002;106:550-555
Changes in diameter of isolated human coronary arterioles in response to
NE in absence of endothelium (EC-) (top) and presence of NOS inhibitor
L-NNA (bottom).
(E-)
(L-NNA)
Sun, D. et al. Circulation 2002;106:550-555
Copyright ©2002 American Heart Association
Role of ß-Receptors
Propranolol,
Propranolol eliminated coronary dilations to NE.
a combined ß1- and ß2adrenoceptor antagonist
Copyright ©2002 American Heart Association
Sun, D. et al. Circulation 2002;106:550-555
Role of ß-Receptors
Practolol did not affect coronary dilations to NE.
a ß1-adrenoceptor
antagonist
Copyright ©2002 American Heart Association
Sun, D. et al. Circulation 2002;106:550-555
Role of ß-Receptors
Butoxamine eliminated coronary dilations to NE.
a ß2-adrenoceptor
antagonist
In addition, we have found that salbutamol (10-6 mol/L)
elicited substantial dilation of human coronary arterioles
(60±8 µm, n=5).
Sun, D. et al. Circulation 2002;106:550-555
Copyright ©2002 American Heart Association
Role of α1-Receptors
Methoxamine did not change (except 2) the diameter
of individual coronaries
an α1-agonists
Copyright ©2002 American Heart Association
Sun, D. et al. Circulation 2002;106:550-555
U46619 constricted individual coronary arteries.
a thromboxane A2
mimetic
Insert: % constrictions to U46619
Sun, D. et al. Circulation 2002;106:550-555
Copyright ©2002 American Heart Association
A: Upper panel: Reverse transcription-polymerase chain reaction analysis
of ß-adrenoceptor mRNA in porcine coronary arterioles and myocardial
tissue was performed with the use of gene-specific primers for the
ß2-adrenoceptor (ß2-AR) and the ß1-adrenoceptor (ß-1-AR).
A, Lower panel: ß2-AR transcripts from the subepicardial (EPI) and
subendocardial (ENDO) arterioles were normalized with the corresponding
GAPDH transcripts.
*P<0.05 vs EPI arterioles. Marker= X174-DNA marker.
Copyright ©2004 American Heart Association
Hein, T. W. et al. Circulation 2004;110:2708-2712
B: Immunohistochemical analysis of ß2-adrenoceptor (ß2-AR)
protein in EPI and ENDO arterioles.
Shown as a pseudo-color spectral display. Performed in vessels treated without (–1°) or with
(+1°) anti–ß2-AR primary antibody. Level of ß2-AR protein expression was represented by
the signal intensity of the color pallet.
Copyright ©2004 American Heart Association
Hein, T. W. et al. Circulation 2004;110:2708-2712
Conclusions
• Human coronary arteries and arterioles
dilate in response to norepinephrine via β2receptors located on vascular smooth muscle
Schematic representation of adrenergic receptor distribution
in the coronary circulation.
Endothelium is in light green.
Vascular smooth muscle cell
layer is in yellow.
ß2-adrenoceptor
WSS
Copyright ©2009 BMJ Publishing Group Ltd.
Barbato, E. Heart 2009;95:603-608
Adrenergic receptor balance.
Shifting of the adrenergic vasomotor modulation from normal coronary
arteries through different stages of coronary diseases.
ß2-adrenoceptor
Barbato, E. Heart 2009;95:603-608
Copyright ©2009 BMJ Publishing Group Ltd.
Hormonal/humoral regulation
•
•
•
•
•
•
Estrogen, testosterone, aldosteron,
Insulin, thyroxin, ghrelin
Catecholamines, angiotensin II
ANP/BNP
fever
etc.
Mechanisms involved in the local
regulation of (coronary) blood flow:
1. Smooth muscle (Pressure-Myogenic)
2. Endothelium (Shear stress)
3. Parenchyma (Oxygen-Metabolic)
4. Others
PRESSURE SENSITIVE
MYOGENIC SMOOTH MUSCLE MECHANISM
ROLE OF INTRALUMINAL PRESSURE
Bayliss 1902:
myogenic mechanism
1902
Volume changes
(upper trace) and
arterial pressure
recording (lower
trace) from hindlimb
of dog with occlusion
of the supply artery
for 8 s and then for
20 s.
