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Action potential in the heart involves different conductions of ionic currents, which plays an important role the heart's conductance pathway, contraction and relaxation of the ventricles, and also in determining the duration. In this dissertation, I will be mentioning about the different ionic currents and voltage-gated channels which are involved in the heart's action potential. Further research studies were done to expand the details on the roles of the specific ionic currents / voltage-gated channels in determining the shape and duration of the action potential in the heart. Pathological consequences such as arrhythmia was also mentioned in this dissertation, where was slowing down of depolarization and also sodium overload was the cause.
In this study, it was realized that the action potential has different shapes and duration between the heart of humans and animals and each shape is dependent on the activation and inactivation of the voltage-gated channels. Further details and reviews of the role of the ionic currents which are involved in the shape and duration of heart's action potential will be mentioned below.
The sinoatrial node (SA) conducts ionic current from the right atrium towards the conduction pathway of the heart. This SA node is the normal pacemaker of the heart found in the upper part of the right atrium. Normally, the ionic currents enter this node then goes to the atrioventricular node (AV) node then they travel to the AV bundle then to the Purkinje fibers. When the ionic current passes the AV node, which is located in the lower part of the right atrium, the cardiac rate slows down allowing the atria to complete their contraction before the action potentials are delivered to the ventricles (Seeley et al. 2005). Once the action potentials or ionic currents pass through the Purkinje fibers, they are rapidly conducted along the cardiac muscles of the ventricles causing coordinated ventricular contraction. After the ventricles contract, relaxation follows and another action potential will originate from the sinoatrial node to start another cycle of contractions.
Action potential starts when the sodium gate of a cell membrane opens up for the sodium to enter the cell membrane. This changes the charge of the cell membrane causing its charge to become positive and depolarization to set in. When the sodium channel opens up the potassium channel closes, decreasing the permeability of the potassium towards the outside of the cell membrane, causing depolarization to occur. While this is going on, the calcium channel opens up allowing the entrance of calcium into the cells which can also cause for the state of depolarization to set in. It is only during the plateau phase that most of the calcium channels are open. The state of the voltage - gated channels are the basis of the different shape and duration of the action potential curve of the cardiac muscle. This dissertation will discuss the role of ionic currents in the determination of the shape and duration of the action potential in the heart muscle.
Figure i. Sinoatrial and Atrioventricular nodes, Conduction Pathways (Seeley et al. 2005)
Review of Related Literature
In an article by Klabunde (2010), the depolarizing ionic current is brought in to the heart by the slow entrance of calcium ions instead of the fast sodium ions. There are no fast sodium currents acting in the sinoatrial node and this results to slower action potentials during depolarization. Hence the "pacemaker" action potentials are also called "slow response" action potentials (Klabunde 2010).
The sinoatrial nodal action potentials have three phases which are divided into Phase 0, phase 3, and phase 4 (Klabunde 2010). Phase 4 is the pacemaker potential or the spontaneous depolarization which activates the action potential once the membrane charge reaches the membrane potential threshold between - 30 and - 40 millivolts (Klabunde 2010). Phase 0 is the depolarization phase of the action potential, followed by the phase 3 repolarization phase. Complete repolarization at - 60 millivolts will cause the cycle to be repeated spontaneously (Klabunde 2010).
According to Klabunde (2010), when the membrane potential is very negative the membrane potential has reached the end of the repolarization phase when the potassium ions have exited the cells. This causes the opening of the sodium channels and sodium ions slowly enter the cell causing depolarization.
Further depolarization of the cell is caused by the slow entrance of calcium ions and its channel is called the transient or the T - type calcium channel. Continuous depolarization to - 40 mv causes a secondary calcium channel to open. This latter is also known as the long - lasting or the L - type calcium channels which causes more calcium to enter until further depolarization reaches - 40 and - 30 mv. During phase 4 or depolarization, there is a slow exit of potassium as the potassium channels close which brings about Phase 3 (Klabunde 2010). The decline of potassium exit results to the depolarizing pacemaker potential of the SA node.
Phase 0 depolarization is due to the increased entrance of calcium through the L - type calcium channels. Repolarization or phase 3 occurs when there is increased exit of potassium ions and closure of the calcium channels.
Figure ii. Action potential (Klabunde 2010)
During diastole, the ventricles are relaxed and there are no electric or ionic currents flowing. The inside of the cells becomes negatively charged and the outside becomes positive. This is the resting membrane potential or repolarization when the potassium channels open, allowing the exit of potassium ions out of the cell leaving the inside of the cell negative. According to Opie (2004), an initial depolarization allows the opening of the sodium and calcium voltage - gated channels, enabling the entrance of calcium and sodium into the cell making the inside of the cell positively charged.
