Chapter 2_ Characteristics of Cardiac Muscle Cells | Cardiovascular Physiology: Mosby Physiology Monograph Series, 9e (Mosbys Physiology Monograph)

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Objectives

The student understands the ionic basis of the spontaneous electrical activity of cardiac muscle cells:

Describes how membrane potentials are created across semipermeable membranes by transmembrane ion concentration differences.
Defines equilibrium potential and knows its normal value for potassium and sodium ions.
States how membrane potential reflects a membrane's relative permeability to various ions.
Defines resting potential and action potential.
Describes the characteristics of "fast" and "slow" response action potentials.
Identifies the refractory periods of the cardiac cell electrical cycle.
Defines threshold potential and describes the interaction between ion channel conditions, and membrane potential during the depolarization phase of the action potential.
Defines pacemaker potential and describes the basis for rhythmic electrical activity of cardiac cells.
Lists the phases of the cardiac cell electrical cycle and states the membrane permeability alterations responsible for each phase.

The student knows the normal process of cardiac electrical excitation:

Describes gap junctions and their role in cardiac excitation.
Describes the normal pathway of action potential conduction through the heart.
Indicates the timing with which various areas of the heart are electrically excited and identifies the characteristic action potential shapes and conduction velocities in each major part of the conduction system.
States the relationship between electrical events of cardiac excitation and the P, QRS, and T waves, the PR interval, and the ST segment of the electrocardiogram.

The student understands the factors that control heart rate and action potential conduction in the heart:

States how diastolic potentials of pacemaker cells can be altered to produce changes in heart rate.
Describes how cardiac sympathetic and parasympathetic nerves alter heart rate and conduction of cardiac action potentials.
Defines the terms chronotropic and dromotropic.

The student understands the contractile processes of cardiac muscle cells:

Describes the subcellular structures responsible for cardiac muscle cell contraction.
Defines and describes the excitation-contraction process.
Defines isometric, isotonic, and afterloaded contractions of cardiac muscle.
Describes the influence of altered preload on the tension-producing and shortening capabilities of cardiac muscle.
Describes the influence of altered afterload on the shortening capabilities of cardiac muscle.
Defines the terms contractility and inotropic state and describes the influence of altered contractility on the tension-producing and shortening capabilities of cardiac muscle.
Describes the effect of altered sympathetic neural activity on cardiac inotropic state.
States the relationships between ventricular volume, muscle tension, and intraventricular pressure (Law of Laplace).

Electrical Activity of Cardiac Muscle Cells

In all striated muscle cells, contraction is triggered by a rapid voltage change called an action potential that occurs on the cell membrane. Cardiac muscle cell action potentials differ sharply from those of skeletal muscle cells in three important ways that promote synchronous rhythmic excitation of the heart: (1) they can be self-generating; (2) they can be conducted directly from cell to cell; and (3) they have long durations, which preclude fusion of individual twitch contractions. To understand these special electrical properties of cardiac muscle and how cardiac function depends on them, the basic electrical properties of excitable cell membranes must first be reviewed.

Membrane Potentials

All cells have an electrical potential (voltage) across their membranes. Such membrane potentials exist because the ionic concentrations of the cytoplasm are different from those of the interstitium and ions diffusing down concentration gradients across semipermeable membranes generate electrical gradients. The three ions that are the most important determinants of cardiac membrane potential are sodium (Na⁺) and calcium (Ca²⁺) ions, which are more concentrated in the interstitial fluid than they are inside cells, and potassium (K⁺) ions, which have the opposite distribution. The diffusion of ions across the cell membrane occurs through channels that (1) are made up of protein molecules that span the membrane, (2) are specific for an individual ion (eg, Na⁺ channels), and (3) exist in various configurations that are open, closed, or inactivated (unable to be opened). The permeability of the membrane to a specific ion is directly related to the number of open channels for that ion at any given time.

Figure 2 1 shows how ion concentration differences can generate an electrical potential across the cell membrane. Consider first, as shown at the top of this figure, a cell that (1) has K⁺ more concentrated inside the cell than out, (2) is permeable only to K⁺ (ie, only K⁺ channels are open), and (3) has no initial transmembrane potential. Because of the concentration difference, K⁺ ions (positive charges) will diffuse out of the cell. Meanwhile, negative charges, such as protein anions, cannot leave the cell because the membrane is impermeable to them. Thus, the K⁺ efflux will make the inside of the cell more electrically negative (deficient in positively charged ions) and at the same time make the interstitium more electrically positive (rich in positive ions). Now K⁺ion, being positively charged, is attracted to regions of electrical negativity. Therefore, when K⁺ diffuses out of a cell, it creates an electrical potential across the membrane that tends to attract it back into the cell. There exists one membrane potential called the potassium equilibrium potential at which the electrical forces tending to pull K⁺ into the cell exactly balance the concentration forces tending to drive K⁺ out. When the membrane potential has this value, there is no net movement of K⁺ across the membrane. With the normal concentrations of about 145 mM K⁺ inside cells and 4 mM K⁺ in the extracellular fluid, the K⁺ equilibrium potential is roughly 90 mV (more negative inside than outside by nine-hundredths of a volt).¹ A membrane that is permeable only to K⁺ will inherently and rapidly (essentially instantaneously) develop the potassium equilibrium potential. In addition, membrane potential changes require the movement of so few ions that concentration differences are not significantly affected by the process.

