Ionic Basis of Cardiac Action Potentials PDF

 Ionic Basis of Cardiac Action Potentials Myocardial cells possess an electrical potential across their membrane. This is due to the division of electrical charges on either side of the membrane. Changes in this transmembrane potential o...

 Ionic Basis of Cardiac Action Potentials Myocardial cells possess an electrical potential across their membrane. This is due to the division of electrical charges on either side of the membrane. Changes in this transmembrane potential occur only when electrical charges traverse the membrane, resulting in a current flow. There are two critical implications of this concept: The speed at which the transmembrane voltage changes directly relates to the total current moving across the membrane. The transmembrane voltage remains constant when there is a balance in current, meaning no net current movement across the membrane. Each heart contraction begins from the action potential, resulting in the flow of ions through their respective channels across the plasma membrane of the cardiac muscle cell, and the resting membrane potential of a cardiac muscle cell is based upon the equilibrium potentials of three major ions: Na+, K+, and Ca2+. Click on this tab to learn more about membrane potential. Membrane Potential  If the membrane was only permeable to sodium (Na+), the membrane potential would equal or be very close to the Nernst potential for sodium, i.e., +60 mV. If only permeable to potassium (K+), then the membrane potential would be very close to the Nernst potential for K+, i.e. -90 mV. Similarly, for Ca2+, membrane potential would be +130 mV, i.e., the Nernst potential for Ca2+. It follows that if the membrane was permeable to, say, both Na+ and K+, depending on the relative permeability to the two ions, you could achieve any voltage between EK+ and ENa+, i.e., between -90 mV and +60 mV. This is what happens during an action potential. The relative permeability of the membrane to ions changes, generating changes in membrane potential. In this case, the Nernst or reversal potential of the current will reflect the relative permeability of all permeant ions. If the concentrations of ions change - i.e., the magnitude of the concentration gradient, then you would need to recalculate the Nernst potential for the new conditions. Therefore, membrane potential would also change. Figure 1 summarizes the ionic gradients and extracellular and intracellular concentrations for Na+, K+, and Ca2+ across the cardiomyocyte membrane. Figure 1. Ionic gradients across cardiomyocytes' membrane. Image credit: Dr. Oleksii Hliebov. Before we progress further, let’s provide a brief description of channels and pumps for these ions. Cardiac Ion Channels for Na + The fast voltage-gated Na+ channels are similar to those found in muscle and nervous tissue and have the same characteristics. They are closed at rest and open at negative voltages (e.g., -70 mV). Therefore, they are called “voltage-gated” channels. Depolarization activates rapidly (opening of m-gate) and then inactivates them rapidly (slower closure of h-gates), which closes the channel despite the activation gate still being open. Click on this tab to learn more about this process. Voltage-Gated Channels  Do you remember the role of the membrane potentials for the m (activation) and h (inactivation) gates in Na+ channel activation and inactivation? Both gates need to be open to allow Na+ entry into the cell. At the normal resting membrane potential, the activation gate (m-gate) is closed, and the inactivation gate (h-gate) is open. In this state (closed but ready to open state), the channel is functionally closed but can be activated by a membrane depolarization that exceeds threshold potential.  Image credit: Dr. Oleksii Hliebov In response to such a depolarization, the activation gate (m-gate) opens rapidly, allowing Na+ ions to enter the cell down their electrochemical gradient. This depolarization, as well as opening the activation gate, also initiates the closure of the inactivation gate (h-gate). Still, the inactivation gate closes more slowly than the activation gate opens, so there is a brief period (1-2 msec) during the upstroke of the action potential when both the activation and inactivation gates are open (open state). During the repolarization phase of the action potential, the inactivation gate (h-gate) is closed, but the activation gate is still open. In this state (inactivated or refractory state), Na+ cannot move through the channel despite the open activation gate. In this configuration, the channel cannot be reactivated until the resting membrane potential is achieved, so the channels are in a refractory state. With the completion of repolarization and the re- establishment of the resting membrane potential, the activation gate closes, the inactivation gate opens, and the channel can then be re-activated, and the generation of a new action potential is now possible. The net result of the status of membrane channels for a particular ion is commonly referred to as the membrane’s permeability to that ion. For example, “high permeability to sodium” implies that many Na+ ion channels are in their open state at that moment. The precise timing of the status of ion channels accounts for the characteristic membrane potential changes that occur when cardiac cells are