Opie (2004), mentioned that there are five phases, namely, 0, 1, 2, 3, and 4. In phase 0, there is a rapid initial depolarization, and the Purkinje fibers reach a greater positive charge and after which the fibers repolarize more rapidly during phase 1 before it reaches the plateau phase or phase 2 (Opie 2004). Phase 0 is rapid because Purkinje fibers rapidly conduct the action potential since the duration of the action potential is longer in the Purkinje fibers. Hence, repolarization or phase 3 is slower in the Purkinje fibers.
Figure iii. Action Potential with different shapes and duration (Seeley et al. 2005)
In a study by Matsuoka et al. (2003), it was mentioned that when the production of the adenosine triphosphate (ATP) is depressed, there is shortening of the action potential. The same study has demonstrated the small influx of potassium during depolarization, and there is a delayed increase in the efflux of potassium at + 50 and 60 mv.
Faber and Rudy (2000), made a study on the sodium overload of cardiac cells which can cause fatal cardiac arrhythmias. Elevated intracellular sodium ions can shorten the rapid action potential duration in two phases, particularly in a rapid phase without accumulation of sodium and a slower phase that is sodium - dependent. The shortening of the rapid action potential duration is brought about by accumulation of potassium influx. Another result of the sodium overload on cardiac muscle is the slowing down of depolarization due to increased repolarization and reverse mode of the influx of calcium and sodium which is secondary to an elevated sodium influx over calcium. Furthermore, this can also result to the slowing down of the rate of action potential depolarization which allows more time for calcium influx. In the event that there is sodium and potassium block, the sodium and calcium ions accumulate and the action potential duration shortens. The influx of potassium and sodium to the shortening of the action potential duration cannot be avoided. The slowing down of the depolarization of the action potential and its shortening can enable sodium overload to trigger reentrant arrhythmias (Faber and Rudy 2000).
Likewise, shortened action potential duration with increased calcium levels secondary to sodium accumulation can cause arrhythmia.
In a study by Wehrens et al. (2000), they found out that when the human sodium channel alpha subunit is mutated, there is prolongation of the ventricular action potential despite the absence of a mutation - induced sustained sodium channel current. The prolonged action potential is due to calcium and its enhancement is common at slow cardiac rates which can induce arrhythmia after depolarizations.
Shaw and Rudy (1997) after doing a study on the ions in heart muscles, were able to conclude that action potential upstrokes followed by a dip, is secondary to the charging of the other adjacent downstream cell. According to Shaw and Rudy (1997), during the dip of the action potential, the influx of calcium reaches its maximum then it declines. This maximal inclination of calcium influx is in conjunction with calcium release from the sarcoplasmic reticulum and its decline is secondary to calcium inactivation or calcium - voltage gate closure. Greater inactivation of the calcium gate causes faster action potential repolarization, longer charging time of the adjoining downstream cell. Due to the small size of the calcium L channel, in the overloaded Purkinje fiber, longer intercellular charging time is essential which leads to a decreased sodium channel availability (Shaw and Rudy 1997).
In a research study by Maxwell et al. (1999), they have discovered that sodium calcium exchange is the major means of exit of calcium from the sarcolemma. And this is likewise the major entrance point of calcium. In order to maintain calcium balance greater concentration of calcium efflux is needed. The role of sarcolemmal calcium - ATPase in diastolic calcium efflux is not as significant as the sodium calcium exchange.
In an article by Beeler and Reuter (1977), it was stated that the influx of sodium is responsible for the rapid upstroke of the action potential. The action potential plateau of the heart is brought about by the slow inward flow of calcium ions. This forms a link between the ionic currents at the cell membrane and the contraction of the cardiac muscle.
Li et al. (2002), discovered that aberrations in repolarization can lead to dispersion of repolarization, which can cause a non - excitable gap reentry. Moreover, prolongation of the action potential can cause the occurrence of "early afterdepolarizations", inducing arrhythmias. Li et al. (2002), also believed that potassium current downregulation is correlated with the abnormal ventricular repolarization in heart failure.
In the study of Courtemanche et al. (1998), it was discovered that the action potential shape and ionic current densities depend on frequency and can be regulated by pharmacologic drugs. During cardiac pathologies, action potential shapes change. Some vary from triangular action potentials without plateaus to long action potentials with a spike-and-dome shape, despite its recording from atrial cells.
