Autonomic Nervous System Lecture Notes PDF

Aurora Killi 30.08.21 Autonomic nervous system Lecture 1 Somatic Autonomic Location of the highest Cerebral cortex → Conscious con...

Aurora Killi 30.08.21 Autonomic nervous system Lecture 1 Somatic Autonomic Location of the highest Cerebral cortex → Conscious control Hypothalamus → Subconscious center control We can send impulses to our muscles Even though the autonomic nervous to make them contract system only allows for subconscious control, we can make a conditional reflex which can modify the autonomic reactions in cases that are repeated many times throughout life. Location of the lowest Spinal cord Parts of spinal cord center Somatic centers are in all the Autonomic centers are not present in segments of the spinal cord and all the spinal cord segments. Centers cranial nerve nuclei which performs are present in the thoracic, lumbar, somatic functions (sensory and motor and sacral region. No centers in the function) cervical spinal cord. There are also autonomic centers in IV cranial nerve nuclei which contain autonomic fibers Reflex arch For receptors and afferent pathway there is no difference between the somatic and autonomic reflex arches. The afferent part belongs to the somatic nervous system, and we can trigger both reflexes. The differences begin form the reflex center. Reflex arch differences Somatic nervous system Autonomic nervous system Location of efferent Anterior horn Lateral horn neuron cell body Alpha or gamma motor neuron Efferent pathway Made up of a single neuron Two neuron chain 1st neuron: Preganglionic neuron (leaves the spinal cord and make synapse with second neuron) nd 2 neuron: Postganglionic neuron (outside the spinal cord) Nerve fiber type Alpha motor neuron: Aα fiber Preganglionic fiber: B group (efferent part) Gamma motor neuron: Aγ fiber (myelinated) Postganglionic fiber: C group High speed of impulse conduction (unmyelinated) 1  Aurora Killi 30.08.21 Effector Skeletal muscle Cardiac muscle cell Aα fiber innervates extrafusal fiber Smooth muscle cell Aγ fiber innervates intrafusal fiber Secretory cell Neurotransmitters and Acetylcholine binds to nicotinic Acetylcholine binds to muscarinic receptors in synapse receptor (ionotropic receptor, Na+) receptor (metabotropic, G-protein coupled). Norepinephrine and In the neuromuscular synapses, only epinephrine binds to alpha- or beta- excitation is possible adrenergic receptors (metabotropic) Receptors can be either excitatory or inhibitory Reflex time Fast Longer reflex time There is at least one more synapse compared to the somatic, also they consist of B and C fibers that are slower conducting fibers. Metabotropic receptors are slower. Cotransmission Not possible Possible Acetylcholine + VIP NE + ATP + Neuropeptide Y The autonomic nervous system has two functional parts: Sympathetic Parasympathetic Sympathetic nervous system Classical innervation Highest centers: hypothalamus Lowest centers: spinal cord T1-L3 in the lateral horns Ganglia: Paravertebral ganglions. Preganglionic fibers make synapses in the sympathetic chain of ganglions. These are also Important: called paravertebral ganglions and are located parallelly to the 1 preganglionar neuron of one spinal cord. When the preganglionic fibers enter the ganglion preganglionar fiber innervates chains, it can either go up and synapse in segment level above, or it about 15-20 postganglionar neurons. If you stimulate one can go down and synapse in a ganglion of a lower region. In some neuron in the later part of the cases, the preganglionic fibers go through the sympathetic chains of spinal cord you achieve 15-20 ganglions without synapsing and makes a synapse with the postganglionar neurons active postganglionic neuron in the prevertebral ganglion (far from the spinal cord). Preganglionic fibers: The preganglionic fibers are most often shorter than the postganglionic fiber. Usually, one preganglionic neuron innervates 15-20 postganglionic neuron. Neurotransmitters: o In ganglia: acetylcholine → nicotinic receptor o In synapse with the effector: Norepinephrine or epinephrine → α or β adrenergic receptors o In synapse with the effector: Acetylcholine → muscarinic receptor (in sweat glands and some blood vessels) Norepinephrine is the most common neurotransmitter in synapse with the effector. The sympathetic fibers that release acetylcholine are found in the sweat glands and in some blood vessels of skeletal muscles, coronary circulation, and brain. This causes the blood vessels to make during general 2  Aurora Killi 30.08.21 sympathetic activity, so they prevent restriction of blood flow to these organs which is crucial in fight or flight situations. Sympato-adrenal system The sympathetic nervous system + adrenal medulla makes up the sympato-adrenal system in which the sympathetic nervous system innervates the adrenal medulla. The preganglionic neuron cell body is in the lower thoracic segments in the later horn The preganglionic fibers come to the adrenal medulla and makes a synapse with the postganglionic neuron called chromaffin cells. These cells are modified postganglionic neurons. Adrenal medulla during embryonic life, develops like an autonomic (sympathetic) ganglion. But during the development postganglionic fibers are lost, so these neurons does not have the fiber that should be there for other ganglions. For this reason, substances that are released at the end of sympathetic nerve fibers which are synthesized by chromaffin cells, are released into the interstitial space and blood. They secrete in the blood as hormones and can reach all cells in our body. Epinephrine is the substance that is released the most by the adrenal medulla. It produces about 80% epinephrine while the remaining 20% are norepinephrine, dopamine, and other metabolites. How are chromaffin cells activated? The sympato-adrenal system still functions as the autonomic ganglion. The preganglionic fiber still releases acetylcholine which binds with the nicotinic receptor on the surface of the chromaffin cell, to stimulate hormone production in the blood. This exclusion can also widen the effect of the sympathetic nervous system, not only this previous schematic drawing. Adrenal medulla produced hormones can reach all cells in our body and cause sympathetic effect there. Function of adrenal medullar hormones: Increase metabolic intensity o Increase fat breakdown in adipose tissue o Increase glucose level in blood Increase heart rate and force of contraction Increase blood pressure 3  Aurora Killi 30.08.21 Decrease motility and secretion in gastrointestinal tract Dilate bronchi to stimulate air transport Dilate pupils to increase visual range and relax ciliary muscle Increase sweating intensity, stimulating profound secretion in the body Stimulate platelet aggregation Parasympathetic nervous system Classical innervation Highest centers: hypothalamus (mostly in the anterior part) Lowest centers: located in two divisions o Spinal division: S2-S4 → pelvic region o Cranial division: III, VII, IX, X o III, VII, IX: → eyes, glands in head o X → almost all organs Ganglia: intramural ganglia or prevertebral ganglia. The preganglionic fibers usually synapse in the ganglion located in the wall of innervated organ. Ganglia located here are called intramural ganglions. In some cases, and especially in the head region, ganglions are not located in the wall of innervated organ but rather on the outside, these ganglions are called prevertebral ganglions. Preganglionic fibers: preganglionic fibers are longer than postganglionic Neurotransmitters: In ganglia, the neurotransmitter and receptor are the same whether it is sympathetic or parasympathetic nervous system. o In ganglia: Acetylcholine → nicotinic receptor o In synapse with effector: Acetylcholine → muscarinic receptor Divergence: one preganglionic fiber usually activates 1-2 postganglionic fibers. Therefore, the effect is less spread compares to the sympathetic nervous system. We do not have any gland that can produce acetylcholine as a hormone into the blood stream. Therefore, the parasympathetic nervous system effect is not present some places in the body. Synthesis and degradation of norepinephrine and epinephrine Synthesis Epinephrine is synthesized from tyrosine, which is converted into norepinephrine. With the help of phenylethanolamine-N-methyltransferase, norepinephrine is converted into epinephrine. Phenylethanolamine-N-methyltransferase activity and concentration in varicosities in the presynaptic terminal of adrenergic nerves is very minor Therefore, the majority of neurotransmitter released from the nerve terminal is norepinephrine. Adrenal medulla (exception!): the adrenal gland contains high concentration of