activated. High Na+ conductance through these channels occurs only during the depolarization phase of action potential because of a large inwardly directed electrochemical gradient for Na+ ions. When channels open, Na+ enters the cell down its concentration gradient. This generates an inward membrane current and takes positive Na+ charges into the cell, making the interior less negative (i.e., more positive). This is called depolarization. Repolarization returns them to the closed state, as occurs in the nervous tissue. Cardiac Ion Channels for K + K+ currents are directed outward and make the cell more negative inside when they flow (repolarization). At rest, ungated potassium channels have relatively high permeability, so the Em is close to EK+. There are four different K+ channels (i.e., distinct gene products) in the cardiac muscle that allow outward K+ current to flow at various times during the action potential: Inward rectifying potassium channels (Kir 2.1) Transient outward potassium channel (Ito) Delayed rectifying K+ current- lK * Rapid component of delayed rectifying K+ current - lKr The slow component of delayed rectifying K+ current - lKs *The atrial-specific delayed rectifier potassium channels IKur are not discussed in this fusion session. Inward Rectifying Potassium Channels (Kir 2.1) Inward rectifying potassium channels (Kir 2.1) are high-density, voltage-gated channels open under resting conditions, maintaining high K+ conductance. They function as the “K+” leak channel. High K+ conductance at rest results in Em= -90 mV, which is very close to EK+. These channels are almost all close near the end of depolarization and remain closed during the depolarization period. They reopen during repolarization. Closure of these channels is responsible for the low K+ conductance during the plateau phase, and the plateau phase will not develop until these channels close. Delayed Rectifying K + Channels (lK) Delayed rectifying K+ channels (lK) are closed under resting conditions (when membrane potential is negative). They slowly open in response to depolarization and open more rapidly near the end of the plateau to initiate repolarization. The rapid component of delayed rectifying K+ current (IKr) activates quite slowly, hence the term “delayed,” and it is so termed because it has a faster inactivation rate than the slow component of delayed rectifying K+ current (IKs). The rapid component (IKr) is larger than the slow component (IKs), and so is more important in facilitating the repolarization during action potentials. A small percentage of delayed rectifying K+ channels open during the plateau phase to support a potassium efflux, and the rate of opening of these channels determines the length of the plateau (e.g., faster opening in atria). These channels are similar but not identical to the voltage-gated K+ channels in neurons. Transient Outward Potassium Channel (I t o ) Transient outward potassium channels (Ito) open transiently at the beginning of the plateau phase. They create phase 1 of epicardial and mid-myocardial fibers of the ventricular myocardium and Purkinje fibers. Most of these channels are closed during the main part of the plateau. Cardiac Ion Channels for Ca 2 + Cardiac ion channels for calcium are subdivided into two groups: L-type Ca2+ channels (or long-lasting channels) and T-type channels (or transient). L-type Ca 2 + (Long-Lasting, Large Conductance) Channels They become open at -40 mV and inactivate more slowly and at a more positive membrane potential than T-type channels. Opening of these channels is associated with the inward Ca2+ current and depolarization of the cell membrane. They open during the plateau phase, and Ca2+ that enters through these channels not only participates in the contraction of cardiomyocytes but also contributes to the release of Ca2+ from the sarcoplasmic reticulum (Ca2+ induced Ca2+ release). Opening of these channels leads to a greater flux of Ca2+ across the membrane and, therefore, a more rapid depolarization. They are found throughout the heart, and sympathomimetics (e.g., epinephrine, norepinephrine, etc.) and beta-agonists (e.g., isoproterenol) increase Ca2+ conductance through them when parasympathomimetics (e.g., acetylcholine) and beta-blockers (e.g., propranolol) decrease Ca2+ conductance. T-type Ca 2 + (Tiny Conductance and Transient Openings) Channels They are found predominantly in pacemaker cells (sinoatrial node, atrioventricular node, and Purkinje fibers) and atrial tissue and not in ventricular cardiomyocytes. They become open at -55 mV and inactivate rapidly. They slowly depolarize the cell because of the small conductance for Ca2+, compared to L-type channels. “Funny” Na + /K + Channels or Mixed-Conductance Channels (If) Small conductance channels. These channels are permeable to Na+ and K+ ions and activated by hyperpolarization (i.e., at negative membrane potentials, and that is the reason they were called “funny” as all other currents discovered were activated by depolarization.). They are expressed in nodal tissue and Purkinje fibers and depend on the intracellular cAMP level. The driving force for the conductance of a specific ion (either sodium or potassium) is dependent on the difference between membrane potential and Nernst potential for that ion. Click on this tab to learn more about the difference in potential. Potential