As depicted in the bottom half of Figure 2 1, similar reasoning shows how a membrane permeable only to Na⁺ would have the sodium equilibrium potential across it. The sodium equilibrium potential is approximately +70 mV with the normal extracellular Na⁺ concentration of 140 mM and intracellular concentration of 10 mM. Real cell membranes, however, are never permeable to just Na⁺ or just K⁺. When a membrane is permeable to both of these ions, the membrane potential will lie somewhere between the Na⁺ equilibrium potential and the K⁺ equilibrium potential. Just what membrane potential will exist at any instant depends on the relative permeability of the membrane to Na⁺ and K⁺. The more permeable the membrane to K⁺ than to Na⁺, the closer the membrane potential will be to 90 mV. Conversely, when the permeability to Na⁺ is high relative to the permeability to K⁺, the membrane potential will be closer to +70 mV.² Because of low or unchanging permeabilities or low concentration, roles played by ions other than Na⁺ and K⁺ in determining membrane potential are usually minor and often ignored. However, as will be discussed later, calcium ions (Ca²⁺) do participate in the cardiac muscle action potential. Like Na⁺, Ca²⁺ is more concentrated outside cells than inside. The equilibrium potential for Ca²⁺ is + 100 mV, and the cell membrane tends to become more positive on the inside when the membrane's permeability to Ca²⁺ rises.

Under resting conditions, most heart muscle cells have membrane potentials that are quite close to the potassium equilibrium potential. Thus, both electrical and concentration gradients favor Na⁺ entry into the resting cell. However, the very low permeability of the resting membrane to Na⁺ in combination with an energy-requiring sodium pump that extrudes Na⁺ from the cell prevents Na⁺ from gradually accumulating inside the resting cell.³

¹ The equilibrium potential (E_eq) for any ion (X^z) is determined by its intracellular and extracellular concentrations as indicated in the Nernst equation:

² A quantitative description of how Na⁺ and K⁺ concentrations and the relative permeability (P_Na/P_K) to these ions affect membrane potential (E_m) is given by the following equation:

³ The sodium pump not only removes Na⁺ from the cell but also pumps K⁺ into the cell. Since more Na⁺ is pumped out than K⁺ is pumped in (3:2), the pump is said to be electrogenic. The resting membrane potential becomes slightly less negative than normal when the pump is abruptly inhibited.

Cardiac Cell Action Potentials

Action potentials of cells from different regions of the heart are not identical but have varying characteristics that are important to the overall process of cardiac excitation.

Some cells within a specialized conduction system have the ability to act as pacemakers and to spontaneously initiate action potentials whereas ordinary cardiac muscle cells do not (except under unusual conditions). Basic membrane electrical features of an ordinary cardiac muscle cell and a cardiac pacemaker-type cell are shown in Figure 2 2. Action potentials from these cell types are referred to as "fast response" and "slow response" action potentials, respectively. As shown in panel A of this figure, fast response action potentials are characterized by a rapid depolarization (phase 0) with a substantial overshoot (positive inside voltage), a rapid reversal of the overshoot potential (phase 1), a long plateau (phase 2), and a repolarization (phase 3) to a stable, high (ie, large negative) resting membrane potential (phase 4). In comparison, the slow response action potentials are characterized by a slower initial depolarization phase, a lower amplitude overshoot, a shorter and less stable plateau phase, and a repolarization to an unstable, slowly depolarizing "resting" potential (Figure 2 2B). The unstable resting potential seen in pacemaker cells with slow response action potentials is variously referred to as the phase 4 depolarization, diastolic depolarization, or pacemaker potential.

As indicated at the bottom of Figure 2 2A, cells are in an absolute refractory state during most of the action potential (ie, they cannot be stimulated to fire another action potential). Near the end of the action potential, the membrane is relatively refractory and can be reexcited only by a larger than normal stimulus. Immediately after the action potential, the membrane is transiently hyperexcitable and is said to be in a "vulnerable" or "supranormal" period. Similar alterations in membrane excitability probably occur during slow action potentials but at present are not fully characterized.

Recall that the membrane potential of any cell depends on the relative permeability of the cell's membrane to specific ions at that instant. As in all excitable cells, cardiac cell action potentials are the result of transient changes in the ionic permeability of the cell membrane, which are triggered by an initial depolarization. Panels C and D of Figure 2 2 indicate the changes in membrane permeabilities to K⁺, Na⁺, and Ca²⁺, which produce the various phases of the fast and slow response action potentials. Note that during the resting phase, the membranes of both types of cells are more permeable to K⁺ than to Na⁺ or Ca²⁺. Therefore, the membrane potentials are close to the potassium equilibrium potential (of 90 mV) during this period. In the pacemaker-type cells, at least three mechanisms are thought to contribute to the slow depolarization of the membrane observed during the diastolic interval. First, there is a progressive decrease in the membrane s permeability to K⁺ during the resting phase, and second, the permeability to Na⁺ increases slightly. The gradual increase in the Na⁺/K⁺ permeability ratio will cause the membrane potential to move slowly away from the K⁺ equilibrium potential ( 90 mV) in the direction of the Na⁺ equilibrium potential. Third, there is an increase in the permeability of the membrane to calcium ions, which results in an inward movement of positively charged ions and also contributes to the diastolic depolarization.

When the membrane potential depolarizes to a certain threshold potential in either type of cell, major rapid alterations in the permeability of the membrane to specific ions are triggered. Once initiated, these permeability changes cannot be stopped and they proceed to completion.