Catterall (2000), made a study on the voltage - gated calcium channels and found out that these channels can be mediators to calcium entry when there is membrane depolarization. Moreover, different electrophysiological studies have revealed different calcium currents namely, the L-,N-,P-,Q-,R-, and the T- type. According to Catterall (2000), the calcium v2 family of the alpha 1 subunits conduct the N - type, P or Q - type, and the R- type currents, which induce rapid synaptic transmission and modulated by direct interaction with the G proteins, SNARE proteins, and by protein phosphorylation.
Barry et al. (1995), made a study on the effects of voltage - gated potassium channel subunits in a rat's heart, and they found out that depolarization - activated exit potassium currents can affect the height and duration of the plateau phase of the action potential in heart muscle. In mammalian cardiac muscle, diverse types of depolarization - activated exit of potassium currents are detected based on the differences in time and voltage - dependent properties and sensitivities to pharmacologic drugs.
In an article by Marban et al. (2004), it was mentioned that sodium channels can be mediators of fast depolarization and conductance of electrical impulses. Moreover, these channels move in the course of gating and translocations of ions.
Ravens (2007), mentioned that the shapes of action potentials of the human heart are determined by the use of conventional microelectrodes. The ion current channels are modified once the atria and ventricles of the heart are altered in its structure and function as a result of a cardiac muscle remodeling. During cardiac muscle remodeling, the way ion channels are expressed are changed and their properties are also altered (Ravens 2007).
Clark et al. (1993), discovered in their study that action potential at the base of the left ventricle is longer than the epicardial muscle of the apex. The L - type calcium currents, the resting membrane potential, and the inward potassium current were the same in the left ventricle. The regional differences of the duration of the action potential are implicated in the repolarization in the left ventricle. Furthermore, the regional differences of action potential duration can affect the formation of the T wave in the ECG tracing, and can affect the electrical and mechanical refractoriness or restitution (Clark et al. 1993).
In an article by Dubin (n.d.), the sodium - potassium ATPase pumps are discussed with its ATP metabolization in order to maintain low intracellular sodium ions and high intracellular potassium ions. This concentration difference causes a concentration gradient for each ion across the cell membrane which means that the ions diffuse from an area of greater concentration to an area of lower concentration. The Na-K ATpase pumps according to Dubin (n.d.) use adenosine triphosphate to generate power to pump sodium into the cell and to pump potassium ions out of the cell.
In an article by Jahan (2008), the author mentioned the gradual shortening of the action potential duration shortening in the right endocardium and epicardium. They say that the longest action potential duration is found in the endocardial connective tissue and the shortest action potential duration is found in the atrioventricular region and other areas show intermediate values. The shape and duration of the action potential is dependent on its distance from the sinoatrial node. The farther it is from the sinoatrial node, the shorter the duration of the action potential (Jahan 2008).
Wong (2007), in her article, mentioned that the action potential rapidly rises from a resting membrane potential of - 70 mv, and reaching a maximum near the Nernst potential for sodium, then declines with a negative undershoot near the Nernst potential The positive feedback loop can trigger the action potential in which the initial depolarization causes the opening of the sodium channels, leading to further depolarization of the cell membrane. The outward efflux of potassium ions can cause a slower rate of rise in amplitude and is slightly delayed in its onset compared to the rapidly rising initial influx of sodium ions (Wong 2007).
In an article by Umi (2008), it mentions the physiology of the ion channels in which case when the cell is at resting membrane potential, its energy expenditure (ATP) is used to manipulate the Na+/K+ exchanger. This exchanger translocates 3 sodium ions from the inside to the outside of the cell and at the same time, translocating 2 potassium ions from the outside to the inside. This maintains a high potassium concentration inside and high sodium concentration outside of the cell. When the heart is not contracting or is at rest, the membrane potential is said to be - 90 millivolts (resting membrane potential) (Umi 2008). During this time there is a leakage of the potassium out of the cell.
Sundnes et al. (2006), states that there is a normal fast sodium inward current and a slow inward current of calcium. Changes in ionic concentrations will affect the equilibrium potential and the movement of ions.
Luo and Rudy (1991), describes the fast sodium current as a fast stroke velocity with a slow recovery from the closure of its gates. Potassium, on the other hand, is not dependent on time and it produces a negative - slope phase.
Momtaz et al. (1996), discusses the association of ventricular hypertrophy with an increased action potential plateau amplitude and duration. In this study, rats were made to drink saline or salt, which caused the ventricle to hypertrophy. It was noted that when the saline was eliminated, the condition was reversed which led to the lengthening of the action potential. It was also discovered that action potential plateau amplitude and duration tend to increase more in severe hypertrophy of the ventricle (Momtaz et al. 1996).
