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
Troponin complex I = Inhibits interaction between actin and myosin when phosphorylated C = Ca 2+ binding Protein 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 actinmyosin cross-bridges form
Relation of resting sarcomere length on contractile force
Maximal force is generated with an initial sarcomere length of 2.2 µm Tension (%) 100 50 0
% Cell shortening Sensitivity of myofilaments for Ca 2+ 15 Control 10 Desensitization 5 0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Intracellular Ca2+ concentration (nm)
% Cell shortening Sensitivity of myofilaments for Ca 2+ 15 Sensitization Control 10 5 0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Intracellular Ca 2+ concentration (nm)
Relative Force Development Change of myofilament sensitivity to Ca 2+ 1,2 1,0 0,8 0,6 0,4 a b Temperature Protons ADP Phosphate 0,2 0,0 8 7 6 pca ( log[ca])
The cardiac cycle - Relation of Pressure against Volume
Left ventricular pressure-volume loop Stroke work = SV x Pressure
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?
Systole Different Phases Isovolumetric contraction phase All valves closed Ejection phase Maximum ejection Reduced ejection
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
Duration (sec) of cardiac cycle phases in adult Isovolumetric contraction 0,05 Maximum ejection 0,09 Reduced ejection 0,13 Total systole 0,27 Protodiastole 0,04 Isovolumetric relaxation 0,08 Rapid inflow 0,11 Diastasis 0,19 Atrial systole 0,11 Total diastole 0,53 atz, 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
Aortic valve opens Aortic valve closes Wiggers- Diagram Mitral valve closes Mitral valve opens
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
Simultaneous plotting of ECG and central-venous pressure
Myocardial Perfusion, Oxygen Supply, Oxygen Demand
Anatomy of the coronary arteries Frank Netter, 1990
SYSTOLE DIASTOLE Arterial Blood Pressure 120 100 80 Left Coronary Artery Flow 0 Flow Right Coronary Artery Flow 0 Flow
Main determinants of myocardial oxygen supply O 2 -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
Cardiovascular reflexes = neural feedback loops Afferent Activity Heart Vasculature Regulation and modulation of cardiac function CNS Vasomotor Center Efferent Activity
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 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)
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) Phenylalanine NH 2 CH 2 CH 2 COOH Tyrosine NH 2 HO CH 2 CH 2 COOH HO HO Dopa NH 2 CH 2 CH 2 COOH
Synthesis of dopamine, norepinephrine and epinephrine (2) HO Dopamin CH 2 CH 2 NH 2 HO HO Norepinephrine OH CH CH 2 NH 2 HO HO Epinephrine OH CH CH 2 NH CH 3 HO Dobutamine, Phenylephrine, Efedrine are synthetic!
Degradation of catecholamines Example: Dopamine
Catecholamines act by stimulating adrenergic receptors b-adrenergic receptors b 1 Cardiac stimulation (positive inotropic, lusitropic, chronotropic) Agonists, e.g. Isoprenaline, Dobutamine, Epinephrine Antagonists, e.g. Esmolol, Metoprolol, Atenolol, Bisoprolol, Carvedilol b 2 Smooth muscle relaxation, (increased myocardial contractility) Agonists, e.g. Salbutamol, Terbutalin, Salmeterol Antagonists, e.g. Propranolol b 3 Enhancement of lipolysis, smooth muscle relaxation Agonists + Antagonists, in development e.g. Solabegron
b 1 -Adrenoceptor Ca 2+ Dobutamine, Epinephrine G s A C Milrinone P ATP TnI Actin TnC camp PDE Protein Kinase A Ca 2+ Ca 2+ Sarc. Ret. Ca 2+ Myosin Ca 2+ PL ATP Ca 2+
Catecholamines act by stimulating adrenergic receptors a-adrenergic receptors a 1 Vasoconstriction, renal sodium retention, decreased gastrointestinal motility Agonists, e.g. Norepinephrine, Phenylephrine, Etilefrine, Metaraminol, Methoxamine, Epinephrine Antagonists, e.g. Phentolamine, Phenoxybenzamine, Prazosin, Labetalol, Carvedilol a 2 Central inhibition of sympathetic activity ( vasodilation, bradycardia) Agonists, e.g. Clonidine, Dexmedetomidine Antagonists, e.g. Phentolamine, Tolazoline
a1 a2 b G q G i G s Phospholipase C Adenylatecyclase Adenylatecyclase PIP 2 DAG ATP camp ATP camp IP 3 Ca 2+ Smooth muscle contraction Ca 2+ Inhibition of transmitter release Smooth muscle contraction Heart muscle contraction Smooth muscle relaxation glycogenolysis
Dopamine Stimulates Dopamine-Receptors at low doses (1 3 µg/kg/min) Various subtypes of Dopamine-receptors (D 1 -D 5 ) High receptor density in the proximal tubules of the kidney natriuresis, diuresis High receptor density in the pulmonary artery vasodilation Additionally stimulates b 1 -Receptors at moderate doses (3 10 µg/kg/min) Additionally stimulates a 1 -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 Dobutamine Milrinone Levosimendan Vasoconstriction Enhanced inotropy Increased heart rate Myocardial O 2 consumption Tachyarrhythmias Offset of action min hours hours - days
K + K + Digoxin 3 K + Na + 2 Na + Na + Ca 2+ ATPase Exchanger Ca 2+ Na + Na + Myosin TnI Actin TnC
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!