The characteristic rapid rising phase of the fast response action potential is a result of a sudden increase in Na⁺ permeability. This produces what is referred to as the fast inward current of Na⁺ and causes the membrane potential to move rapidly toward the sodium equilibrium potential. As indicated in panel C of Figure 2 2, this period of very high sodium permeability is short-lived. It is followed by a more slowly developed increase in the membrane's permeability to Ca²⁺ and a decrease in its permeability to K⁺. Also, there is a second slowly developing increase in Na⁺ permeability, which is thought to be caused by a different mechanism than that involved in the initial rapid Na⁺ permeability changes. These more persistent permeability changes (which produce what is referred to as the slow inward current) prolong the depolarized state of the membrane to cause the plateau (phase 2) of the cardiac action potential. The initial fast inward current is small (or even absent) in cells that have slow response action potentials. The slow rising phase of these action potentials is therefore primarily a result of an inward movement of Ca²⁺ ions. In both types of cells, the membrane is repolarized (phase 3) to its original resting potential as the K⁺ permeability increases and the Ca²⁺ and Na⁺ permeabilities return to their low resting values. These late permeability changes produce what is referred to as the delayed outward current.

The overall smoothly graded permeability changes that produce action potentials are the net result of alterations in each of the many individual ion channels within the plasma membrane of a single cell. The experimental technique of patch clamping has made it possible to study the operation of individual ion channels. The patch clamp data clearly indicate that a single channel is either open or closed at any instant in time; there are no graded states of partial opening. What is graded is the percentage of time that a channel spends in the open state, ie, its probability of being open. While a channel may remain closed for long periods, it rarely remains open for more than a few milliseconds at a time. Thus, the probability of a channel's being open depends both on the frequency with which it opens and how long it remains open. An increase in an ion channel's probability of being open (channel "activation") leads to an increase in total open time and an increase in the overall membrane permeability to that ion.

Certain types of channels are called voltage-gated channels (or voltage-operated channels) because their probability of being open varies with membrane potential. Other types of channels, called ligand-gated channels (or receptor-operated channels), are activated by certain neurotransmitters or other specific signal molecules. Table 2 1, at the end of this section, lists some of the major currents and channel types involved in cardiac cell electrical activity.

Table 2 1. Characteristics of Important Cardiac Ion Channels in Order of Their Participation in an Action Potential.

Current	Channel	Gating mechanism	Functional role
i_K1	K⁺ channel (inward rectifier)	Voltage	Maintains high K⁺ permeability during phase 4 Its decay contributes to diastolic depolarization Its suppression during phases 0 to 2 contribute to plateau
i_Na	Na⁺ channel (fast)	Voltage	Accounts for phase 0 of action potential Inactivation may contribute to phase 1 of action potential
i_To	K⁺ channel (transient outward)	Voltage	Contributes to phase 1 of action potential
i_Ca	Ca²⁺ channel (slow inward, L channels)	Voltage	Primarily responsible for phase 2 of action potential Inactivation may contribute to phase 3 of action potential Is enhanced by sympathetic stimulation and -adrenergic agents
i_K	K⁺ channel (delayed rectifier)	Voltage	Causes phase 3 of action potential May be enhanced by increased intracellular Ca²⁺
i_KATP	K⁺ channel (ATP-sensitive)	Ligand	Increases K⁺ permeability when [ATP] is low
i_KACh	K⁺ channel (acetylcholine-activated)	Ligand	Responsible for effects of vagal stimulation Decreases diastolic depolarization (and heart rate) Hyperpolarizes resting membrane potential Shortens phase 2 of the action potential
i_f("funny")	Na⁺ channel (pacemaker current)	Both	Contributes to the diastolic depolarization Is enhanced by sympathetic stimulation and -adrenergic agents Is suppressed by vagal stimulation

Some of the voltage-gated channels respond to a sudden onset, sustained change in membrane potential by only a brief period of activation. However, changes in membrane potential of slower onset but the same magnitude may fail to activate these channels at all. To explain such behavior, it is postulated that these channels have two independently operating "gates" an activation gate and an inactivation gate both of which must be open for the channel as a whole to be open. These gates both respond to changes in membrane potential but do so with different voltage sensitivities and time courses.

These concepts are illustrated in Figure 2 3. In the resting state, with the membrane polarized to near 80 mV, the activation or m gate of the fast Na⁺ channel is closed, but its inactivation or h gate is open (Figure 2 3A). With a rapid depolarization of the membrane to threshold, the Na⁺ channels will be activated strongly to allow an inrush of positive sodium ions that further depolarizes the membrane and thus initiates a "fast" response action potential as illustrated in Figure 2 3B. This occurs because the m gate responds to membrane depolarization by opening more quickly than the h gate responds by closing. Thus a rapid depolarization to threshold is followed by a brief but strong period of Na⁺ channel activation wherein the m gate is open but the h gate has yet to close.

The initial membrane depolarization also causes the activation (d) gate of the Ca²⁺ channel to open after a brief delay. This permits the slow inward current of Ca²⁺ ions, which helps maintain the depolarization through the plateau phase of the action potential (Figure 2 3C). Ultimately, repolarization occurs because of both a delayed inactivation of the Ca²⁺ channel (by closure of the f gates) and an opening of K⁺ channels (which are not shown in Figure 2 3). Multiple factors influence the operation of K⁺ channels. For example, high intracellular Ca²⁺ concentration contributes to activation of K⁺ channels during repolarization. The h gates of sodium channels remain closed during the remainder of the action potential, effectively inactivating the Na⁺ channel and contributing to the long cardiac refractory period which lasts until the end of phase 3. With repolarization, both gates of the sodium channel return to their original position and the channel is now ready to be reactivated by a subsequent depolarization.