Difference  The driving force for an ion is the difference between the Nernst potential for that ion and the membrane potential. Consider the Nernst potential for Na+ (+60 mV) and K+ (-90 mV). At a membrane potential of -60 mV, the driving force for the efflux of K+ from the cells is the difference between -90 and -60 mV = 30 mV of the driving force. For Na+, the driving force for the influx of Na+ into the cells is the difference between the Nernst potential for Na+ and the membrane potential. Therefore, the difference between +60 and -60 mV = 120 mV of the driving force (i.e., 4x the driving force for the exit of K+ from the cell). This is why at negative membrane potential when the “funny” current opens, the current that flows is mainly an inward sodium current. At a membrane potential of -60 mV, the driving force for Na+ influx is greater than for K+ efflux. Therefore, net inward Na+ current through the funny channels predominates. Sodium/Calcium Exchanger (NCX) Ca2+/Na+ exchanger (NCX) is an example of secondary-active transport that uses a Na+ concentration gradient to pump out Ca2+ ions from the cell. This exchange is electrogenic, generating current: three Na+ ions enter the cell in exchange for one Ca2+ ion (three positive charges enter the cell, and two positive charges leave the cell, creating a net inward current). The movement of Na+ determines the direction of the current.  Conduction and Contractile Cells of the Heart Cardiac fibers are classified in two ways:  Force-generating cells (cardiomyocytes): these fibers have a stable resting membrane potential and a long plateau phase and produce fast response action potentials in atria and ventricles. Specialized fibers (modified cardiomyocytes): these fibers have an unstable resting membrane potential that permits them to act as pacemaker tissue, which produces slow response action potentials in sinoatrial (SA) and atrioventricular (AV) node and Purkinje fibers. Ionic Basis of the Ventricular Action Potential (Fast Response Fibers) Figure 2. The shape of the ventricular action potential (fast response fibers). Image credit: Dr. Oleksii Hliebov. The action potential of a cardiac muscle cell may last as long as 300 milliseconds (compared to 3-5 msec in skeletal muscle and around 1 msec in nerve). The start of the action potential looks like the start of an action potential in a nerve or skeletal muscle cell. However, shortly after the membrane begins to repolarize, there is a long plateau phase that differs from that of neural tissue or skeletal muscle. The fast response (non-pacemaker) action potential is seen in contractile muscle cells (atrial and ventricular) and is commonly divided into five phases (Figure 2). Refer to Figure 3 and click the tabs below to review the fast response action potential phases. Figure 3. Ionic basis and phases of the ventricular action potential (fast response fibers). Image credit: Dr. Oleksii Hliebov.   Phase 0 (depolarization phase)  During phase 0, fast voltage-gated Na+ channels open, and the cells become most permeable to Na+. The inward Na+ current depolarizes the membrane towards ENa+ (+60 mV). Na+ channels inactivate rapidly (1-2 msec) and remain closed until membrane potential returns to a negative voltage (around -50 … -70 mV). As membrane potential becomes more positive during the upstroke, the inward rectifier K+ channels shut. This reduces the permeability of the cell membrane to K+.  Did you Know? A more positive resting membrane potential reduces the fast channels available for activation. This reduces the slope and the magnitude of phase zero, which slows the conduction of the action potential. When the resting membrane potential reaches about -55 mV, a fast fiber becomes a slow fiber. Phase 1 (early repolarization)  Produced by the closure of fast voltage-gated Na+ channels and by the opening of transient outward voltage-gated K+ channels (Ito). At that moment (Figure 3), the membrane is most permeable to potassium (net current is efflux of K+). Pharmacological Correlate Class I antiarrhythmic drugs (e.g., quinidine, lidocaine, flecainide, etc.) affect the slope of phase I by blocking Na+ channels. Phase 2 (plateau phase)  Produced by the opening of voltage-gated slow L-type Ca2+ channels (Figure 3). This leads to the influx of Ca2+ ions. These Ca2+ ions participate in contraction and also trigger the release of Ca2+ from the sarcoplasmic reticulum. If there is no influx of Ca2+ during this phase, there is no Ca2+ for contraction. The downward slope later during this phase is produced by the opening of the delayed rectifier K+ channels (IKr and IKs), leading to the efflux of K+. During this phase, there is a balance between depolarizing inward calcium current and repolarizing outward potassium current, so there is mixed conductance to these two ions. Therefore, the plateau voltage is determined by the relative permeability of each ion.  