Bayliss (from Handbook of
Physiology)
Autoregulation of the coronary
circulation
The flow is constant between 60 to 180
Hgmm perfusion pressure.
Below 60 Hgmm the flow decreases in
subendocardial layer.
Control
}*
150
80
60
40
-10
10
30
50
70
90
110 130 150
Pressure (mmHg)
100
5
50
-10
10
30
50
70
90
110 130 150
Pressure (mmHg)
Myogenic Index
Diameter ( µ m)
200
% of passive diameter
Passive
100
4
3
2
1
0
-1
-10
10
30
50
70
90
110 130 150
Pressure (mmHg)
∆ smooth muscle [Ca2+]i (%)
Pressure-induced changes in arteriolar smooth
muscle [Ca2+]i in the presence and absence of
extracellular Ca2+.
40
control
20
0
-20
Ca2+ free
-40
-60
0 20 40 60 80 100 120 140
Pressure (mmHg)
Increases in smooth muscle [Ca2+]i and development
of myogenic tone at 80 mmHg
as a function of extracellular [Ca2+].
100
80
50
60
40
25
20
0
0
-4
-3
CaCl2 (log mol/L)
-2
∆smooth muscle
2+
[Ca ]i (%)
Myogenic tone (µm)
75
Mechanisms involved in the local
regulation of (coronary) blood flow:
1. Smooth muscle (Pressure-Myogenic)
2. Endothelium (Shear stress)
3. Parenchyma (Oxygen-Metabolic)
4. Others
Endothelium
Endothelium
A new organ! Discovered in 1980!
Smooth muscle
Endothel
Discovery of the vasomotor role
of endothelium
Relaxation
Vasomotor function is regulated
by the endothelium
ACh
E+
E-
Nobel Prize 1999: Furchgott, Ignarro, Murad
Endothelium as an organ
The endothelium is a new organ
The total mass of
the endothelium is
about 1.5 kg
An endocrine
organ, which size
and importance
similar to the liver
EDRF
15 years of research:
chemical identification of EDRF:
Nitric-oxide (NO)
R. Furchgott: endothelium, EDRF, NO
L. Ignarro: nitrate compounds, nitroglycerin, NO
F. Murad: role of NO vs. cGMP in vasodilation
Nobel Prize 1999
nitric-oxide:
NO
EFFECTS OF NO
vasodilatation
trombocyte
aggregation
L-ARGININE
eNOS
L-CITRULLIN
NO
monocyte adhesion
Superoxide
elimination
smooth muscle
proliferation
LDL oxidation
NO prevent
vascular diseases!
www.surgery.usc.edu
www.szulo.hu/kids/k39/nikot39.htm
www.astrazeneca.fi
FUNCTIONS OF VASCULAR ENDOTHELIUM I
Release of vasodilator agents
Nitric oxide (=EDRF)
Prostacyclin (PGI2)
Bradykinin
EDHF (endothelium-derived hyperpolarizing factor)
Release of vasoconstrictor agents
Endothelin
Angiotensin I (angiotensin II)
Protection of vascular smooth muscle
vasoconstrictor → to vasodilator stimuli
(acetylcholine and serotonin)
FUNCTIONS OF VASCULAR ENDOTHELIUM II
Antiaggregatory effect
Acts via NO (nitric oxide) and PGI2 (prostaglandins)
Prevention of coagulation
Thromboresistant surface
Immune function
Supply of antigens to immuncompetent cells
Secretion of interleukin I
Enzymatic activity
Angiotensin-converting enzyme (ACE)
Carbonic anhydrase (large amounts in lung
endothelium)
Growth signal to vascular smooth muscle
VEGF (vascular endothelial growth factor)
Heparin-like inhibitors of growth
Stimuli of NO production
1. Humoral agonists of eNOS increase [Ca2+]i:
acetylcholine (M3-receptor), bradykinin, thrombin, substance P,
vasoactive intestinal polypeptide (VIP), insulin, histamine)
2. Mechanical agonist (wall shear stress)
- flow induced vasodilatation
- Mechano-sensitive ion channels, tyrosine kinase, PECAM
3. Endotoxin shock and inflammation (via iNOS)
in shock: -lipopolysacharide induced shock
-direct reaction to TNF-α from monocytes
-results too much NO ->generalized vasodilatation
in inflammation:
-in reaction to interleukins (e.g. IL-1) and TNF
-contributes to reddening (rubor), and local heat
(calor) in inflammation
4. Nitrites- sodium nitroprusside etc.
Nitric oxide, a gas, as a biological
signaling molecule
Prostaglandins
COX1/2
Endothelium:
SHEAR STRESS SENSITIVE MECHANISM
Intraluminal flow
1990:
Shear stress
mechanism
Flow-induced dilation in coronary arterioles
A
30
CONTROL
Control
Dilation (µm)
L-NNA
HHcy
20
∗
10
0
-10
0
10
20
30
40
Flow (µL/min)
50
HEMODYNAMIC FORCES VS. VASOMOTOR TONE
Myogenic mechanizmus
DIAMETER
endothelium independent
Shear stress mechanizmus
NO and prostaglandins mediates
40
100
30
20
75
10
0
50
0
20 40 60 80 100 120 140
PRESSURE
0
10
20
FLOW
METABOLIC MECHANISM
30
40
Hagen-Poiseuille-equation
(P1 - P2) π r4
Q =
8ηL
8ηL
R =
π r4
Haemodynamic basis
Laplace-Frank law:
P×r
T=
w
T
P
w
Wall shear stress (WSS):
4ηQ
WSS =
πr 3
dv
WSS = 4η
dr
50 µm
SCELETAL MUSCLE MICROCIRCULATION
Role of mechanosensitive mechanisms
• The pressure and shear stress sensitive
mechanisms are important in the
optimization of microvascular network
function to deliver blood flow to tissues.
• Minimal energy loss
Mechanisms involved in the local
regulation of (coronary) blood flow:
1. Smooth muscle (Pressure-Myogenic)
2. Endothelium (Shear stress)
3. Parenchyma (Oxygen-Metabolic)
4. Others
PARENCHYMA
METABOLIC MECHANISM
”OXYGEN” SENSITIVE
Metabolic
mechanisms
Metabolites from the
functioning myocardium
have vasomotor effects
(1860)
„Metabolic” vasoactive substances
PO2 ↓
PCO2
[H+] ↑
Adenosine
ATP
ischaemia
Change in diameter (%)
Change in diameter (%)
Arteries
Arterioles
35
30
25
}
20
15
*
ADO
10
5
0
-5
-10
-9
-8
-7
-6
-5
-4
40
35
30
25
NE
20
15
10
5
0
-5
-10
-9
-8
-7
-6
Log dose (M)
-5
-4
Reactive hyperemia
• substantial increase in blood flow (due to
dilation of arterioles) following arterial
occlusion
1867: Gaskell
1902: Bayliss
1912: Anrep
Folkow, Gregg,
Coffman,
Berne, Rubio,
Olsson, Belloni,
Sparks, and
many others
who are also
here today
Flow/Diameter
Reactive hyperemia: substantial increase in blood flow (due to
dilation of arterioles) following arterial occlusion
occlusion
release
Time
Olsson RA.: Myocardial reactive hyperemia.
Circ Res 37: 263-270., 1975. (present in isolated isolated heart!)
RH
O2 sat.
O2 fel.
Mechanisms eliciting reactive hyperemia
Neuro-humoral factors Tissue factors
• neural tone
• circulating hormones
• substances in the
plasma
• etc.
• adenosine
• pO2 decreases
• hyperosmolality
• ATP-K+ channels
• free radicals
• etc.
Mechanosensitive
vascular mechanisms
• pressure-induced
• flow-dependent
• stretch-induced
• cell deformation
• etc.