The slow response action potential shown in the right half of Figure 2 3 differs from the fast response action potential primarily because of the lack of a strong activation of the fast Na⁺ channel at its onset. This is a direct consequence of a slow depolarization to the threshold potential. Slow depolarization gives the inactivating h gates time to close even as the activating m gates are opening (Figure 2 3D). Thus, in a slow response action potential, there is no initial period where all the sodium channels of a cell are essentially open at once. The depolarization beyond threshold is slow and caused primarily by the influx of Ca²⁺ through slow channels (Figure 2 3E).

While cells in certain areas of the heart typically have fast-type action potentials and cells in other areas normally have slow-type action potentials, it is important to recognize that all cardiac cells are potentially capable of having either type of action potential depending on how fast they depolarize to the threshold potential. As we shall see, rapid depolarization to the threshold potential is usually an event forced on a cell by the occurrence of an action potential in an adjacent cell. Slow depolarization to threshold occurs when a cell itself spontaneously and gradually loses its resting polarization, which normally happens only in the sinoatrial (SA) node. A chronic moderate depolarization of the resting membrane (caused, for example, by moderately high extracellular K⁺ concentration) can inactivate the fast channels (by closing the h gates) without inactivating the slow Ca²⁺ channels. Under these conditions, all cardiac cell action potentials will be of the slow type. Large sustained depolarizations, however, can inactivate both the fast and slow channels and thus make the cardiac muscle cells inexcitable.

Conduction of Cardiac Action Potentials

Action potentials are conducted over the surface of individual cells because active depolarization in any one area of the membrane produces local currents in the intracellular and extracellular fluids which passively depolarize immediately adjacent areas of the membrane to their voltage threshold for active depolarization.

In the heart, cardiac muscle cells are connected end-to-end by structures called intercalated disks. These disks contain the following: (1) firm mechanical attachments between adjacent cell membranes by proteins called adherins in structures called desmosomes and (2) low resistance electrical connections between adjacent cells through channels formed by protein called connexin in structures called gap junctions. Figure 2 4 shows schematically how these gap junctions allow action potential propagation from cell to cell.

Cells B, C, and D are shown in the resting phase with more negative charges on the inside than the outside. Cell A is shown in the plateau phase of an action potential and has more positive charges inside than out. Because of the gap junctions, electrostatic attraction can cause a local current flow (ion movement) between the depolarized membrane of active cell A and the polarized membrane of resting cell B, as indicated by the arrows in the figure. This ion movement tends to eliminate the charge difference across the resting membrane; ie, it depolarizes the membrane of cell B. Once the local currents from active cell A depolarize the membrane of cell B near the gap junction to the threshold level, an action potential will be triggered at that site and will be conducted over cell B. Because cell B branches (a common morphological characteristic of cardiac muscle fibers), its action potential will evoke action potentials on cells C and D. This process is continued through the entire myocardium. Thus, an action potential initiated at any site in the myocardium will be conducted from cell-to-cell throughout the entire myocardium.

The speed at which an action potential propagates through a region of cardiac tissue is called the conduction velocity. The conduction velocity varies considerably in different areas in the heart. This velocity is directly dependent on the diameter of the muscle fiber involved. Thus, conduction over small-diameter cells in the atrioventricular (AV) node is significantly slower than conduction over large-diameter cells in the ventricular Purkinje system. Conduction velocity is also directly dependent on the intensity of the local depolarizing currents, which are in turn directly determined by the rate of rise of the action potential. Rapid depolarization favors rapid conduction. Variations in the capacitive and/or resistive properties of the cell membranes, gap junctions, and cytoplasm are also factors that contribute to the differences in conduction velocity of action potentials through specific areas of the heart.

Details of the cardiac conduction system are shown in Figure 2 5. Specific electrical adaptations of various cells in the heart are reflected in the characteristic shape of their action potentials, as shown in the right half of Figure 2 5. Note that the action potentials shown in Figure 2 5 have been positioned to indicate the time at which the electrical impulse that originates in the SA node reaches other areas of the heart. Cells of the SA node act as the heart's normal pacemaker and determine the heart rate. This is because the spontaneous depolarization of the resting membrane is most rapid in SA nodal cells, and they reach their threshold potential before cells elsewhere.

The action potential initiated by an SA nodal cell first spreads progressively through the atrial wall. Action potentials from cells in two different regions of the atria are shown in Figure 2 5: one close to the SA node and one more distant from the SA node. Both cells have similarly shaped action potentials, but their temporal displacement reflects the fact that it takes some time for the impulse to spread over the atria.

As shown in Figure 2 5, action potential conduction is greatly slowed as it passes through the AV node. This is because of the small size of the AV nodal cells and the slow rate of rise of their action potentials. Since the AV node delays the transfer of the cardiac excitation from the atria to the ventricles, atrial contraction can contribute to ventricular filling just before the ventricles contract. Note also that AV nodal cells have a faster spontaneous depolarization during the resting period than other cells of the heart except those of the SA node. The AV node is sometimes referred to as a latent pacemaker, and in many pathological situations it (rather than the SA node) controls the heart rhythm.

Because of sharply rising action potentials and other factors, such as large cell diameters, electrical conduction is extremely rapid in Purkinje fibers. This allows the Purkinje system to transfer the cardiac impulse to cells in many areas of the ventricle nearly in unison. Action potentials from muscle cells in two areas of the ventricle are shown in Figure 2 5. Because of the high conduction velocity in ventricular tissue, there is only a small discrepancy in their time of onset. Note in Figure 2 5 that the ventricular cells which are the last to depolarize have shorter duration action potentials and thus are the first to repolarize. The physiological importance of this unexpected behavior is not clear but it does have an influence on the electrocardiograms that will be discussed in Chapter 4.