Pharmacological Correlate Class IV antiarrhythmic drugs (e.g., verapamil, diltiazem) affect phase II by blocking L-type Ca2+ channels During the plateau phase, the membrane potential changes only slowly. Due to the increase in Ca2+ in the cells, the inward current carried by NCX (net sodium current: three Na+ for each Ca2+ ion) also contributes to maintaining the plateau phase. The sustained contracted state of cardiomyocytes is maintained because of the sustained open state of sarcolemma-based voltage-gated L-type calcium channels during this phase. Control of the specific intracellular concentration of Ca2+ over time in each myocyte, in turn, produces control of the intensity and duration of whole-heart pressure generation for blood pumping. Note! Plateau duration is a major factor in determining the length of the absolute refractory period. The long plateau phase delays the reopening of the inactivation gate of voltage-gated Na+ channels, producing a long absolute refractory period. Phase 3 (rapid repolarization)  Phase 3 (rapid repolarization). It is produced by the closure of L-type Ca2+ channels and the opening of several K+ channels, leading to the net efflux of K+. The slow delayed rectifier (IKs) and rapid delayed rectifier (IKr) currents repolarize the membrane to about -60 mV when they close (Figure 3). Still, at this negative voltage, the inward rectifier K+ current is now open, completing the final repolarization phase. Clinical & Pharmacological Correlate  Hyperkalemia increases K+ conductance and shortens the plateau. Hypokalemia reduces K+ conductance and lengthens the plateau. Class III antiarrhythmic drugs (e.g., amiodarone, dofetilide, ibutilide, etc.) block K+ channels during this phase. Phase 4 (resting membrane potential)  During this phase, both delayed K+ rectifier channels have closed. Still, the inward K+ rectifier channels remain open and maintain the resting membrane potential close to the Nernst potential for K+ (-90 mV). Na+/K+ ATPase activated, restoring the resting membrane potential (Figure 3).  Figure 3. Ionic basis and phases of the ventricular action potential (fast response fibers). Image credit: Dr. Oleksii Hliebov. Absolute and Relative Refractory Periods The refractory periods in cardiac muscles create timeouts between excitation periods and allow complete emptying of the ventricles before the next contraction. In cardiac muscle, refractory periods and long action potential duration prevent tetany and loss of pump function. The refractoriness of each phase of the ventricular action potential is governed by the number of sodium channels ready to activate or slowly recover from inactivation. Refer to Figure 4 and click the following tabs to learn about each period. Figure 4. Refractory periods in fast response fibers (ARP – absolute refractory period; ERP – effective refractory period; RRP – relative refractory period). Image credit: Dr. Oleksii Hliebov.   Absolute Refractory Period (ARP)  The refractory period is due to a characteristic of the fast sodium current, which inactivates rapidly at the start of the ventricular action potential but does not become reactivated again until negative membrane potentials (around -70 mV) are achieved during the repolarization phase of the action potential. So, until this membrane potential is achieved, the tissue is refractory, and no further action potentials can be generated regardless of stimulus strength. This period of refractoriness is known as the absolute refractory period (Figure 4), and it is considerably longer in duration than observed in skeletal muscles. Effective Refractory Period (ERP)   The effective refractory period may allow for non-propagated depolarization (i.e., an action potential could be generated, but it would not propagate to adjacent tissue as surrounding tissue is in the absolute refractory period). The Relative Refractory Period (RRP)  During this period, another action potential can be generated. Still, the stimulus required is larger than normal. Moreover, the action potential generated during this period is smaller than the usual action potential. Since it is difficult to generate another action potential during the repolarization period, it is difficult to initiate another contraction. This means that one contraction cannot build on the previous contraction. Physiologically, this is important because it means that for every contraction period (systole), there is a resting period (diastole), during which the heart can refill with blood. Supranormal Period (SNP)  This period can occur when the ventricular tissue is more depolarized than normal – present in a hyper-excitable state. Therefore, a slightly smaller than normal stimulus can elicit a propagated response. However, the amplitude of the action potential is reduced compared to normal. This can lead to the generation of abnormally timed action potentials and ventricular (or atrial) dysrhythmia. Ionic Basis of the SA and AV Nodal Action Potential (Slow Response Fibers) Pacemaker cells are located in the sinoatrial (SA) node and atrioventricular (AV) node of the heart. These cells have no true resting membrane potential; rather, the most negative the membrane potential becomes is called the maximum diastolic potential (approximately -60 mV). SA nodal cells generate regular, spontaneous (automatic) action potentials due to the phase 4 pacemaker potential (Figure 5). Figure 5. Ionic basis and phases of the SA and AV nodal action potential (slow response fibers). Image credit: Dr. Oleksii Hliebov. Click the following tabs to learn more about the phases of SA and AV nodal action potential (slow response fibers). Note that Phase 1 and Phase 2 are absent!   