Cardiac Automaticity and Action Potentials PDF

16 Cardiac automaticity ILOs By the end of this lecture, students will be able to 1. Relate the autorhythmic cells to the heart pacing. 2. Compare the ionic basis and phases of fast and slow action potential in relation to cardiomyocyte activity. 3. List the characteristics of pacemaker potential in...

16 Cardiac automaticity ILOs By the end of this lecture, students will be able to 1. Relate the autorhythmic cells to the heart pacing. 2. Compare the ionic basis and phases of fast and slow action potential in relation to cardiomyocyte activity. 3. List the characteristics of pacemaker potential in sinoatrial and atrioventricular node. 4. Interpret the role of autonomic innervation of the heart pacemaker in relation to heart rate variability. THE RESTING POTENTIAL OF A CARDIAC MUSCLE CELL The resting potential of a cardiac muscle cell is about - 85mV and, as in other excitable cells, this occurs as a result of the ionic concentration gradients maintained by the action of the Na+ /K+ ATPase. The intracellular potassium is about 140 mmol/L while the extra-cellular potassium is about 4 mmol/L. There is a theoretical cell with a concentration gradient for K+ and, initially, an equal number of positive and negative charges inside the cell. There is a diffusion gradient for positively charged potassium ions to move out of this theoretical cell and thus create a charge imbalance (potential difference) across the cell membrane with the inside of the cell negatively charged. The negative charge inside cells is mainly in the form of organic phosphates and ionizable groups on proteins, molecules which are too large to follow the K+ across the cell membrane. Eventually a situation is reached where the tendency for K+ ions to move out of the cell down the concentration gradient is balanced by the electrical gradient which will tend to move K + ions back into the cell. This concept of the balance between the diffusive gradient and the electrical gradient is the basis for the Nernst equation. The equilibrium potential for potassium is the membrane potential at which the net of flow of potassium ions out of a cell down the diffusive gradient is exactly balanced by their net movement into a cell down the electrical gradient. The equilibrium potential for K + in cardiac muscle cells (94 mV) this means that K+ will be in electrochemical equilibrium when the cell is 94 mV lower than the extracellular environment. It is slightly more negative than the RMP because the resting potential is also partly determined by movements of ions other than potassium. However because the membrane is relatively permeable to potassium, and there is a substantial K+ gradient maintained by the Na /K -ATPase, potassium normally has the greatest influence on the magnitude of the resting potential. In practice the membrane is also a little permeable to Na +. The cell membrane at rest has a very low permeability to Na+, which means Na+ is far from electrochemical equilibrium and the membrane potential is far from the Na+ equilibrium potential of +60 mV. It is possible to calculate the true resting potential by combining the concentration gradients of K+ and Na+ and other ions weighted according to their relative permeabilities. Negatively charged ions have their concentration gradient reversed. The resulting equation is called the Goldman equation CARDIAC ACTION POTENTIAL IN VENTRICULAR MUSCLE The resting potential in cardiac myocytes is about -85mV. When, as a result of a wave of excitation generated by pace-maker tissue, the cardiac muscle membrane potential has depolarized to the threshold potential (-60 to -65mV) the opening of sodium gates in the membrane is triggered. As in other excitable cells, an action potential is then generated. The action potential in typical cardiomyocytes is composed of 5 phases (0-4), beginning, and ending with phase 4. (Fig.1) Initial Rapid depolarization followed by rapid, partial early repolarization. Prolonged period of slow repolarization which is plateau phase A rapid repolarization phase Complete repolarization The atrial action potential is similar in shape to that of the ventricle although the plateau phase is shorter. Phase 4: The resting phase: The resting potential in cardiac myocytes is about - 85mV In phase 0 the sodium gates open and the permeability to sodium increases about a hundred-fold which makes the sodium permeability much greater than that for other ions, including K +. As a result Na+ influx takes place down its electrochemical gradient and the membrane potential rises to between +20 and +30 mV, that is approaching the equilibrium potential for sodium which is about +60 mV. At this point the sodium gates are ‘inactivated’ by the electric charge distribution across the cell membrane and the sodium permeability falls. In phase 1 the K+ permeability begins to increase and K+ leaves the cell at an increased rate down both a favourable concentration and electrical gradient. However the membrane potential does not immediately fall to equilibrium potential for potassium because there is a simultaneous opening of L-type voltage gated calcium channels and an inward flow of calcium. This calcium current results in a plateau phase of the membrane potential In phase 2 which lasts for as long as the calcium current flows. As described earlier, these events cause the release of a larger quantity of Ca++ from the sarcoplasmic reticulum which generates myocyte contraction. Eventually the calcium channels are inactivated partly as a direct result of the rise in intracellular calcium. The membrane potential, under the influence of increased K+ channel opening, falls (phase 3) to a value close to the potassium equilibrium potential (EK). At this stage the cycle begins again from the resting potential (phase 4). The shape of the cardiac action potential is crucial to the functioning of the heart because the long plateau phase in the muscle cells outlasts the mechanical activity. This means that however hard the heart is stimulated individual contractions cannot fuse into a maintained tetanic contraction as happens in skeletal muscle. Fig.1: Cardiac action potential in ventricular