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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 1 16.05.2014 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]) 2 16.05.2014 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? 3 16.05.2014 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 4 16.05.2014 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 5 16.05.2014 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) 6 16.05.2014 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 7 16.05.2014 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 8 16.05.2014 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 9 16.05.2014 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 10 16.05.2014 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 11