Phase 0 (upstroke)  It is produced by the opening of voltage-dependent L-type Ca2+ channels (influx of Ca2+). The threshold level for opening these channels is -40 mV. The slope and magnitude of this phase are decreased compared to fast fibers. The slower rate of depolarization and the overall smaller magnitude of the action potential not only slow conduction velocity but also increase the probability of blockage. Phase 3 (repolarization)  It is produced by the closure of L-type Ca2+ channels and the opening of delayed rectifier K+ channels. There are two types of delayed rectifier K+ channels (we discussed them above): IKr, which activates slowly but inactivates rapidly and is the larger of the two currents, and the IKs, which activates slowly and inactivates slowly. Repolarization occurs due to potassium efflux during this phase. Phase 4 (pacemaker potential)  As the membrane potential becomes more negative due to the loss of K+ through IKr and IKs, this leads to the closure of these two ion channels and the opening of funny channels (If), which are activated by the negative membrane voltage, allowing a net Na+ influx which opposes the decaying outward K+ current and stops the membrane potential becoming any more negative than -60 mV (so-called maximum diastolic potential). As the funny current continues to flow, membrane potential becomes more positive as Na+ continues to enter. Pharmacological Correlate Ivabradine blocks the “funny” If channels responsible for the cardiac pacemaker current, which regulates heart rate. This results in prolonged diastolic time and reduced heart rate. Cholinergic drugs and beta-blockers produce similar effects. At approximately -55 mV, T-type Ca2+ channels also start to open, which continues the depolarization until the threshold of -40 mV is reached. L-type Ca2+ channels open and generate the upstroke (phase 0) of the SA node action potential. Note that the small increase in cytoplasmic calcium during phase 4 will also activate Na+/Ca2+ exchange to extrude the calcium, which generates a further small inward current carried by sodium. Note! Control of the rate of sodium influx during phase 4 helps determine the time between action potentials. This, in turn, determines heart rate. Setting the Heart Rate The heart beats without any nervous system innervation because of the presence of specialized cells that have intrinsic electrical (pacemaker) activity. Cells of the SA node set the frequency of action potential generation because they lack a stable membrane potential between successive action potentials. Instead, the membrane potential displays a progressive slow depolarization, called the pacemaker potential, during phase 4. The cells of the SA node initiate the action potential at a rate of approximately 60-100 times per minute as this cell type generates action potentials at a faster rate than other pacemaker cells present in the heart (e.g., AV nodal cells can fire 40-60 times per minute and Purkinje fibers only 20-40 beats per minute), the SA node is considered to be the primary pacemaker of the heart. This is caused by a more rapid rate of phase 4 depolarization than in any other cardiac cell type. Since the intrinsic firing frequencies of the secondary (AV node) and tertiary pacemakers (bundle branches and Purkinje fibers) are slower than the SA node, all the pacemakers end up firing at the SA node rate, not their rate because their pacemaker activity will be reset or suppressed by the passage of the SA node generated action potential (e.g., AV node receives impulses from SA node greater than its intrinsic rate). This rapid firing of the SA node causes the secondary and tertiary pacemakers to fire faster than their intrinsic rates. This is called overdrive suppression. An automaticity focus that is pacing the heart will overdrive and suppress all intrinsically slower foci. Should the SA node fail, a backup pacemaker, with the next highest intrinsic rate following a pause, will emerge to pace the heart at its intrinsic rate. Did You Know? Cardiac tissue injury may cause myocardial cells of the atrium and ventricle, outside the specialized fibers, to develop automaticity, which causes ectopic beats. Figure 6 shows that the membrane potential in SA nodal cells is never stable but changes continuously. Cells that display these characteristics can act as pacemaker cells and generate action potentials that can be conducted throughout the heart tissue. Figure 6. Automaticity in the heart (slow response fibers). Image credit: Dr. Oleksii Hliebov. Effects of Parasympathetic Nervous System on Heart Rate The vagus nerve provides parasympathetic stimulation to the heart. It releases acetylcholine (Ach) onto the SA and AV nodes and slows the intrinsic pacemaker activity by three mechanisms via acting on M2 cholinergic receptors. All three effects cooperate to lengthen the time for the SA node to depolarize to the threshold. As a result, the SA node produces fewer action potentials per unit of time, lowering the heart rate. Decreased rate of depolarization: ACh decreases If current in the SA node by inhibiting adenylyl cyclase activity that leads to a decreased cAMP level. cAMP serves as an activator of “funny” channels, and decreased level is associated with reduced steepness of the phase 4 depolarization (main Figure 7. The net effect of the parasympathetic nervous system mechanism). As a result, pacemaker potential is slowed because slower on If conductance. Image credit: Dr. Oleksii Hliebov. depolarization requires more to reach the threshold (Figure 7).  