phenylethanolamine-N-methyltransferase, and thus the predominant hormone released from it is epinephrine Degradation: Norepinephrine and epinephrine can be degraded by two enzymes: 1. Monoamine oxidase (MAO): present in the neuronal tissue. In varicosities of the autonomic nervous system and in the presynaptic terminal in the brain, which release epinephrine 2. Catechol-O-methyltransferase (COMT): present in non-neuronal tissue and in circulatory system. Breaks down circulatory hormones 4  Aurora Killi 30.08.21 Whatever enzyme that is acting on the epinephrine or norepinephrine, they are both broken down to the same final product called vanillyl mandelic acid (VMA), which is excreted through the kidneys into the urine. VMA concentration is measured in the urine if we suspect greater norepinephrine or epinephrine synthesis in the body and degradation of them. This can happen in tumors that are producing more of one of the substances. This can happen in the central nervous system, neuroblastoma or tumors that are growing in the adrenal gland. Adrenergic receptors and effects of their activation All adrenergic receptors which naturally bind epinephrine and norepinephrine from the sympathetic nervous system, are divided into two groups: α or β adrenergic receptors α adrenergic receptors α1 α2 IP3, DAG ↑ cAMP ↓ Upon activation, these receptors lead to IP3 and Upon activation leads to decrease of cAMP DAG generation in the effector cell. concentration in the cell. This receptor is found in Smooth muscle cell (in blood vessels) → two places: contraction Presynaptic terminal → inhibition of Glands → inhibition of secretion through the norepinephrine vascular effect Platelets → stimulates aggregation β adrenergic receptors β1 β2 β3 cAMP ↑ cAMP ↑ cAMP ↑ In heart: Smooth muscles → relaxation Adipose tissue → triggers Heart rate ↑ lipolysis (fat breakdown) Force of contraction ↑ Excitability and impulse conduction speed ↑ Relaxation rate ↑ In kidneys: In juxtaglomerular cells activation of this receptor leads to renin secretion which stimulate production of vasoconstrictor angiotensin Epinephrine Norepinephrine Favors β1 and β2 Favors α1 and α2 In high concentrations it can also activate α1 Can activate β1 and α2 If we look at the effect on the cardiovascular system At the first schematic representation we can heart rate. In the second illustration we can see blood pressure, where the top-line represent systolic blood-pressure, the bottom line is diastolic blood-pressure, and the yellow line is mean arterial blood-pressure. In the last chart we can see peripheral resistance which mainly depends on the blood pressure radius. Meaning if the blood vessel constrict it decreases blood flow to the periphery and we say it resist to the blood flow out of the big arteries. 5  Aurora Killi 30.08.21 If we then inject substances in equal doses in the circulation. If we inject norepinephrine at the rate of 10 mg/min. We can then see it binds to the α1-receptors on smooth muscle cells on blood vessels and constricts them. That is why peripheral resistance increases which leads to the blood pressure increasing in the big arteries since they cannot pour blood for the microcirculation further. Since blood pressure in the big arteries increases the receptors signals to the brain that it should inhibit heart function, not inject so much blood in the arteries which already have an overflooded of blood. That is why by the injection of norepinephrine we will observe heart rate decrease. If we inject epinephrin it will bind to 𝛼1-receptors which stimulates contraction of smooth muscle cells in blood vessels. At the same time, it will also bind to the 𝛽2 -receptors in blood vessels which causes relaxation of smooth muscles cells. 𝛽2 -receptors are in higher concentration than 𝛼 -receptors in blood vessels of skeletal muscles, in the coronary circulation and in the small circuit. This means that there is a large area of the body that achieves vasodilation due to the epinephrine. And because of this it will cause peripheral resistance to decrease and more blood from big arteries can flow to the periphery. Therefore, the blood pressure only increases slightly. Since there is a slight increase of blood pressure, the negative feedback of heart is not realized which means that epinephrine can freely act on the 𝛽1 -receptor and increase heart rate. Adrenergic synapse 1. From the extracellular space, tyrosine is transported into the varicosity/nerve terminal where it is converted into dopamine 2. Dopamine is transported into a vesicle with the monoamine transporter 3. Dopamine is converted into norepinephrine 4. Upon stimulation, norepinephrine is released into the synaptic cleft where it binds to different adrenergic receptors (alpha or beta) 5. In case of high concentrations of norepinephrine in the synaptic cleft, norepinephrine can bind to a2 receptors on the presynaptic receptor, which will lead to inhibition of further neurotransmitter release. 6. On the presynaptic terminal there are also β2 receptors. Activation of these receptors leads to the stimulation of neurotransmitter release. Norepinephrine do not prefer β2 receptors, so they are rather stimulated by epinephrine. A small quantity of epinephrine is produced in the presynaptic terminal, but most of it comes from the blood stream produced by the adrenal medulla. Epinephrine from the blood stream enters the synaptic cleft and activates the β2 receptors to stimulate norepinephrine release. 7. In the presynaptic terminal we have monoamine transporter that can transport the leftover norepinephrine from the synaptic cleft into the presynaptic terminal. This is the main neurotransmitter removal pathway from this synapse. In the presynaptic terminal, some of the norepinephrine is transported back into vesicles by the monoamine transporter, while the rest is broken down by the monoamine oxidase and converted back into vanillyl mandelic acid VMA and excreted into the urine. We can affect the synapse: We can stimulate the receptors on the post-synaptic cell. We can also stimulate 𝛼2-receptors and decrease norepinephrine release into the synaptic cleft. We can stimulate 𝛽2 -receptor and increase norepinephrine release into the synaptic cleft. 6  Aurora Killi 30.08.21 Drugs that block the monoamine transporter: Some substances can block the monoamine-transporter which leads to more norepinephrine in the synapse. Cocaine is known to block this re-uptake which contributes to more norepinephrine in the synaptic cleft. Concentration of norepinephrine will therefore be depleted in the vesicle in the presynaptic terminal. Amphetamine can reverse this effect by being transported inside the presynaptic terminal which then contributes to a release of more epinephrine. Reserpine and amphetamine: We can also block the transported that transports neurotransmitters into the vesicles. This will contribute to greater concentration of norepinephrine in the varicosity and lesser will be up taken. This is done by the reserpine and amphetamine. Monoamine oxidase inhibitors: We can block the monoamine oxidase (MAO) by the monoamine oxidase inhibitors which are mostly used for depression treatment and not for the autonomic nervous system. This will then decrease the degradation of norepinephrine in the neuronal tissues. Cholinergic receptors and effects of their activation These receptors bind acetylcholine which is released from both sympathetic and parasympathetic nervous system Nicotinic receptors (ionotropic receptors) Muscular (NM) Neuronal (NN) Found in the neuromuscular junction Located in the autonomic ganglion. The binding of acetylcholine causes endplate Acetylcholine binding causes fast excitatory potential EPP which causes muscle postsynaptic potential EPP in the postganglionic contraction if threshold is reached neuron Activated by somatic nervous system We are only interested in this type of receptor, because the muscular nicotinic receptor is not activated by ANS Muscarinic receptors (metabotropic receptors) M1 (neuronal) M2 (cardiac) M3 (smooth muscle, gland) M4 M5 IP3, DAG ↑ cAMP ↓ IP3, DAG ↑ In the part of CNS Heart rate ↓ Smooth muscle → relaxation Not found in great responsible for alertness Force of contraction ↓ Endothelium → relaxation abundance and attention regulation. Excitability ↓ GI tract → contraction Conduction speed ↓ Glands → secretion Small quantity in smooth Found in some glands as Speed of relaxation ↓ muscle cells, secretory well. cells, and CNS Sympathetic and parasympathetic effects in the body The sympathetic nervous system mostly increase activity in fight or flight situations, while the parasympathetic nervous system mostly increase activity in rest and digestion. Organ Sympathetic effect Parasympathetic effect Heart ↑ Heart rate ↓ Heart rate ↑ Force of contraction ↓ Force of contraction ↑ Excitability ↓ Excitability ↑ Speed of conduction ↓ Speed of conduction ↑ Speed of relaxation ↓ Speed of relaxation 7  Aurora Killi 30.08.21 These effects are realized through β1 These effects are realized through M2 Arterioles Constriction (α): Dilation: Organs of abdominal cavity Sex organs Skin, mucous membranes Coronary Cerebral Sex organs In males → erection In females → increased blood flow and Dilation (β2) secretion rate Coronary Pulmonary There are two regions in the body in which Skeletal muscle the blood vessel are innervated by parasympathetic fibers: sex organs and coronary Bronchi Dilation (diameter becomes bigger) Constriction (diameter becomes smaller) ↓ Bronchial glands secretion ↑ Bronchial glands secretion Increase exchange of air to have more Usually in the morning for people with oxygen asthma Gastrointestinal ↓ Wall motility ↑ Wall motility system ↓ Gland secretion ↑ Gland secretion Sphincters – contraction Sphincters – relaxation Bladder Wall of bladder → relaxation Wall of bladder → contraction Sphincters → contraction Sphincters → relaxation ↓ Gland secretion ↑ Gland secretion Sex organs Male Ejaculation Erection Uterus Pregnant → contraction Variable (contraction or relaxation) Non-pregnant → relaxation Eye Wider and further vision, poorer close Less wide vision, better close vision vision M. dilator pupillae → contraction M. dilator pupillae → - M. sphincter pupillae → - M. sphincter pupillae → contraction M. ciliaris → relaxation M. ciliaris → contraction (more convex lens) ↑ Lacrimal glands Skin M. erector pili → contraction Not present ↑ Sweat glands secretion To look bigger during fight or flight Liver ↑ Glycogenolysis Not present ↑ Gluconeogenesis Fat tissue ↑ Lipolysis Not present 8  Aurora Killi 30.08.21 Sympathetic receptor function on the heart muscle Effect is caused by norepinephrine or epinephrine binding to the β 1 receptor 1. Neurotransmitter activates G protein (stimulatory one), which further activates adenylyl cyclase 2. Adenylyl cyclase converts ATP into cAMP which increases permeability of sodium and calcium channels in the cardiac muscle membrane If more sodium or calcium flows into the cell, then they depolarize quicker, and this leads to increase of the heart rate, force of contraction, excitability, and speed of conduction. It increases calcium pump activity in the smooth endoplasmic reticulum which pumps calcium back into the internal stores faster, which causes faster relaxation of the cardiac muscle cell Parasympathetic receptor function on the heart muscle The effect is triggered by acetylcholine which binds to the muscarinic second subtype M 2 receptor 1. M2 receptor activates G protein (inhibitory one) 2. G protein inhibits adenylyl cyclase 3. cAMP quantity in the cell decreases which decrease the activity of sodium and calcium channels 4. Gamma subunit of the G protein activates potassium channels in the cardiac muscle cell membrane, which causes greater potassium outflux → hypopolarization. This decreases heart rate, force of contraction, excitability etc. Pharmacological effects on the autonomic nervous system In our everyday life, both parts of the autonomic nervous system function in a dynamic equilibrium. Sympathetic activity is increased during physical activity, stress, fight or flight so that our body can move during a stressful situation. Parasympathetic activity is increased during rest and digest situation. If we for instance infuse drugs like epinephrine or norepinephrine which are the general neurotransmitters for the sympathetic nervous system, we can increase sympathetic effect over parasympathetic effect in the body. We divide the substances into two groups: adrenergic and cholinergic Adrenergic drugs work on adrenergic receptors (norepinephrine and epinephrine normally works on these receptors) Cholinergic drugs act on cholinergic receptors Adrenomimetic drugs Works directly α1 α2 β1 β2 Phenylephrine Clonidine Dobutamine Terbutaline Stimulates α1 receptors Stimulates α2 receptors Stimulates β1 receptors Stimulates β2 receptors located on smooth located presynaptic and located on the cardiac located on smooth muscle cells, causing they inhibit muscle. Causes muscle cells. Causes contraction. This drug norepinephrine release increased heart rate, relaxation of the stimulates the in the synaptic cleft. stronger heart muscle. Can be used to contraction of the blood These drugs decrease contraction. Can be treat bronchial asthma 9  Aurora Killi 30.08.21 vessel wall leading to its arterial blood pressure, used if the heart is too and chronic obstructive constriction, which will decreasing contraction weak to stimulate heart pulmonary disease. increase arterial blood of smooth muscle cells. function for instance pressure. Therefore, Used to treat glaucoma. after operation. Can this might be used for In cases in which there also be used for people with low blood is a high intraocular pharmacological stress pressure. Also used for pressure, we can test. nasal constriction in the decrease this pressure nasal cavity to treat with this drug. running nose. There are also Adrenomimetic drugs that act indirectly. These drugs may treat Parkinson disease 1. Releasing agents (amphetamine): stimulates the release of norepinephrine 2. Uptake inhibitors (cocaine): 3. MAO/COMT inhibitors (pargyline and entacapone): inhibit enzymes that breaks down epinephrine and norepinephrine. They increase quantity of neurotransmitters in synapses. Adrenoblockers Inhibit norepinephrine and epinephrine binding to receptor α1 α2 β1 β2 Phentolamine Phentolamine Propranolol Propranolol Prazosin Yohimbine Atenolol Non-selective blockers such as phentolamine. Non-selective blocker such as Propranolol which Blocks both α1 and α2 receptors. This drug is most block both β receptors. Decreases arterial blood used for treatment of phelcrocitoma, which is pressure, blocking sympathetic effect on β1 cardiac tumors that are growing in the adrenal medulla, receptor, decreasing heart rate and force of secreting enormous quantities of norepinephrine contraction. However, an unwanted side effect is or epinephrine. the block of the β2 receptor located in the respiratory tract on the smooth muscle cell and its Selective blocker like prazosin blocks α1 receptor stimulation will lead to bronchial dilation. If this and is mostly used to decrease blood pressure by drug is used on a person with chronic asthma or a dilating the blood vessels. Another selective bronchial disease, it will cause bronchial blocker is yohimbine which blocks α2 receptor and obstruction and will make the condition more is used to increase blood pressure. However, it is severe. not very much used in medicine. Selective blocker for β1 is atenolol. It will only block β1 receptors and is therefore an option to the selective blocker propranolol. There are no β2 receptor blockers used in medicine. Cholinomimetics Nicotinic Muscarinic Nicotine Pilocarpine In the autonomic nervous system these receptors These drugs will cause parasympathetic effect are in the sympathetic and parasympathetic mostly. Used to treat glaucoma causing pupil ganglion. If we infuse nicotinic cholinomimetic constriction and decreasing pressure in the lateral drug, we cannot predict which effect we will get. angle where the tumor … Also used for treatment Therefore, they are not widely used in medicine. of dry mouth and autoimmune diseases to However, each part of autonomic nervous system stimulate saliva production. Can be used in predominantly controls one or the other body bronchial reactivity test in which the person is system. Sympathetic has dominant control over tested before and after inhalation of muscarinic, 10  Aurora Killi 30.08.21 the cardiovascular system, that means that people and people with bronchial asthma we can see a who smoke cigarettes with nicotine in high stronger bronchial constriction. concentration will get more sympathetic effects in the cardiovascular system. That is why they are more prone to high blood pressure. The gastrointestinal system and respiratory system most of the control is done by the parasympathetic nervous system, that is why people smoking will have a greater concentration of saliva and gastric juice, secretion of mucous membrane. Cholinoblockers Prevents acetylcholine from exerting the correct action on the effector cells Nicotinic (ganglioblockers) Muscarinic Hexametonium Atropine Nicotinic cholinoblockers working on the Blocks mostly parasympathetic functions in the autonomic nervous system are called body. Used ophthalmology to dilate pupil. Can be ganglioblockers. They block impulse transmission used to decrease gastrointestinal juice secretion, in