Download Cardiovascular Physiology and Pharmacology

Cardiovascular Physiology
and Pharmacology
Peter Paal
Perioperative Medicine, Barts Heart Centre
St. Bartholomew’s Hospital, Barts Healt NHS
Queen Mary University of London
and
Department of Anaesthesiology and Intensive Care
University Hospital Innsbruck, Austria
Thanks to
Prof. Dr. W. Toller, MBA, DESA
Head of the Division of Cardiovascular Anesthesiology
Department of Anesthesiology and Intensive Care Medicine
Medical University of Graz
Austria
CARDIOVASCULAR
PHYSIOLOGY
Myocardial contraction
and
Frank-Starling-Relationship
Actin-Myosin-Filaments
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Troponin complex
C = Ca2+ binding Protein
I = Inhibits interaction
between actin and
myosin when
phosphorylated
T = Tropomyosin-binding
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Frank–Starling law of the heart
(Starling's law)
• Stroke volume ↑ in response to end- diastolic
volume↑
• Volume ↑ stretches ventricular wall  more
forceful contraction
• Mechanism: Stretching increases affinity of
troponin C for calcium  greater number of actinmyosin cross-bridges form
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Relation of
resting
sarcomere
length
on contractile
force
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Maximal force is generated with an
initial sarcomere length of 2.2 µm
Tension (%)
100
50
0
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Sensitivity of myofilaments for
Ca2+
Control
% Cell shortening
15
Desensitization
10
5
0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Intracellular Ca2+ concentration
(nM)
Sensitivity of myofilaments for
2+
Ca
% Cell shortening
Sensitization
15
Control
10
5
0
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7
Intracellular Ca2+ concentration (nM)
Change of myofilament sensitivity
to Ca2+
1,2
Relative Force Development
1,0
0,8
0,6
Temperature
b Protons
ADP
Phosphate
a
0,4
0,2
0,0
8
7
6
pCa (–log[Ca])
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The cardiac cycle
Relation of Pressure against
Volume
Left ventricular pressure-volume
loop
Stroke work
=
SV x Pressure
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Sources of errors
Does aortic pressure peak
at end of systole?
Does AV open when
ventricular contraction begins?
Volume change during
isometric contraction?
All valves closed at
the onset of systole?
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Systole
Different Phases
• Isovolumetric
contraction
phase
• All valves closed
• Ejection phase
• Maximum ejection
• Reduced ejection
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Diastole
Different Phases
• Isovolumetric relaxation
• Ends with AV
opening
• Rapid filling phase
• Diastasis
• Atrial systole
• Ends with start of systole
• 80% of the blood flows
passively down to the
ventricles
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Duration (sec) of cardiac cycle
phases in adult
Isovolumetric contraction
Maximum ejection
0,05
0,09
Reduced ejection
0,13
Total systole 0,27
Protodiastole
Isovolumetric relaxation
Rapid inflow
0,04
0,08
0,11
Diastasis
Atrial systole
0,19
0,11
Heart Rate
75/min
S:D = 1:2
Total diastole 0,53
Katz, Physiology of the Heart 2nd ed., p363; 1992 Raven press
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Relationship of duration of systole
+ diastole with increasing heart
rate
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End-systolic and end-diastolic
pressure-volume relationship
Inotropy
Lusitropy
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Decreased contractility, increased
end-diastolic volume
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Vasoconstriction, fluid retention
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Increased contractility, increased
lusitropy
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Wiggers Diagram
Relation of Pressures, Volume
and ECG over Time
Aortic valve
opens
Mitral valve
closes
Aortic valve
closes
Mitral valve
opens
WiggersDiagram
Central venous pressure
waveform
atrial
systole
cusps bulge
into atrium as
AV closes
Filling of atria;
concomitant
ventricular systole
x
y
atrial relaxation;
ventricle contracts,
downward movement of base
AV opens;
rapid drainage
into ventricle
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Simultaneous plotting of ECG and
central-venous pressure
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Myocardial Perfusion, Oxygen
Supply,
Oxygen Demand
Anatomy of the coronary arteries
Frank Netter, 1990
SYSTOLE
120
Arterial Blood Pressure
100
80
Left Coronary Artery Flow
0 Flow
Right Coronary Artery Flow
0 Flow
DIASTOLE
Main determinants of myocardial
oxygen supply
• O2-Content of coronary blood
• Haemoglobin
• Coronary perfusion
•
•
•
•

Coronary resistance
Diastolic aortic pressure
LVEDP
Heart Rate
Main natural mechanism to increase supply:
– Coronary vasodilation (!)