Electrocardiograms

Fields of electrical potential caused by the electrical activity of the heart extend through the body tissue and may be measured with electrodes placed on the body surface. Electrocardiography provides a record of how the voltage between two points on the body surface changes with time as a result of the electrical events of the cardiac cycle. At any instant of the cardiac cycle the electrocardiogram indicates the net electrical field that is the summation of many weak electrical fields being produced by voltage changes occurring on individual cardiac cells at that instant. When a large number of cells are simultaneously depolarizing or repolarizing, large voltages are observed on the electrocardiogram. Since the electrical impulse spreads through the heart tissue in a stereotyped manner, the temporal pattern of voltage change recorded between two points on the body surface is also stereotyped and will repeat itself with each heart cycle.

The lower trace of Figure 2 5 represents a typical recording of the voltage changes normally measured between the right arm and the left leg as the heart goes through two cycles of electrical excitation; this record is called a lead II electrocardiogram and will be discussed in detail in Chapter 4. The major features of an electrocardiogram are the P wave, the QRS complex, and the T wave. The P wave corresponds to atrial depolarization, the QRS complex to ventricular depolarization, and the T wave to ventricular repolarization.

Control of Heart Beating Rate

Normal rhythmic contractions of the heart occur because of spontaneous electrical pacemaker activity (automaticity) of cells in the SA node. The interval between heartbeats (and thus the heart rate) is determined by how long it takes the membranes of these pacemaker cells to spontaneously depolarize to the threshold level. The SA nodal cells fire at a spontaneous or intrinsic rate (100 beats per minute) in the absence of any outside influences. Outside influences are required, however, to increase or decrease automaticity from its intrinsic level.

The two most important outside influences on automaticity of SA nodal cells come from the autonomic nervous system. Fibers from both the sympathetic and parasympathetic divisions of the autonomic system terminate on cells in the SA node and these fibers can modify the intrinsic heart rate. Activating the cardiac sympathetic nerves (increasing cardiac sympathetic tone) increases the heart rate. Increasing cardiac parasympathetic tone slows the heart. As shown in Figure 2 6, the parasympathetic and sympathetic nerves both influence heart rate by altering the course of spontaneous depolarization of the resting potential in SA pacemaker cells.

Cardiac parasympathetic fibers, which travel to the heart through the vagus nerves, release the transmitter substance acetylcholine on SA nodal cells. Acetylcholine increases the permeability of the resting membrane to K⁺ and decreases the diastolic permeability to Na⁺.⁴ As indicated in Figure 2 6, these permeability changes have two effects on the resting potential of cardiac pacemaker cells: (1) they cause an initial hyperpolarization of the resting membrane potential by bringing it closer to the K⁺ equilibrium potential and (2) they slow the rate of spontaneous depolarization of the resting membrane. Both these effects increase the time between beats by prolonging the time required for the resting membrane to depolarize to the threshold level. Since there is normally some continuous tonic activity of cardiac parasympathetic nerves, the normal resting heart rate is approximately 70 beats per minute.

Sympathetic nerves release the transmitter substance norepinephrine on cardiac cells. In addition to other effects discussed later, norepinephrine increases the inward currents carried by Na⁺ (i_f) and by Ca²⁺ during the diastolic interval.⁵ These changes will increase heart rate by increasing the rate of diastolic depolarization as shown in Figure 2 6.

In addition to sympathetic and parasympathetic nerves, there are many (usually less important) factors that can alter heart rate. These include a number of ions and circulating hormones, as well as physical influences such as temperature and atrial wall stretch. All act by somehow altering the time required for the resting membrane to depolarize to the threshold potential. An abnormally high concentration of Ca²⁺ in the extracellular fluid, for example, tends to decrease heart rate by shifting the threshold potential. Factors that increase heart rate are said to have a positive chronotropic effect. Those that decrease heart rate have a negative chronotropic effect.

Besides their effect on heart rate, autonomic fibers also influence the conduction velocity of action potentials through the heart. Increases in sympathetic activity increase conduction velocity (have a positive dromotropic effect), whereas increases in parasympathetic activity decrease conduction velocity (have a negative dromotropic effect). These effects are most notable at the AV node and can influence the duration of the PR interval.

⁴ Acetylcholine interacts with a muscarinic receptor on the SA nodal cell membrane which in turn is linked to an inhibitory G protein, G_i. The activation of G_i has two effects: (1) an increase in K⁺ conductance resulting from an increased opening of the K_Ach channels and (2) a suppression of adenylate cyclase leading to a fall in intracellular cyclic adenosine monophosphate (cAMP) which reduces the inward-going pacemaker current carried by Na⁺ (i_f).

⁵ Norepinephrine interacts with ₁-adrenergic receptors on the SA nodal cell membrane which in turn are linked to stimulatory G proteins, G_s. The activation of G_s increases adenylate cyclase, leading to an increase in intracellular cyclic AMP which increases the open-state probability of the pacemaker Na⁺ current channel (i_f).

Mechanical Activity of the Heart

Cardiac Muscle Contraction

Contraction of the cardiac muscle cell is initiated by the action potential signal acting on intracellular organelles to evoke tension generation and/or shortening of the cell. In this section, we shall describe (1) the subcellular processes involved in coupling the excitation to the contraction of the cell (E-C coupling) and (2) the mechanical properties of cardiac cells.