autonomic ganglion. This drug is used to treat decrease the motility and sweating intensity high blood pressure. Because the cardiovascular system is mostly controlled by the sympathetic nervous system, most of the sympathetic effects will be blocked there. Pupillary reactions to light Pupillary reflex organization 1. Light enters the pupil 2. Optic pathway is activated 3. Impulses are sent to the precten nucleus in midbrain 4. Impulses are sent to the Edinger nucleus 5. Via the third cranial nerve impulses are sent to the ciliary ganglion 6. The constrictive pupil muscle contracts causing constriction of iris, so the pupil shrinks There are two pupillary light reflexes: Direct reflex: light entering the eyeball causes constriction of pupil of the same eye. The direct reflex activates uncrossed lateral optic nerve fibers that send impulses to same side of midbrain, and thereby contract same-side constrictive pupil muscle. At the same time, the indirect reflex is activated. Indirect reflex: impulse is transmitted through the crossed nerve fiber to the opposite side of the midbrain, activating the nucleus there. This causes constriction of the opposite pupil. For this reason, both pupils usually constrict at the same time. Types of damage: These pupillary reflexes are checked in the clinic to determine whether these pathways are healthy of not. Traumatic events or fracture of bones in the skull may disrupt the optic pathway. (1) Optic nerve: If we cut the optic nerve in one eye, we will not have a direct reflex in the damaged eye and thus no indirect 11  Aurora Killi 30.08.21 reflex in the other eye. But the healthy eye will still have direct reflex, giving the damaged eye an indirect reflex. (2) Chiasma: If we have damage to the chiasma (where the optic nerve fibers are crossed, in the same exact point), we can observe direct reflex in both eyes, but no indirect reflex. (3) Optic tract: If we have damage in the optic tract of one eye, both reflexes will be damaged in that eye. The healthy eye will still have both direct and indirect reflex because the impulse can reach the midbrain and cause constriction. Accommodation The refractive power of lens can be changed by the help of ciliary muscles. This process is called accommodation which allows a person to see clearly far and close objects. If ciliary muscle is relaxed the suspensory ligament of the lens is tense and they make lens flatter. If ciliary muscle contract this suspensory ligament becomes more flatter, and lens is more relaxed and round shaped. This means that the refractive power increases. Ciliary muscle contraction is regulated by the same reflex as the pupillary reflex. In case the person is looking at a close object, the impulses through the optic nerve which are sent to the midbrain activate ocular motor muscles. This leads to ciliary contraction and make lens more spherical and round to increase refractive power. This makes us able to see close object. The pathway for accommodation is the same as for the pupillary reflex to the eye. Impulses which are carried to the optical nerve → pretectal → Edinger Westphal → ocular motor nerve → return to the eyeball. The ocular motor nerve stimulates contraction of the ciliary muscle, which is just behind the lens. This regulates the shape of the lens. AT the same time, when accommodation reflex is triggered, the pupillary reaction is triggered. The rule of pupillary constriction is to prevent light scattering into the eyeball due to the spherical abbreviation of the lens. In case if the lens is made more round than different parts of the lens refract light waves differently. From close objects this light rays going to the distal parts of the lens is refracted more so they make a clear image. Light rays going to the middle of the lens is refracted less. This means that light rays which are going through different places of the lens is refracted differently and making clear image point in different places in the eyeball. To prevent this the ciliary muscle contraction is also supplied by the constriction of pupil. If pupil constrict in the front of eyeball, they eliminate the spherical light rays from entering the eyeball. The eliminate light scattering or image blurring from close objects. 12  Aurora Killi 01.11.21 Table of contents Functions of circulatory system. Functional parts of circulatory system, their functions................................................................... 2 Changes of blood pressure, linear velocity, and summary cross-sectional area in different functional parts in circulatory system. 4 Conductive system of the heart. Impulse propagation in the heart. Velocity of impulse conduction in conductive system and cardiac muscle. Automaticity of the separate elements of conductive system.................................................................................. 6 Action potential of pacemaker cell. The changes of ion permeability of cell membrane during the different phases of action potential............................................................................................................................................................................................... 9 Action potential of the working myocardium cell. The changes of ion permeability of cell membrane during the different phases of action potential.............................................................................................................................................................................. 10 Changes of excitability during the action potential of working myocardium.................................................................................... 11 Specific properties of cardiac muscle. Extrasystole and compensatory pause................................................................................. 13 Electromechanical coupling in working myocardium........................................................................................................................ 15 Electrocardiography. Electrocardiography leads. Normal electrocardiogram. Genesis and normal values of waves, segments, and intervals.............................................................................................................................................................................................. 17 Electrical axis of the heart. Einthoven’s hypothesis........................................................................................................................... 21 1  Aurora Killi 01.11.21 Functions of circulatory system. Functional parts of circulatory system, their functions. Functions of circulatory system Transport function The circulatory system provides pathways through which blood can be transported It transports substances and heat from one place of the body to another Such a circulatory system is necessary because not all cells contact directly with the external environment, so they cannot exchange substances with the external environment directly. The circulatory system must transport these substances via the blood to the interstitial space and back from the interstitial blood to the excretory organs Functional parts of the circulatory system Functional part Explanation In the series of circulation Heart Pumps blood from low pressure region (veins) to high pressure regions Pump (arteries) by creating a pressure gradient Artificial substitution: if the heart fails to pump blood from veins to arteries, we can use artificial pumping devices o Artificial pumping device: the ventricles of the heart can be substituted with an artificial chamber. Outside the body, there is a pumping device which generates a pressure in the artificial chamber located inside to facilitate blood flow into arteries. Such a pump is heavy and interrupts daily activities (not used a lot). o Assist device for ventricles: in medicine we can use assist devices for ventricles to increase pressure for circulation of blood, which substitutes one or both ventricles. Outside the body there is regulating device and batteries, however, people can still engage in some daily activities. Compression chambers Elastic arteries consist of elastic membranes which expand during ejection. Elastic type arteries There are two types of elastic arteries: Aorta Trunk Functions of elastic type arteries Provide continuous blood flow o During systole when the heart ejects blood, the wall of elastic type arteries will expand, to prevent the pressure from rising too much o During diastole when the heart does not eject blood, the elasticity of the wall of these arteries, allows them to regain their initial shape to push the blood forward Decreases work of the heart o Since elastic type arteries expand during ejection, the heart does