– Coronary oxygen extraction already maximal at rest!
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Main determinants of myocardial
oxygen demand
• Heart Rate
• Tachycardia increases oxygen demand
• Bradycardia decreases oxygen demand (e.g. b-Blockers)
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Relationship of duration of systole +
diastole with increasing heart rate
Main determinants of myocardial
oxygen demand
• Heart Rate
• Tachycardia increases oxygen demand
• Bradycardia decreases oxygen demand (e.g. b-Blockers)
• Myocardial contractility
• Inotropes increase oxygen demand (e.g. epinephrine)
• b-Blockers decrease oxygen demand
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Effects of Milrinone or
Levosimendan on Myocardial
Oxygen Consumption
Kaheinen, J Cardiovasc Pharmacol 43:555, 2004
Main determinants of myocardial
oxygen demand
• Heart Rate
• Tachycardia increases oxygen demand
• Bradycardia decreases oxygen demand (e.g. b-Blockers)
• Myocardial contractility
• Inotropes increase oxygen demand (e.g. epinephrine)
• b-Blockers decrease oxygen demand
• Wall tension of the myocardium
• High wall tension increases oxygen demand
• Decrease of wall tension decreases oxygen demand
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Wall tension of the myocardium
Laplace‘s Law
T=

𝑝𝑥𝑟
2ℎ
• T = wall tension
• p = internal pressure
• r = internal radius
• h = wall thickness
Increase in preload ± afterload increases wall tension
 e.g. Nitrates decrease wall tension


Dilated cardiomyopathy increases wall tension
Ventricular hypertrophy decreases wall tension
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Same pressure, same stroke
volume, higher wall stress
Cardiovascular Reflexes
Cardiovascular reflexes
= neural feedback loops
Afferent
Activity
Heart
Vasculature
Regulation and
modulation of
cardiac function
Efferent
Activity
CNS
Vasomotor
Center
Cardiovascular reflexes
• Baroreceptor Reflex
• Bainbridge-Reflex
• Bezold-Jarisch-Reflex
• Valsalva Manoeuvre
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Baroreceptor Reflex
Definition
• Homeostatic mechanism for maintaining blood
pressure
• Elevated blood pressure reflexively decreases heart rate
+ blood pressure
• Decreased blood pressure increases heart rate + blood
pressure
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Baroreceptors
Afferents
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Target:
Solitary tract
nucleus
= vasomotor
center
Pressure sensing results
in greater afferent
activity which inhibits
vasomotor center
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Baroreceptor Reflex
Efferents
• To heart
• Primarily governs rate
• To kidney
• To peripheral vasculature
• Primarily governs degree of vessel constriction
• Subdivisions
• Carotid baroreceptor reflex - Heart
• Aortic baroreceptor reflex - Vascular
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Bainbridge-Reflex
Definition
• Rapid intravenous infusion of volume produces
tachycardia
• Tachycardia is reflex in origin
• Stretch receptors in the right and left atria
• Vagus nerve constitutes afferent limb
• Withdrawal of vagal tone primary efferent limb
Bainbridge, The influence of venous filling upon the rate of the heart. J Physiol 50:65–84, 1915
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Bezold-Jarisch-Reflex
Definition
• Inhibition of sympathetic outflow to blood vessels and the
heart
• Mediated by mechano- and chemosensitive receptors
located in the wall of the ventricles
• “Preservation” of the heart
• Vasodilation during heart failure
• Hypotension
• Bradycardia
• Apnea possible
• Possible cause of profound bradycardia and circulatory
collapse after spinal anesthesia
Albert von Bezold (1836 – 1868) and Adolf Jarisch Jr. (1891–1965)
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The Valsalva Manoeuvre
• Test of
• Sympathetic nerve system function
• Parasympathetic nerve system function
• Straining by blowing into mouthpiece against a
pneumatic resistance while maintaining a pressure
of 40 mmHg for 15 sec
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Four phases of the
Valsalva Manoeuvre
1. BP ↑ via mechanical factors
2. BP ↓ (due to ↓ venous return);
reflex HR ↑ and SVR ↑
return of BP despite SV ↓
3. BP ↓ via mechanical factors after expiratory
pressure is released
4. Venous return ↑ and SV ↑ (back to normal over
several min), but PVR and CO cause BP ↑↑ and
HR ↓ (reflex)
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Four phases of the
Valsalva Manoeuvre
CARDIOVASCULAR
PHARMACOLOGY
Synthesis of dopamine,
norepinephrine and epinephrine (1)
Phenylalanine
NH2
CH2 – CH2
COOH
Tyrosine
NH2
CH2 – CH2
COOH
HO
Dopa
HO
NH2
CH2 – CH2
COOH
HO
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Synthesis of dopamine,
norepinephrine and epinephrine (2)
HO
HO
Dopamin
CH2 – CH2 – NH2
NorepiOH
nephrine
HO
CH – CH2 – NH2
HO
EpiOH
nephrine
HO
CH – CH2 – NH – CH3
HO
Dobutamine, Phenylephrine, Efedrine are synthetic!
