Electric- cell Channel structure - 4 subunits

- Each with 6 alpha helixes (D1-D6)

- D1,D2,D3: membrane interaction

- D4: voltage sensor

- D5, D6: aqueous pore

- Na and Ca: one single tetramers,

connected by a single polypeptide chain

- K: 4 independent subunits

Sodium currents - INa

- Rapid activation kinetics

- Activated at -70 to -80 mV until 0 mV

- Depolarization

- Fast response fibers

Potassium currents

Transient outward - Ito

- Immediately after depolarization

- Initial repolarization

- Subepicardial myocardium

Delayed rectifying - IK

- Very slow kinetics

- Main current for repolarisation

- Fast and slow response fibers

- IKur: very early repolarisation, atrial

myocytes

- IKr: early repolarisation

- IKs: late repolarisation

rectifier - IK1

- Fast activation

- Fast response fibers

- Activates at -20 mV during

repolarisation -> anomalous rectification
during Platou phase -> prolonging
platou phase

- Maintaining resting potential

Acetylcholine activated - IK-Ach

- Sinus node, atrioventricular node, atrial

myocardial cells

- Muscarinic receptors

- Hyperpolarization -> flowering firing rate

ATP sensitive - IK-ATP

- Inhibited by ATP presence f

- Hyperpolarization
Calcium Channels

L type - activated at 20 to 0 mV

- Inactivated at 0 to -50 mV

- Closure is triggered at high intracellular

Ca concentration

- Slow current

- Fast response fibers: platou phase

- Slow response fibers: depolarization

T type - activated at - 55 mV

- Inactivated at sufficient depolarization

Hyperpolarization activated inward - If for funny

- Mainly Na

- Spontanous depolarization

Na/K ATPase - alpha subunit: binding of 3 Na, 2K and

ATP binding and hydrolysis

- Beta subunit -> regulatory

Ca ATPase - one binding site

- Less important than Na/Ca exchanger

- Sarcolemma, but also sarcoplasmic

reticulum

Na/Ca exchanger - expells one Ca for the entering of three

Na

Na/H exchanger - expells one H for one Na entering

- Activated by acidic intracellular space

during myocardial ischemia

- Problem: inactivity of Na/K ATPase

during ischemia, leading to Na overload

Action potentials

Fast response - atrial and ventricular myocardium

- Mainly Na and K currents

- IKur only in atrial myocytes

- IK and L Type Ca current-> Platou

phase

Slow response - sinuatrial and antrioventricular node

cells

- Mainly funny and Ca currents

Lidocaine Blocks INa -> suppressing arrhythmias

Beta blockers (metoprolol or bisprolol - Blocks sympathetic nervous system

adrenergic receptors-> inhibit If (also
reduces cardiac contractility)

- Ivabradine selectively blocks If

Amiodarone and sotalol - prolonging action potentials by blocking

IK

- Stopping arrhythmia without influencing

conduction velocity

Adonosine - stimulating IK-Ach current

 Ca channel blockers (verapamil an - decreased depolarization in pacemaker
dilitiazem) cells

- Negative inotropic effect on contractility

- Inhibts smooth muscle cells in arterial

walls (nifedipine only acts on vessels ->
increase in heart rate

Na/K ATPase blockers (digital glycoldes, - inhibit Na/Ca exchanger

like digoxin) - Increased contractility -> positive

inotropic

- Conduction delay in atrioventricular

node

electric- heart Excitability - bathmotropy phases

Absolute refractory period - no reaction on stumuli, regardless of the

intensity

- Inactivity of Na channels in fast

response fibers, reactivation at -40 to
-65 mV

Effective refractory period - local excitability with high intensity

electric stimuli

Relative refractory period - action potential can only be elicited with

an higher stimulus then normal

- Slower action potentials with small

amplitude

Supernormal period - higher excitability

- No cardioversion
Duration - voltage dependent in fast response
fibers, because Platou phase allows Na
channels to recover

- Time dependent in slow response

fibers, because without platou phase Ca
channels need to recover, before new
action potential can be elicited

- Increased activation rates leading to Na

accumulation inside the cell, which in
turn leads to higher Na/K ATPase
activity -> deficit of positive ions,
accelerates repolarization

- Slow kinetics of Ca channels doesn’t

allow them to counterbalance K efflux
(fast kinetics) -> accelerating
repolarization

- Class 3 antiarrythmic drugs like

amiodarone block IK channels ->
prolonging depolarization

Automaticity (chronotropy)

Influenced - decreased slope of depolarization

- Increased treshold of ICa-L

- Decreased maximum diastolic potential

 Conductivity (dromotropy) - gap junctions

- Ratio between longitudinal and lateral

conduction velocities:

- 3:1 in the ventricles

- 10:1 in the atrias

Myocyte

Myosin Types - isoenzyme V1 - two alpha chains (high

ATPase activity)