muscle As described, the Na+ channels in the muscle cell close at the peak of the action potential. They clearly have to be returned to a state where they can be stimulated to re-open before another action potential can be produced.The Na+ channels remain closed during the plateau phase of the action potential and stimulation of the muscle during this phase cannot produce a further action potential. This is the ‘absolute refractory’ period of the myocytes. During repolarization (phase 3) many, but not all, of the Na channels have re-opened by the time the membrane potential reaches 50 mV. Between 50 mV and complete repolarization a further action potential can be generated but this requires a greater than normal stimulation. This is the ‘relative refractory period’. This has an important consequence in clinical medicine PACEMAKER TISSUE Cardiac muscle differs from skeletal muscle and most neurones in that in some areas of the heart the ‘resting potential’ is particularly unstable. After an action potential in these areas the membrane potential gradually depolarizes until a threshold potential is reached where the opening of sodium ion channel gates is triggered and ion permeability rises rapidly producing another action potential. Cardiac muscle therefore has the property of producing rhythmic depolarizations which, in turn, result in rhythmic contractions. The mammalian heart is said to be capable of myogenic activity. This can be seen when a piece of cardiac muscle is removed from a living heart. If it is kept warm and oxygenated in an artificial extracellular fluid environment it will continue to contract and relax spontaneously for some time. The ability of a piece of cardiac muscle tissue to undergo spontaneous depolarization and hence generate action potentials is called automaticity. The parts of the heart which display automaticity are the sinoatrial node, the atrioventricular node and the bundle of His together with its Purkinje fibres. Ordinary ventricular muscle cells do not normally have automaticity. The rate of contraction of any given piece of muscle will depend upon the rate of depolarization of the resting potential in the muscle cells. The part of the heart with the fastest rate of drift of the resting potential will have the fastest intrinsic rhythm. In the human heart this is the sinoatrial node (SAN), which is a band of tissue in the right atrium close to the junction with the superior vena cava. In the SAN the K+ permeability is lower hence the initial resting potential (-60 mV) is less negative than elsewhere in the heart mainly because of the absence of one type of K channel (the ‘inward rectifier’ potassium channel). The membrane potential drifts upwards (depolarizes) faster than in other parts of the heart and is called a pacemaker potential or "the prepotential".. The ionic events which contribute to the pacemaker potential are complex.It has three phases only. (Fig.2) Phase 4: Diastolic depolarization (pacemaker pre-potential), Is caused by specifically influx of Na+ through slow sodium channels called funny channels or h” channel which slowly depolarizes the membrane above −60 mV (funny current- pacemaker current), associated with decreasing outward movement of potassium ions. Once the pacemaker potential has depolarized to -55mV, there is an inward calcium current (through voltage-gated Ttype Ca++ (transient)- channels which accelerates the rate of depolarization towards the threshold potential of between -55mV and -40mV at which an action potential is triggered. Phase 0: Depolarization phase: Is mainly due to Ca++ influx through L-type (long lasting) Ca++ channels. Depolarization phase is relatively slow to develop and of smaller magnitude; maximum depolarization goes up to ±10 mV, compared to +30 mV for the contractile myocardial cells. Phase3: Repolarization phase: Immediately follows depolarization. Ca++ channel inactivation and opening of voltage-gated K+ channels occur just after peak of the action potential. Fig.2: Pacemaker action potential In the normal heart the SAN serves as the cardiac primary pacemaker and determines the rate at which the whole heart beats. The intrinsic rate of the human SAN is about 110– 120 beats per minute (bpm) but at rest it is normally under tonic parasympathetic inhibition so that the resting heart rate is typically about 70 bpm. If, for some reason, the SAN fails to function or becomes electrically isolated from the rest of the heart then the area with the next fastest intrinsic rhythm is the atrioventricular node (AVN) which has an intrinsic rate of about 50bpm. If the conduction of activity to the ventricle through the AVN is interrupted (‘complete heart block’) then the ventricles will beat at their own rate of about 30– 40 bpm driven by the intrinsic depolarization rate of the Purkinje fibres. FACTORS AFFECTING MYOCARDIAL RHYTHMICITY Sympathetic nerve stimulation at the SAN increases the rate of phase 4 depolarization and therefore the threshold potential is reached more quickly and heart rate increases. Parasympathetic nerve stimulation via the vagus nerve slows the heart rate by a combination of two mechanisms. The SAN cells are hyperpolarized and the rate of rise of the phase 4 resting potential is also reduced. Therefore, it takes longer for the resting potential to reach the threshold potential. (Fig.3) Fig.3: Effect of Autonomic innervation on cardiac automaticity Hyperkalaemia, a rise in plasma potassium, is a frequent consequence of acidosis or inadequate excreion of K+ from the body, a process normally regulated by aldosterone effects on the kidney. Hyperkalaemia may become life threatening because it will lead to depolarization of cardiac myocytes, that is a rise in the resting potential towards zero. This will mean that return to a sufficiently low (negative) membrane potential to ensure opening of all sodium channels will not occur which may lead to cardiac arrest. Fig. 4: Effect of hyperkalemia on cardiac automaticity Reference: 1. Ganong's Review of Medical Physiology, 26e Eds. Kim E. Barrett, et al. McGraw-Hill Education, 2019, 2. Noble A, Johnson R, Thomas A,Bass P. 2010 systems of the body, the cardiovascular system. Elsevier. Second Eds