not have to contract that strong Atherosclerosis Wall of elastic type arteries is stiff → great pressure rise during ejection Heart needs to contract stronger Over longer period this will cause ventricles to fail → congestive heart failure 2  Aurora Killi 01.11.21 Since the artery is stiff and not able to push on the blood, the pressure will decrease more during diastole in case of atherosclerosis Resistance vessels Can regulate the peripheral resistance because they consist of smooth Muscle type arteries & muscle cells that can constrict/dilate them arterioles o Constriction → resist blood flow form large arteries to periphery o Dilation → resistance to blood flow to periphery is decreased Functions Regulation of blood pressure in larger arteries o Blood pressure drop → constriction of resistance vessels to conserve the blood in large blood vessels and maintain normal blood pressure o Blood pressure increase → resistance vessels dilate, to let more blood go to the periphery and decrease blood pressure Regulate blood flow to the microcirculation o Peripheral tissues active → resistance vessels dilate o Peripheral tissues inactive → resistance vessels contract Precapillary sphincters Precapillary sphincters open and close to regulate the number of open capillaries Resting state → closes to inhibit blood flow to non-working tissues Active state → opens to allow blood flow to working tissues Exchange vessels Substance exchange takes place in these capillaries due to: Capillaries Thin wall → one layer of endothelial cells and BM Slow blood flow 0.5 mm/s Small diameter → short diffusion distance Depot vessels Store blood that is not used in the arteries by providing slow blood flow Venules and veins back to the heart Veins of systemic circulation contain 65% of total blood volume o Veins are better storage places due to their compliant wall → can expand due to pressure increase and accumulate more blood Arteries contain 13% of total blood volume Smooth muscle cells in the wall of veins can be activated by the sympathetic nervous system Vessels parallel to the circulatory system Shunt blood vessels Shunt vessels are anastomoses between arterioles and venules Arteriovenous Pour arterial blood into venous blood vessels without exchange of anastomoses respiratory gases with tissues Functions Increase rapid venous return to the heart Wider than capillaries (let leukocytes enter venous circulation) Thermoregulation (if located in the skin) Provide alternative pathway if capillaries are obstructed, damaged, or closed Resorptive vessels Have closed ends in the interstitial space Lymph vessels Absorb extra interstitial fluid into their lumen that cannot reabsorb in capillaries after filtration Fluid in the lymphatic vessels is transported back into the circulatory system in big veins blood to the heart Regulate interstitial fluid volume in tissues 3  Aurora Killi 01.11.21 Changes of blood pressure, linear velocity, and summary cross-sectional area in different functional parts in circulatory system. Blood pressure x-axis: all blood vessels in the systemic regulation y-axis: pressure [mmHg] Pressure of blood exerted on the blood vessel wall Systemic circulation Highest blood pressure in the circulatory system is in the arteries near the heart Aorta: 100 mmHg Arteries: 70 mmHg Arterioles: 35 mmHg o Greatest decrease happens in arterioles Capillaries: 15 mmHg Veins, venules: 0 or -3 mmHg o Can decrease to -3 in vena cava during inspiration due to chest expansion that will also cause expansion of the veins, thus lowering pressure below atmospheric The blood pressure in arteries is fluctuating and dependent on the phase of the cardiac cycle o Pressure rises during systole o Pressure decreases during diastole These changes disappear in arterioles Capillaries and veins and independent on phase of cardiac cycle Pulmonary circulation Arteries: 5 times lower than that of the systemic circulation Pressure is dependent on o Pulmonary trunk: 18-20 mmHg phase of cardiac cycle Capillaries o Arterial end: 12 mmHg o End of capillaries: 6 mmHg Veins: 2 mmHg Summary cross sectional area x-axis: blood vessels in systemic circulation y-axis: S [cm2] Definition: sum of cross-sectional area of same type blood vessels It is impossible to draw this graph correctly according to the vertical axis, because summary cross sectional area differs much between different places of the systemic circulation Systemic circulation Aorta: 4 cm2 Capillaries: 2000-3000 cm2 Vena cava: 8 cm2 In general: summary cross-sectional area of venous blood vessels is double of arterial blood vessels 4  Aurora Killi 01.11.21 Pulmonary circulation Capillaries: 4000 cm2 Linear velocity x-axis: blood vessels in the systemic circulation y-axis: V [m/s] Speed of each particle of blood (erythrocyte, water, etc.) Inversely proportional to summary cross sectional area Aorta: 0.5 m/s o Since aorta has small summary cross sectional area, linear velocity is the highest Capillaries: 0.5 mm/s o Towards the capillaries, summary cross- sectional area rises, thus linear velocity decreases. o In capillaries it is the slowest (thousand times smaller than in aorta) Vena cava: 0.2 m/s o In veins, cross sectional area decreases, thus linear velocity increase to approximately half of speed in arterial blood vessels 5  Aurora Killi 01.11.21 Conductive system of the heart. Impulse propagation in the heart. Velocity of impulse conduction in conductive system and cardiac muscle. Automaticity of the separate elements of conductive system. Conductive system Made up of pacemaker cells, which can generate impulses (automaticity), conduct them fast, but are weak in weak in contraction. Pacemaker cells in the wall of the heart are located in two nodes and several bundles: Sinoatrial node: located in superolateral wall of the right atrium between orifices vena cava Beckmann´s bundle: left atrium Internodal pathways Atrioventricular node: lower part of interatrial septum Atrioventricular bundle o Intraventricular septum o Right and left (anterior and posterior) bundle branch o Purkinje fibers Impulse propagation 1. Impulse is generated in the sinoatrial node 2. Through the Beckmann´s bundle impulses are conducted to the left atrium causing it to excite together with the right atrium. At the same time internodal pathways conducts impulses to the atrioventricular node 3. Atrioventricular node conducts impulses to atrioventricular bundle which branches into left and right bundle branch 4. The bundle branches end with Purkinje fibers which contact with working myocardial cells all around the ventricles Velocity of impulse conduction Velocity of impulse conduction The conductive system is made to conduct impulses fast through the cardiac muscles In atria In the atrial conductive system element (meaning Bachmann’s bundle and 1 m/s internodal pathways) speed of conduction is 1 m/s. In atrioventricular Slowest impulse conduction node Sometimes named the atrioventricular delay, since it delays the impulse from 0.1 m/s atria to ventricles This delay is good since it separates in time the atrial contraction from the ventricular contraction This means that we are giving time for atria to contract and push blood into the ventricles before ventricles start to contract In case when both the atria and ventricles contract at the same time, atria will not be able to rise pressure high enough to push blood into the ventricles Wolff-Parkinson-White syndrome: In normal heart there is no possibility for impulse to go out of the atrioventricular node because atrial and ventricular muscles are separated by a fibrous ring. 6  Aurora Killi 01.11.21 In some pathologies there are accessory pathways that can cross the fibrous ring and therefore transmit pulses to the ventricles faster than atrioventricular node Atrial systole is not separated from the ventricular systole In ventricles If impulses in the normal heart travel out of the atrial ventricular node, then 1-4 m/s in ventricles bundles, bundle branches and Purkinje fibers the speed of impulse conduction is 1-4 m/s This is very fast and the impulse travels all around the ventricular muscle and almost at the same time, all ventricular muscle contract which rises the pressure inside the ventricle to push blood into the big blood vessels Why is speed of impulse conduction in atrial ventricular node cells and Purkinje fibers so different? o This is related with the size of the cells and resistance in between cells o Small atrial ventricular node cells have few gap junctions → great resistance to current flow (lower speed) o Big Purkinje cells have many gap junctions → low resistance to current flow (greater speed) In working myocardium (0.3-0.5 m/s) Usually, lower speed of impulse conduction in working