A negative shift in maximum diastolic potential. ACh increases relative K+ conductance by opening K+ channels, thus making the maximum diastolic potential of SA nodal cells more negative (hyperpolarization). Starting from a more negative diastolic potential requires more time to reach the threshold (Figure 8). Figure 8. The net effect of the parasympathetic nervous system on maximum diastolic potential. Image credit: Dr. Oleksii Hliebov. A positive shift in the threshold. ACh reduces ICa2+ in the SA node, thereby reducing the steepness of the phase 4 depolarization and moving the threshold to more positive values. Reaching a more positive threshold requires more time (Figure 9). Figure 9. The net effect of the parasympathetic nervous system on threshold level. Image credit: Dr. Oleksii Hliebov. Did You Know? An increase in vagal tone with exercise training is primarily responsible for the decrease in resting heart rate. The effects of ACh on currents in the AV node are similar to their effects on those in the SA node. However, because the pacemaker normally does not reside in the AV node, the physiological effect of ACh on the AV node is to slow conduction velocity. The mechanism involves an inhibition of ICa2+ that also makes the threshold more positive for AV nodal cells. Because it is more difficult for one cell to depolarize its neighbors to the threshold, conduction velocity falls. The vagus nerve also stimulates the AV node to keep its depolarization rate below the SA node’s. Effects of Sympathetic Nervous System on Heart Rate Sympathetic stimulation leads to the release of norepinephrine from sympathetic nervous fibers and epinephrine from the adrenal medulla, contributing to increasing heart rate by the following mechanisms: Increased rate of depolarization. Norepinephrine and epinephrine increase the cAMP level within cardiomyocytes, and cAMP acts as an activator of the funny current (If), speeding up the depolarization rate of the phase 4 pacemaker potential (Figure 10). Figure 10. The net effect of the sympathetic nervous system on If conductance. Image credit: Dr. Oleksii Hliebov. A positive shift in maximum diastolic potential. The delayed rectifier current (IKs) is increased by the sympathetic nervous system as well. It increases repolarization and reduces the duration of the SA node and ventricular action potential. The IKs current is also deactivated more quickly with increased sympathetic nervous system activity so Figure 11. The net effect of the sympathetic nervous system on that IKs channels close at a more positive maximum diastolic potential. Image credit: Dr. Oleksii Hliebov. membrane potential. As a result, the permeability of the cells to K+ is decreased in the pacemaker potential range, making maximal diastolic potential more positive (Figure 11).  A negative shift in the threshold. As the L-type Ca2+ channels are also phosphorylated, the increasing channel current increases the upstroke rate of the SA node action potential. Phosphorylation also makes the L-type Ca2+ channels open at a slightly more negative voltage than -40 mV (Figure 12). Figure 12. The net effect of the sympathetic nervous system on threshold level. Image credit: Dr. Oleksii Hliebov. Because of sympathetic nervous system effects, action potentials are generated more frequently by the SA node and propagated through the heart more rapidly. Ventricular action potentials become shorter in duration at higher heart rates. The strength of contraction associated with each action potential is increased, leading to an increased rate of development of ventricular pressure. Lastly, the ventricular relaxation rate is increased (this is called the positive lusitropic effect), so the duration of each contraction is reduced. It is important to mention that the tone between sympathetic and parasympathetic stimulations determines the final heart rate: e.g., the most negative phase 4 potential is -70 mV, and the least negative threshold potential is -40 mV. To achieve the threshold, this cell needs time to depolarize the membrane from -70 mV to -40 mV, a total of +30 mV. You can shorten the time by reducing the voltage difference between most negative membrane diastolic potential and threshold. If you make the threshold more negative, -70 mV to -50 mV is only +20 mV (so is -60 mV to -40 mV, of course). If you also make the resting potential less negative, -60 mV to -50 mV is only +10 mV, which is achieved much faster than depolarization on +30 mV.  Check Your Knowledge Check your knowledge by completing the following exercises.   