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Degradation of catecholamines
Example: Dopamine
Catecholamines act by stimulating
adrenergic receptors
• b-adrenergic receptors
• b1
• Cardiac stimulation (positive inotropic, lusitropic, chronotropic)
• Agonists, e.g. Isoprenaline, Dobutamine, Epinephrine
• Antagonists, e.g. Esmolol, Metoprolol, Atenolol, Bisoprolol, Carvedilol
• b2
• Smooth muscle relaxation, (increased myocardial contractility)
• Agonists, e.g. Salbutamol, Terbutalin, Salmeterol
• Antagonists, e.g. Propranolol
• b3
• Enhancement of lipolysis, smooth muscle relaxation
• Agonists + Antagonists, in development e.g. Solabegron
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Ca2+
b1 -Adrenoceptor
Dobutamine, Epinephrine
Gs
ATP
A
C
P
Milrinone
cAMP
PDE
Ca2+
Protein
Kinase A
Sarc. Ret.
TnI
Actin
TnC
Ca2+
Ca2+
Myosin
PL
Ca2+
ATP
Ca2+
Catecholamines act by stimulating
adrenergic receptors
• a-adrenergic receptors
• a1
• Vasoconstriction, renal sodium retention, decreased
gastrointestinal motility
• Agonists, e.g. Norepinephrine, Phenylephrine, Etilefrine,
Metaraminol, Methoxamine, Epinephrine
• Antagonists, e.g. Phentolamine, Phenoxybenzamine, Prazosin,
Labetalol, Carvedilol
• a2
• Central inhibition of sympathetic activity ( vasodilation,
bradycardia)
• Agonists, e.g. Clonidine, Dexmedetomidine
• Antagonists, e.g. Phentolamine, Tolazoline
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a1
a2
b
Gq
Gi
Gs
Phospholipase C
Adenylatecyclase
Adenylatecyclase
PIP2
ATP cAMP
DAG
ATP cAMP
IP3
Ca2+
Smooth muscle
contraction
Ca2+
Inhibition of Smooth muscle
contraction
transmitter
release
Heart muscle
contraction
Smooth muscle
relaxation
glycogenolysis
Dopamine
• Stimulates Dopamine-Receptors at low doses (1 – 3
µg/kg/min)
• Various subtypes of Dopamine-receptors (D1-D5)
• High receptor density in the proximal tubules of the
kidney  natriuresis ↑, diuresis ↑
• High receptor density in the pulmonary artery 
vasodilation ↑
• Additionally stimulates b1-Receptors at moderate
doses (3 – 10 µg/kg/min)
• Additionally stimulates a1-Receptors at high doses
(> 10 µg/kg/min)
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Effects of various catecholamines on
different adrenergic receptors
Cardiac
b-receptors
+
++
+++
Vascular
a-receptors
++
+
-
Vascular
b-receptors
++
+++
Dopamine
Dobutamine
+
++
+
-
(+)
Phenylephrine
Ephedrine
+
+++
++
+
Norepinephrine
Epinephrine
Isoproterenol
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Comparison of clinical effects of
inotropes
Epinephrine,
Norepinephrine
Dopamine
Dobutamine
Milrinone
Levosimendan
hours
hours - days
Vasoconstriction
Enhanced
inotropy
Increased heart
rate
Myocardial O2
consumption
Tachyarrhythmias
Offset of action
min
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Digoxin
2 Na+
Ca2+
K+
ATPase
K+
3 K+
Na+↑
TnI
Actin
TnC
Myosin
Na+
Exchanger
Na+
Na+
Ca2+↑
• Myocardial Contraction and Frank-Starling-Relationship
• The cardiac cycle- Relation of Pressure against Volume
• Wiggers Diagram- Relation of Pressures, Volume and ECG over Time
• Myocardial Perfusion, Oxygen Supply, Oxygen Demand
• Cardiovascular Reflexes
• Cardiovascular Pharmacology-Synthesis, Metabolism and Action of
Catecholamines
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Questions?
Thank you!
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