myocardial cells compared to pacemaker cells Damage: in case of damage in the pacemaker cell, impulses are conducted through the working- myocardial cells to the muscle cells in the ventricles. Automaticity of the conductive system Automaticity of the conductive system Automaticity is characterized by frequency of impulses that can be generated by different parts of the conductive system. Decreases downwards from the basis to apex of heart Sinoatrial node First degree pacemaker cells 60-80 x/min Sympathetic and parasympathetic nervous system can modify this frequency Atrioventricular node Second degree pacemaker cells 40-60 x/min If sinoatrial node fails to generate of conduct impulses, the atrioventricular node can generate impulses Automaticity is lower In between cardiac muscle cells there are electrical synapses that can conduct impulses in both directions, which means that atrioventricular node also through the gap junctions or electrical synapses can conduct impulses into the atrial muscle. This heart rate would be enough to provide a normal blood flow for the person at rest (not enough during physical exercise) Atrioventricular bundle Third degree pacemaker cells 15-40 x/min If atrioventricular node fails to generate or conduct impulses from the sinoatrial node to the ventricles, atrioventricular bundle can generate impulses This is not enough to provide normal blood circulation. Ventricles will push blood out into the aorta less frequently, and blood pressure in the aorta will decrease, and not be able to maintain normal blood circulation for the brain the person might become unconscious 7  Aurora Killi 01.11.21 Artificial pacemakers Pads o Then we can use artificial pacemakers, which can be placed on the person´s chest and deliver electrical signals through the skin to the heart to make it contract. o Pads on the chest are not very pleasant because they also stimulate skeletal muscle contraction all around it. Constant pacemaker o That is why if it is possible, we put wires through the big blood vessels into the heart o If constant use of pacemaker is necessary, we suture the battery under the clavicular bone and this gives signals which through the wires are conducted to the atria, ventricle or one of them, and deliver electrical signal to the wall of the heart. o Since cardiac muscle is made up of electrical synapses in between the muscle cells, then impulses from the stimulation site are conducted all over the ventricle and makes it contract. Wireless pacemaker o In some cases, even we can use wireless pacemakers, that are put inside the heart through a catheter driven through the femoral vein and let there in the heart which can stimulate the cardiac muscle at necessary rate to provide normal blood flow. 8  Aurora Killi 01.11.21 Action potential of pacemaker cell. The changes of ion permeability of cell membrane during the different phases of action potential. Description of curve: Pacemaker cells have no resting membrane potential Lowest membrane potential: -55 to -60 mV in sinoatrial node o The lowest membrane potential value is rather positive due to the great permeability of cell membranes to sodium ions Funny sodium channels x-axis: time [ms] y-axis: membrane potential [mV] Sinoatrial node 1. Funny voltage gated sodium channels open due to hyperpolarization (when membrane potential decreases below -40 mV) 2. When membrane potential reaches -55 to -60 mV, sodium influx will trigger pacemaker potential or slow diastolic depolarization 3. At -50 mV, T-calcium channels (transient) opens, and calcium influx helps funny sodium channels to depolarize the membrane until threshold is reached 4. At threshold (-40mV), L-calcium channels open and calcium influx triggers fast depolarization 5. When L-calcium channels close, voltage gated potassium channels open, and potassium outflux causes repolarization, bringing the membrane potential to lower values 6. When membrane potential again reaches below -40 mV, funny sodium channels start opening and from about -55 to -60 mV the next pacemaker potential or slow diastolic depolarization begins In atrioventricular node and bundle Second- and third-degree pacemaker cells can generate impulses at a lower rate than the sinoatrial Atrioventricular node (-70 mV) → slow diastolic depolarization takes longer time to reach threshold Purkinje fibers (-80 to -85 mV) → even longer time 9  Aurora Killi 01.11.21 Action potential of the working myocardium cell. The changes of ion permeability of cell membrane during the different phases of action potential. Working myocardial cells have resting membrane potential of -85 to -90 mV (=potassium equilibrium potential) Dependent on stimulus from o Pacemaker cells (normally) o External electrical stimuli (touching wire, lightning) x-axis: time [ms] y-axis: membrane potential [mV] 1. Fast depolarization (phase 0) When pacemaker impulse come to the working myocardial cell Voltage gated Na+ channels open Na+ ions rapidly rush into the cell → fast depolarization 2. Initial fast repolarization (phase 1) At about 35-40 mV Voltage gated Na+ channels close Voltage gated K+ channels open Minor chloride influx helps to trigger initial fast repolarization 3. Slow repolarization/plateau (phase 2) In working myocardial cells there L-Ca+ channels open → calcium influx are at least four different types of K+ outflux potassium channels which open Membrane potential does not change much → plateau initially, at plateau, and at the end L-Ca+ channels remain open for 100 ms of repolarization. There are several 4. End fast repolarization (phase 3) potassium channels involved to bring potassium ions out of the cell. L-Ca+ channels close Additional K+ channels open → K+ outflux End fast repolarization until RMP is restored NO hyperpolarization due to RMP = K+ equilibrium potential 10  Aurora Killi 01.11.21 Changes of excitability during the action potential of working myocardium. Voltage gated sodium channels in the cell membrane has two gates: Activation gate located outside, responds to stimulation. If we depolarize the cell membrane activation gate opens. After certain time it closes Inactivation gate located inside. They are opened if membrane potential is below -40 mV, and they are closed if membrane potential is greater than -40 mV. 1. Resting membrane potential Activation gate closed Inactivation gate open 100% excitability Stimulus has not reached the cell yet 2. Absolute refractory period Stimulus Beginning of ARP o Activation gate open o Inactivation gate open o Excitability drops to 0 End of ARP o Inactivation gate close o Excitability remains 0 until -40 mV 3. Relative refractory phase (< -40 mv) Activation gates closed Inactivation gates start to open Excitability rises back to 100% Effective refractory phase Used to characterize excitability of working myocardial cells Fast depolarization Initial fast repolarization Includes ARP and half of RRP Plateau phase The period in which contraction is not possible End fast repolarization until -40 mV Ventricular and atrial fibrillation: Relative refractory period The relative refractive period allows cardiac muscle to contract rhythmically Due to pathologies in the cardiac muscle cell membranes, ectopic regions of impulse generation can arise Ectopic regions cause the cardiac muscle cells to contract unsynchronically so blood cannot be ejected out o In atria → atrial fibrillation o In ventricles → ventricular fibrillation Defibrillation o Electrical current is transmitted through anterior wall of the chest to the heart o This will excite all cardiac muscle cells at the same time to restore synchronized contraction Re-entry excitation Absolute refractory period Absolute refractory period prevents impulse circulation through the cardiac muscle. Normally, impulses cannot be transmitted backwards trough the same pathway due to the absolute refractory period 11  Aurora Killi 01.11.21 In case of late repolarization or directional block, impulse cannot be transmitted through this specific region/pathway Impulses are transmitted through the healthy pathway and will eventually reach the pathological region which previously was not excitable. However, since it now has recovered normal excitability, causing impulses to circulate in certain loops through the cardiac muscle. Wolff-Parkinson´s-White syndrome: have accessory pathways located in the wall of the heart, which can transmit impulses backwards through the atria so they can re- enter the ventricles, leading to high rate of impulse transmission to the ventricles (faster than what the sinoatrial node can generate → life threatening arrythmias) 12  Aurora Killi 01.11.21 Specific properties of cardiac muscle. Extrasystole and compensatory pause. The cardiac muscle has three specific