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16.05.2014
CARDIO‐CIRCULATORY PHYSIOLOGY AND PHARMACOLOGY
CARDIO‐CIRCULATORY
PHYSIOLOGY
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
Actin‐Myosin‐Filaments
Myocardial Contraction and
Frank‐Starling‐Relationship
Troponin Complex
Frank–Starling law of the heart (Starling's law)
C = Ca2+ binding Protein
I = Inhibits interaction
between actin and
myosin when
phosphorylated
• Stroke volume ↑ in response to volume ↑ (end‐ diastolic volume)
• Volume ↑ stretches ventricular wall  more forceful contraction
• Mechanism: Stretching increases affinity of troponin C for calcium 
greater number of actin‐myosin cross‐bridges form
T = Tropomyosin‐binding
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Maximal force is generated with an initial sarcomere length of 2.2 µm
Relation of resting
sarcomere length
on contractile force
Tension (%)
100
50
0
Sensitivity of Myofilaments for Ca2+
Sensitization
Control
Desensitization
10
Control
15
% Cell shortening
15
% Cell shortening
Sensitivity of Myofilaments for Ca2+
5
0
10
5
0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Intracellular Ca2+ concentration (nM)
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+
Relative Force Development
1,2
The cardiac cycle
‐
Relation of Pressure against Volume
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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Left ventricular pressure‐volume loop
Left ventricular pressure‐volume loop
Left ventricular pressure‐volume loop
Left ventricular pressure‐volume loop
Left ventricular pressure‐volume loop
Typical errors during EDA 1
Stroke work
=
SV x Pressure
Aortic pressure peaks
at the end of systole?
Aortic valve opens when
ventricular contraction begins?
Volume change during
isometric contraction?
All valves closed at
the beginning of systole?
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Systole ‐ Different Phases
Diastole ‐ Different Phases
• Isovolumic contraction
phase
• All valves closed
• Isovolumic relaxation
• ends with AV‐valve
opening
• Rapid filling phase
• Diastasis
• Atrial systole
• Ejection phase
• Maximum ejection
• Reduced ejection
• ends with start of systole
• 80% of the blood flows passively down to the ventricles
Durations (in seconds) of the phases of the
cardiac cycle in adult man
Isovolumic contraction
Relationship of duration of systole + diastole with increasing heart rate
0,05
Maximum ejection
0,09
Reduced ejection
0,13
Total systole 0,27
Protodiastole
0,04
Isovolumic relaxation
0,08
Rapid inflow
0,11
Diastasis
0,19
Atrial systole
Heart Rate
75/min
S:D = 1:2
0,11
Total diastole 0,53
Katz, Physiology of the Heart 2nd ed., p363; 1992
End‐systolic and end‐diastolic pressure‐volume relationship
Decreased contractility, increased
end‐diastolic volume
Inotropy
Lusitropy
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Vasoconstriction, Fluid retention
Increased contractility, increased lusitropy
Aortic valve
opens
Wiggers Diagram
‐
Relation of Pressures, Volume and ECG over Time
Central Venous Pressure Waveform
atrial
systole
cusps bulge
into atrium as
AV‐valve closes
Mitral valve
closes
Aortic valve
closes
Wiggers‐Diagram
Mitral valve
opens
Simultaneous plotting of ECG and Central‐
venous pressure
Filling of atria;
concomitant
ventricular systole
x
y
atrial relaxation;
ventricle contracts, downward move‐
ment of base
AV‐valve opens;
rapid drainage
into ventricle
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Anatomy of the Coronary Arteries
Myocardial Perfusion, Oxygen Supply,
Oxygen Demand
modified from Netter, Farbatlanten der Medizin Band 1, Thieme‐Verlag 1990
Systole
Main determinants of myocardial
oxygen supply
Diastole
120
Arterial Blood Pressure 100
80
• O2‐Content of coronary blood
• Hemoglobin
• Coronary perfusion
Left Coronary Artery Flow
• Coronary resistance
• Diastolic aortic pressure
• LVEDP
• Heart Rate
0 Flow
Right Coronary Artery Flow
0 Flow
Main determinants of myocardial
oxygen demand

Main natural mechanism to increase supply:
– Coronary vasodilation (!)
– Coronary oxygen extraction already maximal at rest!
Relationship of duration of systole + diastole with increasing heart rate
• Heart Rate
• tachycardia increases oxygen demand
• bradycardia decreases oxygen demand (e.g. ‐Blockers)
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Main determinants of myocardial
oxygen demand
Effects of Milrinone or Levosimendan on Myocardial Oxygen Consumption
• Heart Rate
• tachycardia increases oxygen demand
• bradycardia decreases oxygen demand (e.g. ‐Blockers)
• Myocardial contractility
• inotropes increase oxygen demand (e.g. epinephrine)
• ‐Blockers decrease oxygen demand
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. ‐Blockers)
Wall tension of the myocardium ‐ Laplace‘s Law
T = • Myocardial contractility
• inotropes increase oxygen demand (e.g. epinephrine)
• ‐Blockers decrease oxygen demand
• T = wall tension
• p = internal pressure
• r = internal radius
• h = wall thickness

Increase in preload ± afterload increases wall tension

Dilated cardiomyopathy increases wall tension
Ventricular hypertrophy decreases wall tension
• Wall tension of the myocardium
• high wall tension increases oxygen demand
• decrease of wall tension decreases oxygen demand
 e.g. Nitrates decrease wall tension

