Experimentally induced
arrhythmias in rat
•Adrenergic hyperstimulation
•Hyperkalemia
•Block of cardiac calcium channels
Normal ECG curve in human…
…and in rat heart
Note the missing ST segment (phase 2 = plateau of the ventricles)
SA nodal rate about 300/min
Vegetative nervous system and the heart
Receptors:
Sympathetic nervous system:
1 - positively inotropic, dromotropic
and chronotropic (mainly through
opening of pacemaker F-channels and
Ca2+ channels in SA node, AV node
and working myocardium)
2 – apical myocardium, vessels –
vasodilatation
α1, α2 – vasoconstriction (lower
effect in coronary vessels,
norepinephrine effect)
Parasympathetic:
M2 – negatively chronotropic
(inhibits opening of Ca2+ channels,
opens KAch channels)
Effects of vegetative nervous system on pacemaker cells
Heart during catecholamine overload
↑ heart rate
↑ contractility
– Increase systolic function at the expense of diastolic dysfunction
Calcium overload of cardiomyocytes
– DAD → premature beats
– ↑ oxygene consumption → ischemia
β2-receptor phosphorylation – transition from Gs to Gi
signalization → decreased contractility in the apex
– but it acts against Ca overload and necrosis
Vasoconstriction?
Potassium
The most abundant intracellular cation (98%
intracellulary)
Most willingly passes cellular membrane
Concentration gradient is maintained by Na+/K+ ATPase
The extra/intracellular distribution is regulated by
hormones (insulin, adrenaline, aldosterone) and pH
Its total body content depends mainly on renal functions
Both hyper- and hypokalemia are frequent conditions in
clinical practice and both are proarrhythmogenic
Potassium and the membrane potential
Positively charged, intracellular ion: ↑
concentration → lowering of membrane
polarity (analogy of a small and a large basin
connected by a hose)
Various functionally different K+ channels
By various mechanisms, potassium
increases the permeability of K+ channels
– direct binding
– competion with Mg2+ that closes the K+ channels
– changes in expression and translocation
Effect on sodium channels
Mild hyperkalemia – easier excitation
Severe hyperkalemia – block of a portion of Na+ channel
– Slower conduction
– Finally the threshold voltage „runs away“ from baseline voltage and the
depolarization is no longer possible
Mild hypokalemia – hyperpolarization
Severe hypokalemia – lack of substrate for the Na/K ATP-ase →
lower polarity, easier excitation
Potassium – main effects
Hyperkalemia
– Peaked T wave (dif. dg. hyperacute phase of MI)
– Wide QRS (may merge into sinusoid wave with T)
– Widening, flattening and event. disappearing of the P wave (but sinus
rhythm remains for a long time)
– Higher excitability at the beginning, then lower, diastolic arrest in the end
(heart is depolarized compared to the normal state)
– ↑ risk of re-entry (↑ differences in conduction velocities)
Hypokalemia
– Flat, wide T-wave
– Pathologic U wave (delayed repolarization), lengthening of QT (QU) interval
– EAD, torsades de pointes
– Sometimes, peaked P is present
– ↑ risk of re-entry (↑ differences in refraktory periods)
– First lower excitability (hyperpolarization), then higher
Changes of ECG in hyper-
/hypokalemia
Calcium
Ion that is necessary for muscle contraction
Intracellulary, it is present in very low concentration
(making high gradient between cytoplasm and cell)
In cardiomyocyte and skeletal muscle, it is also present
in sarcoplasmic reticulum
Cardiomyocyte (and smooth muscle cell) bears specific
Ca2+-channels, that are necessary for phase 2 (plateau),
pacemaker function and conduction through slow cells
They can be blocked by specific agents to slow the heart
rate and enhance vasodilatation by smooth muscle
relaxation
Calcium and the membrane potential
Extracellular ion – Membrane potential gets into more
negative values
During the action potential, Ca2+ activate potassium (and
chloride) channels, which shortens the phase 2 →
repolarization leads into the closing of Ca2+ L-channels
– the proces is impostant for maintaining the calcium
homeostasis in the cell
– in extreme hypercalcemia, phase 2 may be missing
– opposite effect may be present in hypocalcemia
Mechanical effects
– Extreme hypercalcemia: triggered activity (DAD), systolic
arrest (very rare)
– Extreme hypocalcemia: triggered activity (EAD),
hypocalcemic cardiomyopathy, heart failure
Blocking the calcium channels
Verapamil – class IV antiarrhythmic drug
Tissue distribution roughly symmetrically in the
heart and smooth muscle
Indikace: antiarrhythmic, antihypertenzive
(rather rarely), local vasodilatant
Overdose – effect mainly on the slow cells
– SA arrest and block
– AV block
– Low contractility
– Long QT may sometimes be present
ECG in calcium levels changes
The Ca2+ channels-blockers mainly induce the conduction (SA or AV)
node blocks and slower pacemaker function
Practical