properties Automaticity Contraction due to “all or none” law Long absolute or effective refractory period Automaticity Pacemaker cells can generate impulses which makes cardiac muscles contract without any external stimulus Contraction due to “all or none” law Action potentials follows the all or nothing principle everywhere (skeletal, smooth, and cardiac muscles), however in cardiac muscles, we also have this law for contraction Skeletal muscles: strength of contraction is dependent on strength of stimuli o Threshold stimuli → weak contraction since only most the excitable motor units contract o Suprathreshold stimuli → stronger contraction because more motor unit’s contract Cardiac muscles: if threshold is reached, maximal contraction is triggered. This is due to two properties of the cardiac muscles: 1. Electrical synapses: cardiac muscle cells are connected by electrical synapses, which means that one cell can excite the neighboring cell 2. Same excitability of cells Long absolute/effective refractory period The presence of absolute refractory period can be determined if the stimulate cardiac muscle cell with artificial external stimuli during a certain time of the cardiac cycle x-axis: time y-axis: force of contraction Black triangles: impulses from pacemaker cells Upgoing part: contraction of ventricle (systole) Downgoing part: relaxation of ventricles (diastole) Absolute refractory phase in ventricles: 0.25-0.30 s In ventricles 1. Absolute refractory period takes up the whole systole and 1/3 or diastole. During this time, cardiac muscle will not respond to stimulus 2. If we give external artificial stimulus during the last 2/3 or diastole, we can observe an extra systole 3. After the extra systole we get a compensatory pause. The compensatory pause is longer than the 13  Aurora Killi 01.11.21 pauses of normal cardiac cycle because the heart skips a beat because impulse form pacemaker cells come during the systolic phase of the extra systole, when the cardiac muscle is absolute refractory In atria Absolute refractory phase is 0.15 s After extra systole, compensatory phase does not follow Absolute refractory phase in atria ends before the next impulse is generated from the sinoatrial node Extra systole can be observed External stimulus through patches on the skin (defibrillation) Touching electrical wires Lightening Internal stimuli generated in the cardiac muscle due to abnormal channels in the muscle cell membrane Due to the activity of the sympathetic nervous that increase excitability of the cardiac muscles Impulses which are abnormally generated in the heart 14  Aurora Killi 01.11.21 Electromechanical coupling in working myocardium Organization of contraction In the cardiac muscle we have two types of calcium channels Dihydropyridine receptors (L-Ca2+) Cardiac muscle Skeletal muscle o Location: T-tubule cell membrane T-tubule more T-tubule less o Open: plateau phase developed developed Ryanodine receptors Sarcoplasmic Sarcoplasmic o Location: sarcoplasmic reticulum membrane reticulum less reticulum more o Open: calcium binding to dihydropyridine developed (most Ca developed receptors still comes from sarcoplasmic reticulum) Mechanism of contraction 1. Action potential travels along the cell membrane and down the T-tubule where it activated dihydropyridine receptors, triggering Calcium channel blockers calcium influx Decrease release of Ca2+ from 2. Ca2+ binds to ryanodine receptors and facilitates Ca2+ release sarcoplasmic reticulum form the sarcoplasmic reticulum Decrease muscle contraction 3. Ca2+ binds to troponin-C and changes the conformation of it No possibility for 4. Tropomyosin if removed from the active sites of the actin electromechanical coupling filament between the two receptors 5. Myosin head binds to the active sites and rotates by bending its because they are far away neck, moving actin filament along the myosin from each other 6. Sarcomeres decrease in length, actin and myosin remains the same length Differences between skeletal and cardiac muscle contraction In cardiac muscle, troponin-T and -I is called cardio selective troponin and has a little different structure o Determination of troponin type levels in the blood can be used to find out if something is wrong with the skeletal muscles or cardiac muscle Concentration of cardio selective troponin can indicate the severity of infarction o Large infarction → high cardio selective troponin levels o Small infarction → troponin levels might be several times greater than reference value Organization of relaxation Calcium concentration is decreased by two important calcium transport mechanisms Calcium pump o Calcium pump in cell membrane o Pumps calcium ions out of the cell o Calcium pump in smooth ER membrane o Pump calcium ions into sarcoplasmic reticulum o Phospholamban (PLN) inhibits calcium pump in smooth ER membrane o Inhibitory action of PLN can be removed by the sympathetic nervous system → greater speed of relaxation and stronger contraction afterwards Na /Ca exchanger + 2+ o Dependent on sodium/potassium pump o Ca2+ is transported out of the cell in exchange for Na+ 15  Aurora Killi 01.11.21 o Cardiac glycosidases are drugs that can block the Na+/K+ pump and is derived from digitalis purpurea (foxglove) o Concentration increased out of therapeutic range → defective relaxation o Short therapeutic range → help with contractility Mechanism of relaxation 1. Calcium ions are removed from the cytoplasm via the calcium pump or Na+/Ca2+ exchanger 2. Troponin releases calcium and regains its initial conformation, putting tropomyosin back on the active the sites of actin 3. Myosin head detaches 4. Due to elastic forces of the titin like filaments, the sarcomere regains its initial length 16  Aurora Killi 01.11.21 Electrocardiography. Electrocardiography leads. Normal electrocardiogram. Genesis and normal values of waves, segments, and intervals Electrocardiography Method of registration of electrical activity of the heart 1. When cardiac muscle cell excites, sodium ions flow into the cell to depolarize it 2. The extracellular fluid in the excited region becomes more electronegative in respect to the non- excited region 3. The charge differences produce circular currents which are transmitted through the interstitial space to the person´s skin 4. If electrodes are placed on the skin, they can pick up the potential differences between two regions, amplify them, and send it to the electrocardiogram which present it in curve form In a typical electrocardiogram we use 4 electrodes. Red, green, yellow, and black Red electrode → right arm Yellow electrode → left arm Green electrode → left leg Black electrode (ground electrode) → right leg Electrocardiography leads All leads are divided into Bipolar leads o Two active electrodes used o Potential difference between electrodes is measured o Can be placed from extremities and chest Unipolar leads o One active electrode, while the other electrodes are standard leads and through resistance joined to the negative pole of the electrocardiography o Can be recorded from extremities and chest Bipolar leads From extremities Standard leads Active electrodes: both arms and left leg Ground electrode: right leg Lead I Lead II Lead III - electrode: right arm - electrode: right arm - electrode: left arm + electrode: left arm + electrode: left leg + electrode: left leg Lead electrical axis is horizontal Lead electrical axis is directed Lead electrical axis is directed from right to left, shows impulse downwards and to the left. downwards and to the right. conduction from right to left Impulse conduction is mostly Shows impulse conductions side in the heart recorded, since normal heart downwards and to the right side impulses are conducted in this of the heart direction From chest Chest electrodes are used in three situations Heart electrical activity during physical exercise 17  Aurora Killi 01.11.21 o For athletes: during physical exercise movement of extremities will record a high amplitude electromyogram which will hide all the waves of the electrocardiogram. Therefore, electrodes are placed on the chest which does not move as much o For patients: to determine if myocardial blood flow is normal Intensive care unit o To determine if the heart works normally For people that do not have one extremity Unipolar leads From extremities Three unipolar leads where the last letter shows where the active electrode is placed Augmented leads aVR aVL aVF Augmented voltage from right arm Augmented voltage from left arm Augmented voltage from foot Active electrode: right arm Active electrode: left arm Active electrode: left foot Standard leads: left leg, left Standard leads: right arm, Standard leads: both arms arm left leg Lead electrical