Coronary blood flow is phasic
Phasic character of the
blood flow is less explicit
in the right ventricle
Furthermore blood flow
in the right ventricle is
higher during systole (due
to higher systolic blood
pressure) than diastole.
Aorta
Pressure
diameter (µm)
200
150
100
Time (s)
Pressure
+ Flow
diameter (µm)
200
150
100
Occlusions:
30 s
60 s
120 s
Biomechanical events
during and following occlusion
Physical forces elicit:
•Deformation
•Stretch
•Wall shear stress
Resulting in:
•Constriction
•Dilation
occlusion
release
Time
olic
meta
b
flow
myo
gen
deformation
ic
stret
ch
Diameter / Flow
Proposed scheme for sequential and relative contribution of
deformation, stretch-, myogenic-, flow-dependent and metabolic
vascular mechanisms in the development of reactive hyperemia.
vasoactive agents
in local regulation of blood flow
PO2 ↓
PCO2
[H+] ↑
lactate
Adenosine
ATP
EDHF
Prostaglandins
Endothelin
NO (nitric-oxide)
Etc.
LOCAL MECHANISMS
REGULATING TISSUE BLOOD FLOW
Dilation
[Ca 2+]i and Ca2+-sensitivity
Transmural pressure
Wall shear stress
Constriction
Vascular smooth muscle
Endothelium
(NO, PG, EDHF, ROM, ET)
Blood flow
(mass transport, e.g. oxygen)
Parenchyma
(adenosine…)
PATHOPHYSIOLOGY
DIABETES
INCREASED PRESSURE-INDUCED CONSTRICTION
C (-Endo)
DM (-Endo)
Diameter (%)
100
75
*
*
50
**
** * ** * *
0 20 40 60 80 100 120 140
PRESSURE (mmHg)
REDUCED SHEAR STRESS-INDUCED DIALTION
∆ Diameter (µm)
Control
30
DM
*
20
10
0
0
5
10
15
20
Áramlás
FLOW (µL/min)
HYPERTENSION
Effect of high pressure (hypertension)
HYPERHOMOCYSTEINAEMIA
Homocystein metabolism
Protein
Remethylation
Transmethylation
Methionine
R
S-Ado-Met
MS
RCH3
THF
S-Ado-Hcy
Homocysteine
CBS
cystathionine-β-synthase
Transsulfuration
B6
Cystathionine
B6
Cysteine
B12
MethylTHF
Folsav
Methylenetetrahydrofolate
MTHF
reductase
Homocysteine
Nem proteint alkotó aminósav
methionin anyagcsere
reactív thiol (-SH) csoport
plazmaszint: 5-12 µmol/L
IN HHCY-ATHEROSCLEROSIS
CONTROL
Kontroll
HHC
DIAMETER
∆ Átmérõ (µm)
40
30
20
10
0
-10
-20
-30
-40
0
5
10
15
20
Áramlás
FLOW (µL/min)
25
30
HHCY PROMOTES ATHEROSCLEROSIS
HHcy
Shear stress
endothelium
eNOS
Xanthineoxidase
oxypurinol
.O2
NO
SOD
L-NAME
AA
COX
Indo
PGH2
OONOPGI2
TxA2
PLATELET AGGREGATION,
THROMBOSIS
dilation
constriction
Smooth muscle
HYPERTROPHY
If NO and superoxide are produced peroxynitrite is formed:
The biological activity of NO is decreased
_
.
O2
NO
ONOO
_
H+
_
.
OH
antioxidants
Role of the endothelium in regulation of
microcirculation
HEALTH:
Diameter (tone)
Permeability
Hemostasis
NO
DISEASE:
stimulus
PGI2 EDHF
endothelium
smooth muscle
Proliferation
Remodeling
Inflammation
TXA2 ET
•O2-
In pathological conditions vascular
production of:
Dilators are reduced (NO, PGI2)
Constrictors are increased (TXA2, endothelin)
Role of reactive oxygen species
Thank You
The End