The law of periodic inexcitability of

the heart; effect of ions on the

heart;effect of ANS on the heart
Voltage gated Na+ channel
⚫Alpha subunit- functional

⚫4 subunits, I-IV, each having a transmb segments, S1-

S6

⚫S4- voltage sensor

⚫Beta subunit- adhesion role

Functional structure
⚫1. ionic selection filter- loop between S5-S6 segments
of each subunit- external pore is narrow.

⚫2. voltage sensor- diagrams present only one subunit-

for simplification

!!!!!!!!!Really- more voltage sensors should be

activated in order for the channel to get open
⚫3. Gate
⚫Activation(M)- open/close is voltage gated

⚫Inactivation (H)- limits the period in which a

channel stays open, stoping re-stimulation
Ion channel states
⚫3 states

⚫Closed but activable

⚫Active opened

⚫Closed inactive
Voltage sensor and activation gate opening
⚫ -70 mV- channel opened
⚫ Depolarisation- opening of
the activation gate- voltage
sensor moves upward and
drags the gate along
⚫ + 30 mV- inactivation gate
closed- remains closed
until the cell is repolarised
and reaches at least -40
mV
Law of periodic inexcitability of the heart
⚫while depolarized, the heart doesn’t react to any other
stimulus, being in the absolute refractory period

⚫short period of time, at the end of the action potential,

when the cardiac cell can respond to additional
stimuli, generating a premature depolarization and a
premature contraction, called extra-systole or
premature beat, which is usually followed by a
compensatory pause.
Cause
⚫In the absolute refractory period all fast Na+-channels
are voltage-inactivated and closed, which prevents
sustained tetanus. As a consequence, no stimulus is
sufficient to trigger contraction regardless of size.
⚫In the relative refractory period, enough of the fast
Na+-channels are recovered, so that a sufficiently large
stimulus can break through and produce an action
potential although smaller than normal.
⚫PRA- 250 msec
Effect of ions on the heart
⚫Hyperpotasemia (hyperkalemia): decline in heart rate and
contractility; for high K+ levels, the heart stops in diastole.
⚫Hypercalcemia: rise in heart rate and contractility; at very
high Ca concentration, the heart stops in systole (rigor
calcis).
⚫Acidosis (lactic acid): decline in heart rate and
contractility; high acidity can irreversible damage the
heart.
⚫Ions effects on the frog heart can be simulated on a
computer using the PhysioEx 8.0 software.
Hyperkalemia
⚫ Driving force of an ion depends on two factors, voltage and
concentration gradient.

⚫ For K voltage gradient is pushing K into the cell but the

concentration gradient is driving K out of the cell.
However, the total driving force for K is out of the cell
because the concentration gradient is that strong.

⚫ When there is an increase in K on the outside, the driving

force for K decreases🡪 K inside the cell🡪 depolarisation
Hyperkalemia
⚫More positive ions inside🡪 depolarization reaching
threshold🡪 Na+ fast channels opened

⚫Cell cannot regain resting potential (K+ is not

expelled anymore, and the voltage for activating the
Na+ channels is -40mV)🡪 arythmyas and heart arrest
⚫decrease in both the resting membrane potential
⚫phase 2 and 3 of the action potential have a greater slope in
the setting of hyperkalemia compared with the normal
action potential
Causes may be:
⚫adverse effects of medication (ACE inhibitors,
trimethoprim, digitalis),
⚫ reduced kidney function,
⚫mineralocortcoid deficiency,
⚫rhabdomyolysis,
⚫KCl intake (this is the substance injected in death
penalty)
Symptoms
⚫not specific
⚫generalised fatigue,
⚫muscle paralysis,
⚫dyspnea,
⚫chest pain,
⚫nausea/vomiting,
⚫paresthesias.
Role of calcium
⚫A normal serum calcium level is 8-10 mg/dL (2-2.5
mmol/L) with some interlaboratory variation in the
reference range

⚫Hypercalcemia is defined as a serum calcium level

greater than 10.5 mg/dL (>2.5 mmol/L).

⚫Primary hyperparathyroidism and malignancy account

for >90% of reported cases
Acidosis on the heart
- High H+ outside the cell🡪 H+ enters the cell in order to
buffer it (how?)
- K+ is pushed outside in order to maintain the
electrical equillibum, so it leads to hyperkalemia
- Less K+ inside🡪 the resting potential becomes more
electronegative🡪 harder to reach depolarisation
Acidosis on the lung
⚫hyperventilation (why?)

⚫lowers Hb affinity for oxygen

Effect of autonomic nervous system mediators
on the heart activity. Vagal stimulation.
Autonomic nervous system and the heart
⚫Centers
⚫Sympathetic- lateral horn of the spinal cord- first thoracic
segments
⚫Parasympathetic- dorsal nucleus of the vagus nerve-
medulla oblongata

⚫Efferent pathway
⚫Sympathetic- preggl fibres synapse in the paravertebral
ganglia🡪 postggl fibres (cardiac nerves)
⚫Parasympathetic- preggl fibres synapse in the intramural
ganglia🡪 short postggl fibres
Sympathetic system effects on the heart=
STIMULATION
⚫NEUROTRANSMITTER= NORADRENALINE
⚫RECEPTORS:
⚫VENTRICLE- BETA1
⚫ATRIA- BETA2

⚫EFFECTS- using G-protein pathway:

⚫Modulation of ionic channels activity
⚫Indirect effects by adenilatcyclase- cAMP system🡪
PKA activation🡪 fosforilation of different proteins
Adenilatcyclase cAMP
⚫Ionic channel phosophorilation🡪 influence of the
electrical phenomena

⚫Contractile protein phosphorilation🡪 influence of the

mechanical phenomena

⚫Intracellular enzyme phosphorilation- energy

producing chemical reactions
Sympathetic nervous system and the heart
rate
⚫Heart rate🡪 sympathetic neurons to the SA node
increase the frequency of action potentials.
⚫Postganglionic neurons release norepinephrine
which binds to ß1 receptors on the SA nodal cells
activating the cAMP second messenger system.
⚫cAMP augments the opening of funny channels and T-
type Ca++ channels which increases the slope of
spontaneous depolarization. The frequency of action
potentials increase and increases the heart rate.
Heart rate change
Sympathetic system and contractility
⚫ Sympathetic neurons release norepinephrine which binds to ß1
adrenergic receptors. These receptors activate adenylate cyclase that
catalyzes synthesis of cyclic AMP. Increased cyclic AMP has the following
effects:
1. Phosphorylation of L type calcium channels in the plasma membrane
causes the calcium channels to remain open longer during action potentials.
2. Phosphorylation of proteins in the sarcoplasmic reticulum enhances
release of calcium from the sarcoplasmic reticulum. 
3. Phosphorylation of myosin increases the rate of myosin ATPase which
increases the speed of crossbridge cycling. 
4. Phosphorylation of calcium pumps in the sarcoplasmic reticulum increases
the speed of calcium re-uptake which increases the rate of relaxation. 
Contractility change
Parasympathetic system and the effect on
the heart
⚫ NEUROTRANSMITTER= ACETYLCHOLINE
⚫ RECEPTOR= MUSCARINIC M1- HIGHER DENSITY (2-5x)
AT ATRIAL LEVEL!
⚫ EFFECT= INHIBITION
⚫ EFFECTS:
⚫ Presynaptic level- low noradrenaline release
⚫ Directly activates K channels (special type of K channel=
KAch)🡪 hyperpolarisation
⚫ Inhibition of adenilatcyclase enzyme (Gi proteins)🡪 low cAMP
⚫ Stimulation of cGMP intracellulary🡪 low Ca2++ channels
activity
Effects of parasympathetic nervous system🡪
affects frequency and conduction
⚫Decreased activity of T Type Voltage Gated Calcium
Channels
⚫Decreased Dromotropy
⚫Increased IK through acetylcholine- activated K
channel
⚫Hyperpolarization
⚫Decreased Chronotropy
⚫Decreased Chronotropy
⚫Decreased Funny Current at SA node (Negative
Chronotropy)
⚫ If vagal stimulation is excessive, the heart stops beating.
After a short time (few seconds), the ventricles begin to beat
again, at a lower frequency. This phenomenon is called
vagal escape and may be the result of an idioventricular
rhythm, acetylcholine depletion or sympathetic stimulation.
⚫ In clinics, parasympathetic stimulation is obtained through
the different vagal maneuvers: Valsalva maneuver; Dagnini –
Aschner (oculo –depressor reflex); carotic sinus massage;
viscero–vagal reflex.
Valsalva
⚫When a person forcefully expires against a closed
glottis, changes occur in intrathoracic pressure that
dramatically affect venous return, cardiac output,
arterial pressure, and heart rate. This forced expiratory
effort is called a Valsalva maneuver.

⚫Cause- baroreceptor reflex

⚫Similar changes occur whenever:
⚫a person conducts a force expiration against either a
closed glottis or high pulmonary outflow resistance
⚫when the thoracic and abdominal muscles are strongly
contracted.
⚫ This can occur when a person strains while having a bowel
movement. 
⚫ Similar changes can also occur when a person lifts a heavy
weight while holding their breath.
Baroreceptor reflex
⚫ Afferent-
⚫ Carotid- nv IX (nv
of Hering)
⚫ Aorta- nv X
⚫ Center- regulatory
center in the
medulla oblongata
⚫ Efferent
- motor fibres of nv X
- Cardiac
sympathetic nv
Carotid sinus massage
⚫Massage of the carotid sinus, carotid sinus massage
is used to diagnose carotid sinus syncope and is
sometimes useful for differentiating supraventricular
tachycardia (SVT) from ventricular tachycardia. Like
the Valsalva maneuver, it is a therapy for SVT. It is less
effective than pharmaceutical management of SVT
though is still the preferred first-line of treatment in a
hemodynamically stable patient.
Disease of the carotid sinus
⚫The carotid sinus can be oversensitive to manual
stimulation, a condition known as carotid sinus
hypersensitivity, carotid sinus syndrome or
carotid sinus syncope, in which manual stimulation
causes large changes in heart rate and/or blood
pressure. This classically presents as a patient who has
"fainted" on several occasions while shaving, or in
some other way coming into contact with their carotid
sinus.
Oculocardiac reflex
⚫The oculocardiac reflex, also known as Aschner
phenomenon, Aschner reflex, or Aschner-Dagnini
reflex, is a decrease in pulse rate associated with
traction applied to extraocular muscles and/or
compression of the eyeball.

⚫May also be used as therapy for

certain arrythmias
Viscero-vagal reflex- Goltz