Varro et al. (n.d.), discovered in a study made on rabbits that at room temperature, about one - half of rabbit heart muscles have demonstrated prominent phase 1 repolarization. A study on guinea pigs heart muscles revealed that they do not produce transient outward efflux of ions. With the study on rats, Varro et al. (n.d.), discovered that the ventricular action potentials in rats are shorter than the other rodents.
Moreover, rat myocytes have demonstrated a prominent phase 1 and lacked a plateau phase at repolarization.
Payet et al. (1981), discovered that an increase of stimulation frequency resulted to a loss of the plateau with a shortening of the action potential, and an increase in the amplitude of the slow influx current.
Shigematsu et al. (n.d.), discussed the change of the duration of action potential as dependent on the rate. This prolongation was inhibited by 4 - aminopyridine which blocks the transient exit of the potassium ions. This dependence on the rate is due to the chelation of the intracellular calcium with the internal application of EGTA.
Puglisi et al. (1999), discovered that exposure to caffeine can deplete calcium ions at the sarcoplasmic reticulum. Calcium influx at temperature of 35 0 C and 25 0 C have resulted from combined higher and faster peak of calcium influx, which was further offset by a more rapid inactivation of the entrance of calcium at 35 0 C (Puglisi et al. 1999).
In a study by Clark et al. (1993), the investigators have discovered that the action potential recordings have shown a longer action potential at the endocardial tissue at the base of the left ventricle as compared from the epicardial tissue at the apex. The drug 4 - aminopyridine had a marked effect on the lengthening of the action potential and inotropic effect on epicardial cells. Similary, the L - type Calcium current, influx of potassium current, and the resting membrane potential were the same in two regions of the left ventricle (Clark et al. 1993). This paper also concluded that the different waveforms of the action potential are dependent on the different distribution of calcium - independent transient efflux of potassium current (Clark et al. 1993). Regional differences of action potential duration, can be implicated in repolarization in the rat's left ventricle, formation of T wave on ECG tracings, and for refractoriness of electrical and mechanical properties of the left ventricle (Clark et al. 1993).
George (2005), have mentioned that activation of the sodium channel is temporary due to inactivation. This sodium channel will reopen once the membrane is repolarized and recovers from inactivation. The membrane repolarization is attained when there is rapid closure of the sodium channels and it can be modulated by activation of the potassium channels.
Cardiovascular research (2003), discusses the alpha and beta subunits found in the Na, K- ATPase which serves as the vehicle for sodium and potassium to go out and enter the myocytes respectively. This active Na - K pump or the Na, K - ATPase can be inhibited by cardiac glycosides. These cardiac glycosides bind with the pump and block its enzyme activity prohibiting the exit of sodium and the entrance of potassium. This results to increased intracellular sodium and the power of the Na, Ca exchanger to drive out calcium, is diminished. The calcium eventually accumulates inside the sarcoplasmic reticulum through the SR Ca-ATPase (SERCA) which are eventually released later on depolarizations causing marked contraction of the heart. This calcium release is due to the binding of the cardiac glycosides with the Ca - release channel or the ryanodine receptor (RyR). This cardiac glycosides lead to a 'slip - mode' conduction of the sodium channels (SOC) which allow the calcium ions to enter the myocytes through this channel (Cardiovascular Research 2003).
French and Zamponi (2005), discussed the role of voltage - gated ion channels which are membrane proteins that allow specific ions to permeate with its corresponding electric current. The channels conform with the membrane which create a specific zone for respective ions to pass through. In this paper it was also mentioned that genetic mutations can cause small agitations in the channel structure.
Kharche et al. (2010), discussed the role of ionic currents on the pacemaker action potential. They have demonstrated through experiments that blocking of these currents with pharmacologic agents can simulate the 400 % increase of these currents from 100 %.
Li et al. (2004), found out that action potential duration and repolarization were longer in abnormal histology group (AH) than in relatively normal histology group (RNH). The same authors mentioned that early afterdepolarization (EADs) were demonstrated in 20 % of the abnormal histology group (AH) and none of the relatively normal histology group (Li et al. 2004). Influx and efflux of potassium were decreased. Both temporary efflux of potassium current and slowly delayed rectifier potassium current were down - regulated in abnormal histology group (AH) and the L - type calcium was not changed in the abnormal histology group (AH) (Li et al. 2004). This down - regulation causes the prolongation of the action potential duration which is more inclined to the occurrence of arrhythmia early afterdepolarizations. The latter is suggestive of cardiac structural and functional abnormalities with arrhythmogenic ionic remodeling (Li et al. 2004).