- Isoenzyme V2 - alpha and beta chain

(lower ATPase activity)

- Isoenzyme V3

- Atria: isoenzyme V1

- Ventricles: all isoenzymes in humans,

mainly V1 in small animals

Tropomyosin - blocking interaction between actin and

myosin

Troponin - Troponin C -> binds Ca

- Troponin T -> binds troponin to

tropomyosin

- Troponin I -> inhibits interaction

between myosin and actin

Titin - anchores myosin to the Z line

Electro-mechanical coupling - inflow of Ca through mainly L-type

channels

- Calmodulin activates the CA dependent

ATPase pump (this is most important for
Ca transport into the sarcoplasmic
reticulum)

Sounds S1 - vibrations of ventricular wall

- S1a: isovolumic contraction

- S1b: rapid ejection

- S1c: rapid to slow ejection

S2 - closure of sigmoid valves

- S2A: aortic

- S2P: pulmonary

- Longer during inspiration

S3 - rapid ventricular filling

S4 - atrial systole

Volume Preload End diastolic volume

pressure curve

Afterload Aortic pressure, discountcted during

diastole
Evaluation of Pre and after load Determination of end diastolic and and
the mechanics systolic volume

Contractility - Maximum velocity of intraventricular

pressure rise ( independent from
afterload)

- Maximum instantanous velocity of

intraventricular pressure rise just before
aortic valve opening (>1200 mmHg/sec)

Ejection phase Ejection fraction (55-75%)

Ventricular diastolic function - isovolumic relaxation time

- Ventricular stiffness (dP/dV)

- Ventricular compliante (dV/dP)

Cardiac output - Fick principle

- O2 uptake by the lungs in 1 min (VO2) /

- Arteriovenous O2 difference (ml/L)

(Conc.O2PV-Conc.O2Pa)
Carotidogramm - half rise time - contractility of left
ventricle

- Pre ejection time (time of

electromechanical systole, Q-S2 -
Ejection time, E point to dicrotic notch)

Cardiac Sympathetic - B-adrenergic stimulation

regulation - -> Gs protein -> Phosphorylation

- If, ICaL, INa -> increased HR,

conductivity, inotropy

- Myosin, TnC -> increased inotropy

- Phopholamban -> increased lusitropy

- Enzymes -> increased metabolism

- a- adrenergic stimulation

- -> Gq protein -> C phospholipase

- IP3 -> increased inotropy

- DAG -> cell proliferation

Parasympathetic - decreased NA release

- Gi proteins -> decreased cAMP, IK-Ach

- cGMP -> decreased Ca

Catecholamines - noradrenalin -> A adrenergic

- Adrenalin -> A and B adrenergic

- Dopamine -> A and B adrenergic,

dopamine

Renin angiotensin - angiotensin 2

- -> type 1 receptors: IP3 DAG

Nitric oxide - positive inotropic

- Positive lusitropic

- Positive chronotropic for low NO

- Negative chronotropic for high NO

- Decrease of myocardial O2
consumption

Adenosine - vasodilation

Opiod - increasing parasympathetic tone

Kidney Macula densa - high blood pressure leads to:

- High glomerular flow and glomerular

capillary pressure leading to

- High GFR leading to

- Delivery of NaCL to macula densa

- Decreasing glomerular capillary

pressure

- ATP secretion -> break down to

Adenosine

- -> afferent vasoconstriction (unlike in

other vessels) which reduces

- Glomerular blood flow

- low blood pressure

- Decrease in delivery of NaCL to macula

densa

- Vasodilation in afferent arterioles

- -> increase in glomerular blood flow

- Renin release
Innervation - sympathetic

- Reducing renal blood flow

- Na reabsorbtion

- Increase in Renin release

- Most of kidney function are regulated by

hormones

Maintance of body homeostasis - excretion of K, Na, Ca, Mg, phosphate,

Cl

- Control of pH, by excretion of H and

HCO3

- Controlling osmolality reabsorption of

water

- Controlled by antidiuretic hormone from

hypothalamus -> water reabsorption

- Also controlling blood pressure this way,

in case of high BP or release of renin in
case of low BP

Hormone production - Calcitrol (active vitamine D) -> raising

Ca levels together with parathyroid
hormone

- Erythropoietin -> stimulates RBC

production as reaction to hypoxia

- Renin -> catalyzes angiotensinogen into

angiotensin 1 -> catalyzed into
angiotensin 2 -> Aldosteron production
in adrenal cortex

- -> increase of water and Na

reabsorption
Glomerular ultrafiltration - GFR = Kf x UP

- Kf -> glomerular ultrafiltration coefficient

- UP -> ultrafiltration pressure

- GFR = Kf x (Pgc - Pbs - COP)

- Pgc -> glomerular capillary hydrostatic

pressure (55 mmHg)