Practice Questions  Flashcards .evitagen erom llec eht gnikam ,slennahc suoirav hguorht tuo swo8 +K Describe the repolarization phase in cardiac cells. tI deliaN  Click kfor O answer wonK t'noD  1/5F   Download Anki Deck Workbook   Instructions: Carefully read the statement provided. Based on the context of the sentence and your understanding of the to logically and scientiOcally into During the plateau phase (Phase 2) of the ventricular action potential, volta ions that participate in contraction and trigger additional release from the s Check answe Open workbook in a new tab (https://my.qbankmanager.com/question_multy/view/eyJ0eXAiOiJKV1QiL  Excitation-Contraction Coupling in Cardiac Muscles Contraction of cardiac muscle cells is initiated by a membrane action potential acting on intracellular organelles to evoke tension generation and/or shortening of the cells. This action potential is generated in specialized cells called pacemaker cells. The impulse from the pacemaker cells flows in a unidirectional manner throughout the heart via specialized conducting tissue and into the heart muscle. The electrical impulse results in the mechanical contraction of the cardiac muscle through a series of intracellular events involving calcium. Mechanism of Cardiac Excitation-Contraction Coupling Muscle action potentials trigger mechanical contraction through a process called excitation- contraction coupling, which is illustrated in Figure 13 (left side). The action potential travels across the surface membrane of the ventricular cell and down the T-tubules, which are wider than in skeletal muscle, to reduce the prospect of depletion of Ca2+ ions in the T-tubular space. Action potential depolarizes the T-tubular membrane where the L-type Ca2+ channels are concentrated. Ca2+ channels are situated directly opposite ryanodine receptors (RyR2) on the surface of the sarcoplasmic reticulum. The dihydropyridine receptors (DHPRs) are not physically connected to the RyR2s as in skeletal muscle. The action potential causes the opening of L-type voltage-gated Ca2+ channels in the sarcolemma and T-tubules, and this leads to the extracellular Ca2+ entry due to the opening of the L-type Ca2+ channels and Ca2+ binding to the RyR2, inducing an increase in its opening probability. RyR2s open, and Ca2+ floods out of the sarcoplasmic reticulum into the cytoplasm. So, the extracellular-derived Ca2+ contributes around 30% of all Ca2+ triggers the release of additional Ca2+ from the sarcoplasmic reticulum (around 70% of all Ca2+) into the sarcoplasm via ryanodine receptor channels (RyR). This is called Ca2+-dependent Ca2+-release. The major event of this excitation–contraction coupling is a dramatic rise in the intracellular free Ca2+ concentration when the depolarization wave passes over the muscle cell membrane and down the T-tubules, leading to Ca2+ release from the SR into the intracellular fluid. The combined Ca2+ ions released from the extracellular fluid and sarcoplasmic reticulum into the sarcoplasm then bind to troponin C on the actin filament. Cross-bridge cycling begins, and contraction occurs. Thin (actin) filament regulation is essentially the same in skeletal and cardiac muscles, providing a Ca2+ signal and subsequent contraction.  Figure 13. Excitation - contraction coupling in cardiac muscle. Image credit: Dr. Oleksii Hliebov. Pharmacological Correlates The contraction force is dependent on the concentration of Ca2+ in the sarcoplasm. Non-dihydropyridine calcium channel blockers – verapamil and diltiazem - block L-type Ca2+ channels, producing antiarrhythmic action (Class IV), decreasing heart rate and myocardial contractility. Digoxin (cardiac glycoside) blocks Na+/K+ ATPase, increasing Ca2+ concentration inside cardiomyocytes, which leads to increased contractility. Increased contractility is termed as “positive inotropic effect.” Mechanism of Relaxation of Cardiac Muscle As in skeletal muscles, relaxation of cardiac muscle is associated with a decreased concentration of intracellular Ca2+ that terminates the contraction. Several processes participate in that. These processes are illustrated on the right side of Figure 13. About 20-30% of the calcium is extruded from the cell into the extracellular fluid either via the Na+/Ca2+ exchanger located in the sarcolemma, 2% of sarcoplasmic Ca2+ is removed via sarcolemmal Ca2+-ATPase pumps (not shown in the image). Approximately 70-80% of the sarcoplasmic calcium is actively taken back up into the sarcoplasmic reticulum by the action of sarco/endoplasmic reticular calcium ATPase (SERCA2) pumps (primary active transport) located in the longitudinal part of the sarcoplasmic reticulum. The activity of the SERCA2 pump is regulated by phospholamban (PLN) and the inhibitory interaction between SERCA2 and PLN exists. Phospholamban can be in phosphorylated or unphosphorylated states, and when phosphorylated, it dissociates from SERCA2, and this increases the uptake rate of Ca2+ back into the sarcoplasmic reticulum, thereby contributing to the lusitropic response (increased rate of myocardial relaxation). This response can be elicited in the heart by beta-agonists (e.g., catecholamines). Click on this tab to learn more about this effect. Effect of a Beta-Agonist  Norepinephrine binds to beta-1 receptors, which, in turn, activates the stimulatory G protein Gs. This G protein has three subunits: alpha, beta, and gamma. When activated, the alpha subunit dissociates from the beta and gamma, moves within the membrane, and binds to adenylate cyclase, activating it. Adenylate cyclase is a protein that converts ATP to cyclic AMP. Increased cAMP binds to the regulatory subunit of protein kinase A (PKA), causing it to dissociate from the catalytic domain of PKA, which then phosphorylates various targets in the cell, regulating their function. Phosphorylation of the L-type Ca2+ channels leads to larger channel conductance (longer openings), increasing the flux of Ca2+ across the membrane. The larger current can induce the release of a larger fraction of the Ca2+ stored in the sarcoplasmic reticulum (as the ‘trigger’ for