axis directed Lead electrical axis is directed Lead electrical axis directed vertically downwards → upwards and to the right → upwards and to the left → shows impulse conduction shows impulse transmission show impulse transmission in from top of the heart to the in this direction this direction tip of heart From chest Wilson´s leads. Active lead placed on chest, while the other electrodes are made from all the three standard leads joined together to form the negative electrode. The active electrode can be placed in six different places on the chest: V1: located in the fourth intercostal space on the right periosteal line V2: located in the fourth intercostal space on the left periosteal line V3: located in the middle of V2 and V4 V4: located in the fifth intercostal space in the left medioclavicular line V5: fifth intercostal space on the anterior axillary line V6: fifth intercostal space on the mid axillary line Bipolar and unipolar leads form extremities → impulse conduction in frontal plane Unipolar leads form chest → impulse conduction in sagittal plane Standard 12-lead electrocardiogram In the standard electrocardiogram we have 12 leads 1. We record all 3 standard leads (bipolar, extremities) 2. We record 3 augmented leads from the extremities (unipolar, extremities) 3. All 6 unipolar leads form the chest Bipolar leads from the chest are not used in the standard electrocardiogram 18  Aurora Killi 01.11.21 Elements of the electrocardiogram x-axis: time [s] Maximal amplitude is 1 mV y-axis: potential difference [mV] Waves Segments Intervals Positive waves: P, R, T Baseline between two waves Combination of waves and Negative waves: Q, S PQ: end of P wave to segments QRS complex: beginning of Q wave RR: distance between o R: always present, ST: end of S wave to neighboring R wave peaks positive beginning of T wave PQ: P wave + PQ segment o Q, S: not always present, TP: not of medical QT: beginning of Q to end of negative importance T wave (QRS complex + ST segment + T wave) Element Explanation P wave Summary activity of right and left atrium depolarization Depolarization of atria Upgoing part → right atrium depolarization Downgoing part → left atrium depolarization Right atrium change If right atrium is hypertrophied or dilated → right atrial impulse conduction takes longer time (thicker wall or longer distance) P wave increase in amplitude Tricuspid valve stenosis → smaller valve opening so the atria cannot eject all the blood into the ventricles during atrial systole Right ventricular failure Left atrium change If left atrium becomes hypertrophied or dilated (mitral valve or left ventricular failure) → left atrium depolarization takes longer time P wave increase in time PQ segment Slowest part of the conductive system Impulse spread through Made of small cells with great resistance of gap junction atrioventricular node Straight line in electrocardiogram (no potential difference between different parts of the heart) PQ interval When impulse goes from the atrioventricular node and spreads in the Impulse spread through ventricles atria till ventricles QRS complex In the QRS complex, the direction of impulse conduction in the Depolarization of ventricles ventricles change → both negative and positive waves in the electrocardiogram Lead II is used to characterize impulse conduction in ventricles At the beginning of ventricular depolarization: summary impulse conduction direction is towards the negative electrode → negative Q wave When all ventricular muscles depolarize: direction of impulse conduction is downwards to the left towards the positive electrode → upgoing R wave At the end of depolarization: summary impulse conduction is directed more horizontally → downgoing R wave 19  Aurora Killi 01.11.21 When last muscle cells excite: direction of impulse transmission is towards the negative electrode → negative S wave ST segment No potential difference in ventricles → straight line in Plateau phase in ventricles electrocardiogram T wave End fast repolarization Repolarization of ventricles Repolarization wave travels towards the negative electrode → positive T wave QT interval Includes QRS complex, ST segment, T wave Depolarization + repolarization of ventricles U-wave Can be present and follows T-wave in the electrocardiogram Late repolarization of Amplitude is less than ¼ than previous T wave ventricles Hypokalemia (low potassium levels in blood) → greater U wave amplitude Majorly registered in children Normal values of electrocardiogram Duration Parameters Maximal value [s] Interval [s] P wave ≤ 0.1 0.06 – 0.1 P wave duration increase indicates hypertrophy and dilation of the left atrium PQ segment ≤ 0.1 0.04 – 0.1 Shorter if person has alternative conduction pathway to the ventricle (Wolff-Parkinson’s White syndrome) Longer in case atrioventricular node conduction problems develop PQ interval ≤ 0.2 0.12 – 0.20 PQ segment depends also on T wave duration, so PQ interval is better QRS complex ≤ 0.1 0.06 – 0.1 Increase of duration indicates Hypertrophy and dilation of ventricle Problems with conductive system in the ventricles Defect in conductive system in atrioventricular bundle or bundle branch QT interval ≤ 0.30-0.45 High heart rate, closer to 100 x/min → QT interval < 0.3 s Low heart rate, closer to 60 x/min → QT interval < 0.45 s Amplitudes Amplitudes of different waves can be different in all leads of electrocardiogram, since lead electrical axis determines how high amplitude of each wave should be. These are the amplitude values for the second standard lead (lead II) Wave Amplitude [mV] P wave 0.1 – 0.3 R wave 0.8 – 1.8 T wave 0.2 – 0.4 20  Aurora Killi 01.11.21 P wave amplitude should not exceed 1/5 of the next R wave, and T wave amplitude should not exceed 1/3 of the previous R wave amplitude. Waves Segments Intervals 21  Aurora Killi 01.11.21 Electrical axis of the heart. Einthoven’s hypothesis Recording of electrical activity of the heart, either on a paper or on a monitor Two working myocardial cell model (A) Action potential of two separate cells: Now we will look at two working myocardial cells. Cell A excites and conduct excitation to the cell B For both cells we have one electrode placed intracellularly while the other is used as a reference and placed extracellularly. We can record potential difference across the cell membrane. When cell A excites, action potential is recorded and when it is conducted to cell B within a short gap of time the B-cell action potential is recorded. (B) Subtracted action potential To get the summary electrical activity from both cells we will put one electrode in the cell A and the other in the cell B. We will then record potential difference in-between these two cells. At the time when A-cell excites the membrane potential is more positive compared to the not-yet exited B-cell. In the subtracted action potential curve, we will record a positive wave. However, at the time when plateau-phase in both cells occur there is no more potential difference between these two cells and the summary action potential curve we will get a straight line. Since A cell is exited first it will also repolarize first. This means that A-cell membrane potential is lesser than the B-cell potential is, which is represented as a negative wave in the subtracted action potential curve. Similar as the summary of these two cells we record in the ECG Electrocardiography (C) Depolarization moving towards positive electrode: In the electrocardiography we put the electrode extracellularly to determine the extracellular potential changes. If we put the negative and positive electrode in such a way that impulses are transmitted through both these cells towards the positive electrodes, we can record a positive wave when depolarization spreads towards the electrode. If repolarization follows, we can record a negative wave if it spreads towards the positive electrodes. 22  Aurora Killi 01.11.21 (D) Depolarization moving perpendicular to electrode axis: If we move these electrodes perpendicularly to the direction the impulse is spread in, there will be no potential difference between these two points. The reason for this is because charge is changed at the same time and in the same direction. (E) Depolarization moving away from positive electrode: If we reverse the electrodes and depolarization spreads towards the negative electrode, we will record a negative wave in the ECG. If repolarization spreads towards the negative electrode, we will record a positive wave. In the case if more cells and only two activate at the same moment then amplitude of the positive or negative wave if these electrodes are placed in opposite direction will be greater Depolarization In case if depolarization wave travels towards positive electrode →