cardio-circulatory physiology and...

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!