Basic histological features of cardiac muscle cells are quite similar to those of skeletal muscle cells and include: (1) an extensive myofibrillar structure made up of parallel interdigitating thick and thin filaments arranged in serial units called sarcomeres, which are responsible for the mechanical processes of shortening and tension development⁶; (2) an internal compartmentation of the cytoplasm by an intracellular membrane system called the sarcoplasmic reticulum (SR), which sequesters calcium during the diastolic interval with the help of the calcium-storage protein, calsequestrin; (3) regularly spaced extensive invaginations of the cell membrane (sarcolemma), called T tubules, which appear to be connected to parts of the SR ("junctional" SR) by dense strands ("feet") and which carry the action potential signal to the inner parts of the cell; and (4) large numbers of mitochondria that provide the oxidative phosphorylation pathways needed to ensure a ready supply of adenosine triphosphate (ATP) to meet the high metabolic needs of cardiac muscle. Students are encouraged to consult a histology textbook for specific cellular morphological details.

⁶ Proteins making up the thick and thin filaments are collectively referred to as "contractile proteins." The thick filament consists of a protein called myosin, which has a long straight tail with two globular heads each of which contains an adenosine triphosphate (ATP)-binding site and an actin-binding site; light chains are loosely associated with the heads and their phosphorylation may regulate (or modulate) muscle function. The thin filament consists of several proteins including actin two -helical strands of polymerized subunits (g-actin) with sites that interact with the heads of myosin molecules to form cross-bridges with the thick filaments; tropomyosin a regulatory fibrous-type protein lying in the groove of the actin helix which prevents actin from interacting with myosin when the muscle is at rest; and troponin a regulatory protein consisting of three subunits: troponin C, which binds calcium ions during activation and initiates the configurational changes in the regulatory proteins that expose the actin site for cross-bridge formation; troponin T, which anchors the troponin complex to tropomyosin; and troponin I, which participates in the inhibition of actin-myosin interaction at rest. In addition, the macromolecule titin extends from the Z disk to the M line and contributes significantly to the passive stiffness of cardiac muscle over its normal working range.

Excitation-Contraction Coupling

Muscle action potentials trigger mechanical contraction through a process called excitation-contraction coupling, which is illustrated in Figure 2 7. The major event of excitation-contraction coupling is a dramatic rise in the intracellular free Ca²⁺ concentration. The "resting" intracellular free Ca²⁺ concentration is less than 0.1 M. In contrast, during maximum activation of the contractile apparatus, the intracellular free Ca²⁺ concentration reaches nearly 100 M. When the wave of depolarization passes over the muscle cell membrane and down the T tubules, Ca²⁺ is released from the SR into the intracellular fluid.

As indicated on the left side of Figure 2 7, the specific trigger for this release appears to be the entry of calcium into the cell via the L-type calcium channels and an increase in Ca²⁺ concentration in the region just under the sarcolemma on the surface of the cell and throughout the t-tubular system. Unlike skeletal muscle, this highly localized increase in calcium is essential for triggering the massive release of calcium from the SR. This calcium-induced calcium release is a result of opening calcium-sensitive release channels on the SR.⁷ Although the amount of Ca²⁺ that enters the cell during a single action potential is quite small compared with that released from the SR, it is not only essential for triggering the SR calcium release but also essential for maintaining adequate levels of Ca²⁺ in the intracellular stores over the long run.

When the intracellular Ca²⁺ level is high (>1.0 M), links called cross-bridges form between two types of filaments found within muscle. Sarcomere units, as depicted in the lower part of Figure 2 7, are joined end to end at Z lines to form myofibrils, which run the length of the muscle cell. During contraction, thick and thin filaments slide past one another to shorten each sarcomere and thus the muscle as a whole. The bridges form when the regularly spaced myosin heads from thick filaments attach to regularly spaced sites on the actin molecules in the thin filaments. Subsequent deformation of the bridges result in a pulling of the actin molecules toward the center of the sarcomere. This actin-myosin interaction requires energy from ATP. In resting muscles, the attachment of myosin to the actin sites is inhibited by troponin and tropomyosin. Calcium causes muscle contraction by interacting with troponin C to cause a configurational change that removes the inhibition of the actin sites on the thin filament. Since a single cross-bridge is a very short structure, gross muscle shortening requires that cross-bridges repetitively form, produce incremental movement between the myofilaments, detach, form again at a new actin site, and so on, in a cyclic manner.

There are several processes that participate in the reduction of intracellular Ca²⁺ that terminates the contraction. These processes are illustrated on the right side of Figure 2 7. Approximately 80% of the calcium is actively taken back up into the SR by the action of Ca²⁺-ATPase pumps located in the network part of the SR.⁸ About 20% of the calcium is extruded from the cell into the extracellular fluid either via the Na⁺-Ca²⁺ exchanger located in the sarcolemma⁹ or via sarcolemmal Ca²⁺-ATPase pumps.

Excitation-contraction coupling in cardiac muscle is different from that in skeletal muscle in that it may be modulated; different intensities of actin-myosin interaction (contraction) can result from a single action potential trigger in cardiac muscle. The mechanism for this seems to be dependent on variations in the amount of Ca²⁺ reaching the myofilaments and therefore the number of cross-bridges activated during the twitch. This ability of cardiac muscle to vary its contractile strength ie, change its contractility is extremely important to cardiac function, as will be discussed in a later section of this chapter.