Same pressures, same stroke volumes,
different wall stresses
Cardiovascular Reflexes
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Cardiovascular Reflexes = neural feedback loops
Afferent
Activity
Heart
Vasculature
Regulation and
modulation of
cardiac function
CNS
Vasomotor
Center
Cardiovascular Reflexes
• Baroreceptor Reflex
• Bainbridge‐Reflex
• Bezold‐Jarisch‐Reflex
• Valsalva Manoeuvre
Efferent
Activity
Baroreceptor Reflex ‐ Definition
Baroreceptors ‐ Afferents
• Homeostatic mechanism for maintaining blood pressure
• Elevated blood pressure reflexively decreases heart rate + blood pressure
• Decreased blood pressure increases heart rate + blood pressure
Target:
Solitary tract
nucleus
= vasomotor
center
Pressure sensing results in greater afferent activity which inhibits vasomotor center
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
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
• Clinical examples:
• Patients presses against tube before extubation
• Pregnant woman presses during labor
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)
4 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)
4 Phases of the Valsalva Manoeuvre
CARDIO‐CIRCULATORY
PHARMACOLOGY
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Synthesis of dopamine, norepinephrine and
epinephrine (1)
Phenylalanine
NH2
Synthesis of dopamine, norepinephrine and epinephrine (2)
HO
CH2 – CH2
COOH
Dopamin
CH2 – CH2 – NH2
HO
NH2
Tyrosine
HO
Norepi‐
OH
nephrine
CH – CH2 – NH2
CH2 – CH2
COOH
HO
HO
HO
NH2
Dopa
HO
CH2 – CH2
Epi‐
OH nephrine
CH – CH2 – NH – CH3
HO
COOH
HO
Dobutamine, Phenylephrine, Efedrine are synthetic!
Degradation of catecholamines
Example: Dopamine
Catecholamines act by stimulating
adrenergic receptors •
‐adrenergic receptors
•
1
• Cardiac stimulation (positive inotropic, lusitropic, chronotropic)
• Agonists: Isoprenaline, Dobutamine, Epinephrine etc.
• Antagonists: Esmolol, Metoprolol, Atenolol, Bisoprolol, (Carvedilol)
•
2
• Smooth muscle relaxation, (increased myocardial contractility)
• Agonists: Salbutamol, Terbutalin, Salmeterol etc.
• Antagonists: Propranolol
•
3
• Enhancement of lipolysis
• Agonists + Antagonists partially in development (e.g. Solabegron)
Ca2+
 -Adrenoceptor
Catecholamines act by stimulating
adrenergic receptors Dobutamine, Epinephrine
Gs
ATP
•
A
C
P
cAMP
PDE
Sarc. Ret.
TnI
TnC
•
Ca2+
Ca2+
Myosin
PL
Ca2+
ATP
Ca2+
1
• Vasoconstriction, renal sodium retention, decreased gastrointestinal motility, ((increased myocardial contractility))
• Agonists: Norepinephrine, Phenylephrine, Etilefrine, Metaraminol, Methoxamine, Epinephrine etc.
• Antagonists: Phentolamine, Phenoxybenzamine, Prazosin, (Labetalol, Carvedilol)
Ca2+
Protein
Kinase A
Actin
‐adrenergic receptors
•
Milrinone
2
• Central inhibition of sympathetic activity (vasodilation, bradycardia)
• Agonists: Clonidine, Dexmedetomidine
• Antagonists: Phentolamine, Tolazoline
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

Dopamine

• Stimulates Dopamine‐Receptors at low doses (1 – 3 µg/kg/min)
Gq
Gi
Gs
Phospholipase C
Adenylatecyclase
Adenylatecyclase
ATP cAMP
DAG
IP3
PIP2
Ca2+
ATP cAMP
Ca2+
Smooth muscle
contraction
Heart muscle
contraction
Smooth muscle
relaxation
glycogenolysis
Inhibition of Smooth muscle
transmitter
contraction
release
Effects of various catecholamines on
different adrenergic receptors
• Additionally stimulates 1‐Receptors at moderate doses (3 – 10 µg/kg/min)
• Additionally stimulates 1‐Receptors at high doses (> 10 µg/kg/min)
Comparison of clinical effects of inotropes
Cardiac
‐receptors
+
Vascular
‐receptors
++
Vascular
‐receptors
‐
Epinephrine
++
+
++
Isoproterenol
+++
‐
+++
Dopamine
+
+
‐
Dobutamine
Norepinephrine
• 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 
vasodila on ↑
++
‐
(+)
Phenylephrine
‐
+++
‐
Ephedrine
+
++
+
Epinephrine, Norepinephrine
Digoxin
2 Na+
Ca2+
ATPase
K+
3 K+
Na+↑
Dobu‐
tamine
Mil‐
rinone
Levo‐
simendan
hours
hours ‐ days
Vasoconstriction
Enhanced inotropy
Increased heart rate
Myocardial O2
consumption
Tachy‐
arrhythmias
Offset of action
K+
Dopamine
min
Na+
Exchanger
Na+
Na+
Ca2+↑
Thank you for your attention
And good luck for the examination!
TnI
Actin
TnC
Myosin
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