cardio-circulatory physiology and...
TRANSCRIPT
Cardiovascular Physiology and
Pharmacology
Peter Paal
MD, PD, MBA, EDAIC, EDIC
Department of Anaesthesiology and Intensive Care
Hospitallers Brothers Hospital, Paracelsus Medical University
Salzburg, Austria
Honorary Senior Clinical Lecturer, Barts Heart Centre, William Harvey Research Institute,
Barts & The London School of Medicine&Dentistry, Queen Mary University of London
NO COI
CARDIOVASCULAR
PHYSIOLOGY
Myocardial contraction and Frank-
Starling-Relationship
Actin-Myosin-Filaments
Troponin complex
C = Ca2+ binding Protein
I = Inhibits interaction
between actin and
myosin
T = Tropomyosin-binding
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 actin-myosin cross-bridges form
Relation of resting
sarcomere length
on contractile
force
Maximal force is generated with an initial
sarcomere length of 2.2 µm
0
50
100
Te
nsio
n (
%)
0.1 0.2 0.5 0.6 0.70.40.3
Sensitivity of myofilaments for Ca2+
0
5
10
15
0.0
Intracellular Ca2+ concentration (nM)
% C
ell
short
enin
g
Control
Desensitization
0.1 0.2 0.5 0.6 0.70.40.3
Sensitivity of myofilaments for Ca2+
0
5
10
15
0.0
Intracellular Ca2+ concentration (nM)
% C
ell
sh
ort
enin
g ControlSensitization
Change of myofilament sensitivity to Ca2+
1,2
Temperature
Protons
ADP
Phosphate
a b
pCa (–log[Ca])
8 7 6
Rela
tive F
orc
e D
evelo
pm
en
t
1,0
0,8
0,6
0,4
0,2
0,0
The cardiac cycle
-
Relation of Pressure against Volume
Left ventricular pressure-volume loop
Stroke work
=
SV x Pressure
Sources of errors
Volume change during
isovolumetric contraction?
Does AV open when
ventricular contraction begins?
Does aortic pressure peak
at end of systole?
All valves closed at
the onset of systole?
Systole
Different Phases
Isovolumetriccontractionphase
– All valves closed
Ejection phase
– Rapid ejection
– Reduced ejection
Diastole
Different Phases
Isovolumetric relaxation
– Ends with MVopening
Rapid filling phase
Diastasis
Atrial systole
– Ends with start of systole
Phases of cardiac cycle (sec) in adult
Isovolumic contraction 0,05
Rapid 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 0,11
Total diastole 0,53
Katz, Physiology of the Heart 2nd ed., p363; 1992 Raven press
Heart Rate
75/min
S:D = 1:2
Relationship of duration of systole + diastole
with increasing heart rate
End-systolic and end-diastolic
pressure-volume relationship
Inotropy
Lusitropy
Decreased contractility, increased end-
diastolic volume
Vasoconstriction, fluid retention
Increased contractility, increased lusitropy
Wiggers Diagram
-
Relation of Pressures, Volume and
ECG over Time
Wiggers-Diagram
Mitral valve
closes
Aortic valve
opens
Aortic valve
closes
Mitral valve
opens
Central venous pressure waveform
atrial
systole
cusps bulge
into atrium as
MV closes
Filling of atria;
concomitant
ventricular systole
x y
atrial relaxation;
ventricle contracts,
downward move-
ment of base
MV opens;
rapid drainage
into ventricle
Simultaneous plotting of ECG and central-
venous pressure
Myocardial Perfusion, Oxygen Supply,
Oxygen Demand
Anatomy of the coronary arteries
Frank Netter, 1990
SYSTOLE DIASTOLE
120
100
80
Arterial Blood Pressure
Left Coronary Artery Flow
0 Flow
Right Coronary Artery Flow
0 Flow
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!
Main determinants of myocardial oxygen
demand
Heart Rate
– Tachycardia increases oxygen demand
– Bradycardia decreases oxygen demand (e.g. b-Blockers)
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
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
Wall tension of the myocardium
Laplace‘s Law
T = 𝑝 𝑥 𝑟
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
Same pressure, same stroke volume, higher
wall stress
Cardiovascular Reflexes
Afferent
Activity
CNS
Vasomotor
Center
Efferent
Activity
Heart
Vasculature
Cardiovascular reflexes
= neural feedback loops
Regulation and
modulation of
cardiac function
Cardiovascular reflexes
Baroreceptor Reflex
Bainbridge-Reflex
Bezold-Jarisch-Reflex
Valsalva Manoeuvre
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
Baroreceptors
Afferents
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
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
Bezold-Jarisch-Reflex
Definition
Inhibition of sympathetic outflow to blood vessels and the heart
Mediated by mechano- and chemosensitivereceptors 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)
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
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)
Four phases of the
Valsalva Manoeuvre
CARDIOVASCULAR
PHARMACOLOGY
Synthesis of dopamine, norepinephrine and
epinephrine (1)
CH2 – CH2
NH2
COOH
Phenylalanine
CH2 – CH2
NH2
COOH
HO
Tyrosine
CH2 – CH2
NH2
COOH
HO
HO
Dopa
Synthesis of dopamine, norepinephrine and
epinephrine (2)
CH2 – CH2 – NH2
HO
HODopamin
CH – CH2 – NH2
OH
HO
HO
Norepi-
nephrine
CH – CH2 – NH – CH3
OH
HO
HO
Epi-
nephrine
Dobutamine, Phenylephrine, Efedrine are synthetic!
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
Sarc. Ret.
b1 -Adrenoceptor
GsP
Protein
Kinase A
ATP cAMP
Ca2+Ca2+
Ca2+
Ca2+ATP
PL
TnC
TnI
Actin
Myosin
Ca2+
Ca2+
A
C
Dobutamine, Epinephrine
PDE
Milrinone
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
PIP2 DAG
IP3
Ca2+
Smooth muscle
contraction
a1
Gq
Phospho-
lipase C
a2
Gi
Adenylate-
cyclase
b
Gs
Adenylate-
cyclase
ATP cAMP
Inhibition of
transmitter
release
ATP cAMP
Heart muscle
contraction
Smooth muscle
relaxation
glycogenolysis
Smooth muscle
contraction
Ca2+
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)
Effects of various catecholamines on
different adrenergic receptors
Cardiac
b-receptors
Vascular
a-receptors
Vascular
b-receptors
Norepinephrine + ++ -
Epinephrine ++ + ++
Isoproterenol +++ - +++
Dopamine + + -
Dobutamine ++ - (+)
Phenylephrine - +++ -
Ephedrine + ++ +
Comparison of clinical effects of inotropes
Epinephrine,
Norepinephrine
Dopamine Dobu-
tamine
Mil-
rinone
Levo-
simendan
Vasoconstriction
Enhanced
inotropy
Increased heart
rate
Myocardial O2
consumption
Tachy-
arrhythmias
Offset of action min hours hours - days
TnC
TnI
Actin
Myosin
ATP-
ase
2 Na+
3 K+
Digoxin
Ex-
chan-
ger
Ca2+
Na+
Na+
Na+
Na+↑Ca2+↑
K+
K+
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
Questions?
Thank you!