Pickoff (2008), discussed the cellular electrophysiology of the conduction system. The sinoatrial node is the normal area of action potential formation in the heart. When there is a slow depolarization of the cell from resting membrane potential of - 50 to -60 millivolts to a threshold potential during phase 4, automaticity results (Pickoff 2008). The action potential of the sinoatrial node has a slow maximum upstroke velocity of 1 to 10 V/s. This is propagated through the atria. And atrial action potentials have an - 80 to - 90 mv of resting membrane potential, a maximum upstroke velocity of 100 to 200 V/s, and lastly, an abbreviated plateau phase. Action potentials are longest in duration when located at the Purkinje fibers (Pickoff 2008). The Purkinje fibers have action potentials with a low resting membrane potential of - 90 mv, a rapid maximum upstroke velocity of 500 to 700 V/s, and a rapid conduction velocity (Pickoff 2008). Longest action potential duration is only in the Purkinje system with 300 to 500 ms (Pickoff 2008). The action potential duration in the ventricle are characterized by a resting membrane potential, maximum upstroke velocity, and duration that are less than the duration of the AP of the Purkinje system (Pickoff 2008).
Narayan et al. (2008), made a study on the action potential amplitude alternans and found out that patients with an abnormal systole demonstrated an action potential amplitude alternans that suggested the presence of a ventricular tachycardia or a ventricular fibrillation. The TWA in computer models was less than 109 beats per minute suggesting a reduction in the uptake of calcium by sarcoplasmic reticulum. Hence, this in vivo AP alternans suggest calcium abnormalities inside the cell linking it with ventricular fibrillation or ventricular tachycardia (Narayan et al. 2008).
In a study by Chockalingam and Nygren (n.d.), it was discovered that as the influx of potassium is increased, the action potential duration decreases and when there is blockage of the potassium channel completely, the action potential duration increases by 7 ms. In the same way, decreasing the influx of calcium decreases the action potential duration.
In an article by Elsevier Medical Images (n.d.), it was mentioned that the sodium and calcium currents in human atrial and ventricular cells are the same. A variety of potassium currents (Kv currents) contribute to the repolarization of the action potentials of the four chambers of the heart.
Song et al. (2005), discovered that the sensitivity of ionic channels can be changed in a way that they open in the presence of calcium, magnesium, and insulin. This is a factor significant in the repolarization of the action potential. And alterations in the non - selective cation channel can lead to arrhythmia or its inhibition.
Varro et al. (1991), revealed that the inward current of calcium and the inward rectifier potassium current control the duration of the action potential at room temperature in the right ventricle of rabbits. With rabbits, 5 seconds of pulses reveal a delayed rectifier outward current to be weaker or even absent in contrast to that of the guinea pig.
Rauwolf and Poll (2002), reported that the most important factor for the spread of electrical currents in the heart is through the versatile properties of the ionic permeation through the voltage - gated ionic channels. The opening and closing of such channels are dependent on the voltage of each.
Demir (2004), has discovered that the variations in the action potential of the right and left ventricles among 'normal, diabetic, aged and spontaneously hypertensive' rats, is due to the differences in the 4 action potential sensitive, calcium - independent temporary outward potassium current. Furthermore, another conclusion that Demir (2004) has discovered was the fact that the 'presence of the four action potential sensitive, slowly inactivating, delayed rectifier potassium current in the mouse is one of the main contributors to a faster repolarization in mouse in contrast to rats.'
Mukherjee and Spinale (n.d.), mentioned that 'severe cardiac hypertrophy and congestive heart failure' are associated with aberrant 'action potential morphology of myocytes and abnormal trans - sarcolemmal ionic currents'. Furthermore, an inference was drawn that action potential prolongation is linked with changes in the outward potassium currents and inward calcium currents (Mukherjee and Spinale n.d.).
The action potential has different shapes and duration in the heart of humans and animals. Each shape is dependent on the voltage - gated channels that are activated or inactivated. The duration of the action potential varies in regions of the heart and its length is dependent on the activation and inactivation of the voltage - gated channels as well. Depolarization is dependent on the entrance of sodium ions into the myocytes of the heart and it is initiated at the sinoatrial node of the right atrium. The entrance of calcium through the calcium - voltage gate is also another contributing factor to the depolarization of an action potential. The efflux of potassium results to a repolarization phase and eventually to a resting membrane potential. Structural defects and functional abnormalities of the heart can result to arrhythmia and heart failure.