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Home , Etilefrine, Lusitropy

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 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)

↑ 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

100 (%)

50 Tension Tension

0 Sensitivity of myofilaments for Ca2+

15 Control

10 Desensitization

5 % Cell shortening Cell %

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 Ca2+

Sensitization 15 Control

10

5 % Cell shortening Cell %

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

1,0

0,8

0,6 Temperature

a b Protons Force Development Force 0,4 ADP Phosphate

0,2 Relative Relative

0,0 8 7 6 pCa (–log[Ca]) The - Relation of Pressure against Volume Left ventricular pressure-volume loop

Stroke work = SV x Pressure Sources of errors

Does peak at end of ?

Does AV open when ventricular contraction begins?

Volume change during isovolumetric contraction?

All valves closed at the onset of systole? Systole Different Phases

 Isovolumetric contraction phase – All valves closed  Ejection phase – Rapid ejection – Reduced ejection Different Phases

 Isovolumetric relaxation – Ends with MV opening  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 75/min Isovolumic relaxation 0,08 Rapid inflow 0,11 S:D = 1:2 Diastasis 0,19 Atrial systole 0,11 Total diastole 0,53

Katz, Physiology of the Heart 2nd ed., p363; 1992 Raven press 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 , fluid retention Increased contractility, increased lusitropy Wiggers Diagram - Relation of Pressures, Volume and ECG over Time Aortic valve closes Wiggers-Diagram Aortic valve opens

Mitral valve Mitral valve closes opens waveform

cusps bulge Filling of atria; atrial into atrium as concomitant systole MV closes ventricular systole

x y

atrial relaxation; MV opens; contracts, rapid drainage downward move- into ventricle ment of base Simultaneous plotting of ECG and central- venous pressure Myocardial , Oxygen Supply, Oxygen Demand Anatomy of the coronary arteries

Frank Netter, 1990 SYSTOLE DIASTOLE

120 Arterial 100

80

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 (!) – 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)  – increase oxygen demand (e.g. epinephrine) – b-Blockers decrease oxygen demand Effects of or 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

푝 푥 푟  T = wall tension T = 2ℎ  p = internal pressure  r = internal radius  h = wall thickness

 Increase in ± 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

Regulation and CNS Heart modulation of Vasomotor Vasculature cardiac function 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 , and epinephrine (1)

Phenylalanine NH2

CH2 – CH2 COOH

Tyrosine NH2

CH2 – CH2 COOH HO

Dopa NH2

HO CH2 – CH2 COOH HO Synthesis of dopamine, norepinephrine and epinephrine (2)

Dopamin HO CH2 – CH2 – NH2

Norepi- HO OH nephrine

HO CH – CH2 – NH2

Epi- OH HO nephrine

HO CH – CH2 – NH – CH3

HO

Dobutamine, , Efedrine are synthetic! Degradation of Example: Dopamine Catecholamines act by stimulating receptors  b-adrenergic receptors

– b1 – Cardiac stimulation (positive inotropic, lusitropic, ) – Agonists, e.g. , , Epinephrine – Antagonists, e.g. Esmolol, , , ,

– b2 – Smooth muscle relaxation, (increased myocardial contractility) – Agonists, e.g. , Terbutalin, – Antagonists, e.g.

– b3 – Enhancement of lipolysis, smooth muscle relaxation – Agonists + Antagonists, in development e.g. Ca2+ b1 -Adrenoceptor Dobutamine, Epinephrine

Gs A P C Milrinone

PDE ATP cAMP Ca2+ Sarc. Ret. TnI Actin Ca2+ 2+ TnC Ca Myosin PL 2+ ATP Ca Ca2+ Catecholamines act by stimulating adrenergic receptors  a-adrenergic receptors

– a1 – Vasoconstriction, renal sodium retention, decreased gastrointestinal motility – Agonists, e.g. Norepinephrine, Phenylephrine, Etilefrine, , , Epinephrine – Antagonists, e.g. , , , , Carvedilol

– a2 – Central inhibition of sympathetic activity ( vasodilation, bradycardia) – Agonists, e.g. , – Antagonists, e.g. Phentolamine, a1 a2 b

Gq Gi Gs

Phospho- Adenylate- Adenylate- lipase C cyclase cyclase

PIP2 DAG ATP cAMP ATP cAMP

IP3

Ca2+ Ca2+ Heart muscle contraction Smooth muscle Inhibition of Smooth muscle Smooth muscle contraction transmitter contraction relaxation release 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  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 Vascular Vascular b-receptors a-receptors b-receptors Norepinephrine + ++ - Epinephrine ++ + ++ Isoproterenol +++ - +++ Dopamine + + - Dobutamine ++ - (+) Phenylephrine - +++ - + ++ + Comparison of clinical effects of inotropes

Epinephrine, Dopamine Dobu- Mil- Levo- Norepinephrine tamine rinone simendan Vasoconstriction Enhanced inotropy Increased heart rate

Myocardial O2 consumption Tachy- arrhythmias Offset of action min hours hours - days Digoxin + 2+ 2 Na Ca + K+ Na Ex- ATP- chan- ase ger + Na+ K 3 K+ Na+ Ca2+↑ Na+↑

TnI Actin TnC Myosin 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!