The duration of the cardiac muscle cell contraction is approximately the same as that of its action potential. Therefore, the electrical refractory period of a cardiac muscle cell is not over until the mechanical response is completed. As a consequence, heart muscle cells cannot be activated rapidly enough to cause a fused (tetanic) state of prolonged contraction. This is fortunate because intermittent contraction and relaxation are essential for the heart's pumping action.

⁷ These channels may be blocked by the plant alkaloid ryanodine and are activated by the methylxanthine caffeine. These agents are chemical tools used to assess properties of these SR channels.

⁸ The action of these pumps is regulated by the protein phospholamban. When this protein is phosphorylated (for example, by the action of norepinephrine) the rate of Ca²⁺ resequestration is increased and the rate of relaxation is enhanced.

⁹ The Na⁺-Ca²⁺ exchanger is powered by the sodium gradient across the sarcolemma which in turn is maintained by the Na⁺/K⁺ ATPase. This exchanger is electrogenic in that three Na⁺ ions move into the cell in exchange for each Ca²⁺ ion that moves out. This net inward movement of positive charge may contribute to the maintenance of the plateau phase of the action potential. The cardiac glycoside, digitalis, slows down the Na⁺/K⁺ pump and thus reduces the sodium gradient which in turn results in an increase in intracellular Ca²⁺. This mechanism contributes to the positive effect of cardiac glycosides on the contractile force of the failing heart.

Cardiac Muscle Cell Mechanics

The cross-bridge interaction that occurs after a muscle is activated to contract gives the muscle the potential to develop force and/or shorten. Whether it does one, the other, or some combination of the two depends primarily on what is allowed to happen by the external constraints placed on the muscle during the contraction. For example, activating a muscle whose ends are held rigidly causes it to develop tension, but it cannot shorten. This is called an isometric ("fixed length") contraction. The force that a muscle produces during an isometric contraction indicates its maximum ability to develop tension. At the other extreme, activating an unrestrained muscle causes it to shorten without force development because it has nothing to develop force against. This type of contraction is called an isotonic ("fixed tension") contraction. Under such conditions, a muscle shortens with its maximum possible velocity (called V_max), which is determined by the maximum possible rate of cross-bridge cycling. Adding load to the muscle decreases the velocity and extent of its shortening. Thus, the course of a muscle contraction depends both on the inherent capabilities of the muscle and the external constraints placed on the muscle during contraction. Muscle cells in the ventricular wall operate under different constraints during different phases of each cardiac cycle. To understand ventricular function, the manner in which cardiac muscle behaves when constrained in several different ways must first be examined.

Isometric Contractions: Length-Tension Relationships

The influence of muscle length on the behavior of cardiac muscle during isometric contraction is illustrated in Figure 2 8. The top panel shows the experimental arrangement for measuring muscle force at rest and during contraction at three different lengths. The middle panel shows time records of muscle tensions recorded at each of the three lengths in response to an external stimulus, and the bottom panel shows a graph of the resting and peak tension results plotted against muscle length.

The first important fact illustrated in Figure 2 8 is that force is required to stretch a resting muscle to different lengths. This force is called the resting tension. The lower curve in the graph in Figure 2 8 shows the resting tension measured at different muscle lengths and is referred to as the resting length-tension curve. When a muscle is stimulated to contract while its length is held constant, it develops an additional component of tension called active or developed tension. The total tension exerted by a muscle during contraction is the sum of the active and resting tensions.

The second important fact illustrated in Figure 2 8 is that the active tension developed by cardiac muscle during the course of an isometric contraction depends very much on the muscle length at which the contraction occurs. Active tension development is maximum at some intermediate length referred to as L_max. Little active tension is developed at very short or very long muscle lengths. Normally, cardiac muscle operates at lengths well below L_max, so that increasing muscle length increases the tension developed during an isometric contraction.

There are three separate mechanisms that have been proposed to explain the relationship between muscle length and developed tension. The first mechanism to be identified suggests that this relationship depends on the extent of overlap of the thick and thin filaments in the sarcomere at rest. Histological studies indicate that the changes in the resting length of the whole muscle are associated with proportional changes in the individual sarcomeres. Peak tension development occurs at sarcomere lengths of 2.2 to 2.3 m. At sarcomere lengths shorter than 2.0 m, the opposing thin filaments may overlap or buckle and thus interfere with active tension development as shown at the top of Figure 2 8. At long sarcomere lengths, overlap may be insufficient for optimal cross-bridge formation.

The second (and perhaps more important) mechanism is based on a length-dependent change in sensitivity of the myofilaments to calcium. At short lengths only a fraction of the potential cross-bridges are apparently activated by a given increase in intracellular calcium. At longer lengths, more of the cross-bridges become activated, leading to an increase in active tension development. This change in calcium sensitivity occurs immediately after a change in length with no time delay. The "sensor" responsible for the length-dependent activation of cardiac muscle seems to reside with the troponin C molecule, but how it happens is not fully understood.

The third mechanism rests on the observation that within several minutes after increasing the resting length of cardiac muscle, there is an increase in the amount of calcium that is released with excitation, which is coupled to a further increase in force development. It is thought that stretch-sensitive ion channels in the cell membranes may be responsible for this delayed response.

To what extent each of these mechanisms is contributing to the length-dependency of cardiac contractile force at any instant is not clear, nor very important in this discussion. The important point is that the dependence of active tension development on muscle length is a fundamental property of cardiac muscle that has extremely powerful effects on heart function.