Ca2+ release is larger). Phosphorylation of the RyR enhances the sensitivity of the sarcoplasmic reticulum Ca2+ release channel to Ca2+ entry via L-type Ca2+ current. This will lead to enhanced Ca2+ release from the sarcoplasmic reticulum. Phospholamban normally acts as a brake on the rate of sarcoplasmic reticulum Ca2+ uptake by SERCA2. However, when phosphorylated, this inhibition of Ca2+ uptake is reduced, allowing sarcoplasmic reticulum Ca2+ uptake to speed up. This causes an increase in the rate of Ca2+ uptake as well as the amount of Ca2+ stored in the sarcoplasmic reticulum so more can be released every beat. In such a way, PLN should be considered a key regulator of cardiac diastolic function. The same amount of Ca2+ that entered the cells during excitation must be removed from the ventricular cells before the next contraction; otherwise, the cells would continually gain calcium. Excitation–contraction coupling in the cardiac muscle differs from that in the skeletal muscle in that it may be modulated; that is, different intensities of actin-myosin interaction (contraction) can result from a single action potential trigger in the cardiac muscle. The mechanism for this largely depends on variations in the amount of Ca2+ reaching the myofilaments and, therefore, the number of cross-bridges activated during the contraction. This ability of the cardiac muscle to vary its contractile strength - that is, to change its contractility - is extremely important to cardiac function, as we will discuss later during the CVS physiology course. Correlating the duration of the cardiac muscle cell contraction and the duration of the action potential, it is important to mention that they are approximately the same. Therefore, the electrical refractory period of a cardiac muscle cell is not over until the mechanical response is completed. Consequently, heart muscle cells cannot be activated rapidly enough to cause a fused (tetanic) state of prolonged contraction. This is fortunate because intermittent contraction and full relaxation of the cardiac muscle cells are essential for the heart’s pumping action. Relationship Between Cardiac Muscle Force and Cardiac Muscle Length Similar to skeletal muscle, the relationship between a cardiac muscle's stretched length and tension is due to the cumulative effect of muscle passive and active tension. The total tension in cardiac muscle, however, is much greater than that in skeletal muscle. Intercalated discs connect cardiac muscle cells to form a hollow organ that rhythmically fills and empties. During the filling phase of the heart, called diastole, muscle cells are relaxed (cytoplasmic Ca2+ is very low), and blood entering the ventricles stretches the cardiac cells, increasing the volume of the chamber. This generates passive tension, of which titin is the greatest contributor. Titin is a long-coiled molecule analogous to a coiled telephone cable in structure. You can compare the stretching of the elastic components of cardiac muscle as being like stretching titin. As long as there are still loops in the phone cord, it stretches easily. Once the loops are all straightened out, it becomes much harder to stretch. Notice that passive tension does not increase much over a wide range of muscle lengths or chamber volumes, increasing significantly only at the point that the peak of the active force relationship is achieved (when titin is almost fully extended). Consequently, it is quite difficult to stretch cardiac muscle beyond the peak of the active force relationship. Because the ventricle is a hollow structure, muscle length is equivalent to ventricular volume, equivalent to diastolic volume (the volume during diastole). The volume in the ventricle at the end of the diastolic phase is called the end-diastolic volume or the preload. The ventricle is enclosed by the pericardium, reducing the prospect of overfilling the ventricles. The normal working range indicates the sarcomere length of a normal ventricle at rest and is also referred to as the resting length. Cardiac muscle is not at its optimal length for active force development (resting sarcomere length is approximately 1.8 micrometers), i.e., on the rising phase of the length-tension relationship. Note! If resting cardiac muscle was at its optimal length for active force development, either an increase or a decrease in sarcomere length would result in a reduction in active force development) This is very important for cardiac function and is the basis of the Frank-Starling Law: if venous return to the heart increases (increased heart filling or increased preload), then the ventricles fill with a greater volume of blood, which stretches the ventricular tissue. Therefore, sarcomere length is increased in the ventricular myocytes, and this leads to the generation of a greater amount of force as more cross-bridges are capable of generating force, which increases the strength of cardiac contraction and expels the greater volume of blood from the ventricles. In enlarged hearts, the sarcomeres are overstretched, and the force of contraction declines. Frank-Starling Law As end-diastolic volume increases (the volume of blood in the ventricles at the end of diastole), which stretches ventricular muscle, stroke volume (the volume of blood that is ejected into the aorta, which equates to the strength of contraction) increases.