- Pbs -> bowmans hydrostatic pressure

(15 mmHg)

- COP -> colloid osmotic pressure by

plasma proteins in glomerular blood
(30mmHg)

Nephritic disease - RBC and red cell casts in urine

- Fall in GFR
Nephrotic disease - proteinuria (3,5 g/d per 1,73 m2 body
surface) hypoalbuminemia (3 g/dl),
generalized edema

Glomerulonephritis - proteinuria and or hematuria

- Progressive loss of functioning

nephrons

Clearance - Cx= (Ux x V)/Px

- Cx -> Clearance

- Ux -> urine concentration of this

substance

- Px -> plasma concentration of

substance

- V -> urine flow rate (urine volume/time)

- Substance usually inulin

- Usually 110 +- 15 ml/min young women

- 125 +- 15 ml/min young men

- Decrease after 45-50y til 30/40 % at 80y

Calculation - filtered inulin = Pin x GFR

- Pin -> plasma concentration of inulin

- Excreted inulin = Uin x V

- Uin -> concentration of inulin in urine

- V -> urinary flow rate

- Filtered inulin = excreted inulin

- Cin = GFR = UinV/Pin

Creatine - inverse relationship

- A drop in GFR leads to a significant

increase in plasma Creatine

Na reabsorbtion - Proximal tubules

- reabsorbtion into epithelial cells

because of there low Na concentration

- Na/K pump transports Na into blood

- K is not reabsorbed in proximal tubules,

but diffuses back to blood

- N/H+ antiporter
 Na contransport for - Proximal tubules

- Glucose

- Amino acids

- Vitamins

- Electrolytes

- Diffusion into blood

- HCO3 cotransport into blood

Other transporters - reabsorption - water diffuses into epithelial cells by

osmotic pressure due to Na and
accompanying solutes

- Cl is antiporter due to a base antiporter

Other transporters - into blood - Cl is cotransportet with K

Urea - coabsorbed with water in proximal

tubules

- Secreted in thin ascending loop of henle

Loop of hence Descending limb of Henle - highly water permeable

- Impermeable for solutes

Ascending limb of Henle - highly permeable for Na and Cl

- Moderately permeable to urea

- Almost completely impermeable for

water

- Na-K2-Cl contrasporter (inhibited by

loop diuretic drugs)

- Na, K, Ca, Mg, NH4 are driven out of

the lime by potential difference between
lumen and blood, reabsorbed between
cells

Distal nephron - reabsorption of 9 % of Na and 19 % of

water, compared to 70 % for both in
Proximal convoluted tube

- Steep gradient

- Na-Cl contransport (inhibited by thiazide

diuretics) -> Calcium sparing

- Aldosterone increases Na reabsorption

and K and H secretion arginine
vasopressin increases water
reabsorption

K secretion - Na/K ATPase

- Lumen negative trasepithlial potential

- Increased permeability of luminal cell

membrane

- High flow rate

ADH - lead to water permeability in loop of
Henle

- Deficiency leads to diabetes insidious

Renin- Renin - release and activation of RAAS is
angiotensin- triggered by

aldosteron- - Macula Densa: reduced Na and Cl

system concentration in distal tubules

- Low BP in afferent arterioles

- Neural mechanisms: sympathicus

 Angiotensin 2 - reduced renal perfusion ->
vasoconstriction of efferent arterioles

- Increases tubular Na reabsorption

- Reduces medullary blood flow ->

increases Na reabsorption and urine
concentration

- Vasoconstrictor

- Aldosteron release

- Stimulates blood pressure, increase in

thirst and salt appetite

Aldosteron - kidneys: increases expression of Na/K

pumps, Increases luminal permeability
of Na

- Sweat glands: stimulates Na and water

reabsorption in exchange for K

- GI tract: stimulates Na and water

reabsorption in exchange for K

Circulation Velocity flow relationship - v = Q/A

- v -> velocity of blood flow

- Q -> circulatory flow

- A -> vascular section area

- Inverse relationship between velocity

and cross sectional area on the system

Types of blood flow - turbulent: high velocity

- Laminar: usual

- Re= (v x p x r)/ n

- Re -> Reynolds number

- v -> velocity of blood flow

- p -> vessel density

- r -> vessel radius

- n -> blood viscosity

Pressure- velocity relationship - constant = ps + 1/2 pv^2

- ps -> static pressure

- 1/2 pv^2 -> kinetic energy

Pressure- flow relationship - Q = pressure gradient / R

- Q -> circulatory flow

- R -> Resistance
Vascular resistance - R = 8/pi x (n x L)/r^4

- R -> resistance

- n -> blood viscosity

- L -> vessel length

- r -> radius

Equation of poiseulli - Q = pi/8 x (p gradient x r^4)/(n x L)

- Q -> circulatory flow

- r -> radius

- n -> blood viscosity

- L -> vessel length