Isotonic & Afterloaded Contractions

During what is termed isotonic ("fixed load") contraction, a muscle shortens against a constant load. A muscle contracts isotonically when lifting a fixed weight such as the 1-g load shown in Figure 2 9. Such a 1-g weight placed on a resting muscle will result in some specific resting muscle length, which is determined by the muscle's resting length-tension curve. If the muscle were to contract isometrically at this length, it would be capable of generating a certain amount of tension, eg, 4.5 g as indicated by the dashed line in the graph of Figure 2 9. A contractile tension of 4.5 g obviously cannot be generated while lifting a 1-g weight. When a muscle has contractile potential in excess of the tension it is actually developing, it shortens. Thus in an isotonic contraction, muscle length decreases at constant tension, as illustrated by the horizontal arrow from point 1 to point 3 in Figure 2 9. As the muscle shortens, however, its contractile potential inherently decreases, as indicated by the downward slope of the peak isometric tension curve in Figure 2 9. There exists some short length at which the muscle is capable of generating only 1 g of tension, and when this length is reached, shortening must cease.¹⁰ Thus the curve on the cardiac muscle length-tension diagram that indicates how much isometric tension a muscle can develop at various lengths also establishes the limit on how far muscle shortening can proceed with different loads.

Figure 2 9 also shows a complex type of muscle contraction called an afterloaded isotonic contraction, in which the load on the muscle at rest, the preload, and the load on the muscle during contraction, the total load, are different. In the example of Figure 2 9 the preload is equal to 1 g, and because an additional 2-g weight (the afterload) is engaged during contraction, the total load equals 3 g.

Since preload determines the resting muscle length, both isotonic contractions shown in Figure 2 9 begin from the same length. Because of the different loading arrangement, however, the afterloaded muscle must increase its total tension to 3 g before it can shorten. This initial tension will be developed isometrically and can be represented as going from point 1 to point 4 on the length-tension diagram. Once the muscle generates enough tension to equal the total load, its tension output is fixed at 3 g and it will now shorten isotonically because its contractile potential still exceeds its tension output. This isotonic shortening is represented as a horizontal movement on the length-tension diagram along the line from point 4 to point 5. As in any isotonic contraction, shortening must cease when the muscle's tension-producing potential is decreased sufficiently by the length change to be equal to the load on the muscle. Note that the afterloaded muscle shortens less than the nonafterloaded muscle even though both muscles began contracting at the same initial length. The factors that affect the extent of cardiac muscle shortening during an afterloaded contraction are of special interest to us, because, as we shall see, stroke volume is determined by how far cardiac muscle shortens under these conditions.

¹⁰ In reality, muscle shortening requires some time and the duration of a muscle twitch contraction is limited because intracellular Ca²⁺ levels are elevated only briefly following the initiation of a membrane action potential. For this and possibly other reasons, isotonic shortening may not actually proceed quite as far as the isometric tension development curve on the length-tension diagram suggests is possible. Since this complication does not alter the general correspondence between a muscle's isometric and isotonic performance, we choose to ignore it.

Cardiac Muscle Contractility

A number of factors in addition to initial muscle length can affect the tension-generating potential of cardiac muscle. Any intervention that increases the peak isometric tension that a muscle can develop at a fixed length is said to increase cardiac muscle contractility. Such an agent is said to have a positive inotropic effect on the heart.

The most important physiological regulator of cardiac muscle contractility is norepinephrine. When norepinephrine is released on cardiac muscle cells from sympathetic nerves, it has not only the chronotropic effect on heart rate discussed earlier but also a pronounced positive inotropic effect that causes cardiac muscle cells to contract more rapidly and forcefully.

The positive effect of norepinephrine on the isometric tension-generating potential is illustrated in Figure 2 10A. When norepinephrine is present in the solution bathing cardiac muscle, the muscle will, at every length, develop more isometric tension when stimulated than it would in the absence of norepinephrine. In short, norepinephrine raises the peak isometric tension curve on the cardiac muscle length-tension graph. Norepinephrine is said to increase cardiac muscle contractility because it enhances the forcefulness of muscle contraction even when length is constant. Changes in contractility and initial length can occur simultaneously, but by definition a change in contractility must involve a shift from one peak isometric length-tension curve to another.

Figure 2 10B shows how raising the peak isometric length-tension curve with norepinephrine increases the amount of shortening in afterloaded contractions of cardiac muscle. With preload and total load constant, more shortening occurs in the presence of norepinephrine than in its absence. This is because when contractility is increased, the tension-generating potential is equal to the total load at a shorter muscle length. Note that norepinephrine has no effect on the resting length-tension relationship of cardiac muscle. Thus norepinephrine causes increased shortening by changing the final but not the initial muscle length associated with afterloaded contractions.

The cellular mechanism of the norepinephrine effect on contractility is mediated by its interaction with a ₁-adrenergic receptor. The signaling pathway involves an activation of the G_s protein-cAMP-protein kinase A, which then phosphorylates the Ca²⁺ channel increasing the inward calcium current during the plateau of the action potential. This increase in calcium influx not only contributes to the magnitude of the rise in intracellular Ca²⁺ for a given beat but also loads the internal calcium stores, which allows more to be released during subsequent depolarizations. This increase in free Ca²⁺ during activation allows more cross-bridges to be formed and greater tension to be developed.

Because norepinephrine also causes phosphorylation of the regulatory protein, phospholamban, on the sarcoplasmic reticular Ca²⁺ ATPase pump, the rate of calcium retrapping into the SR is enhanced and the rate of relaxation is increased. This is called a positive lusitropic effect. In addition to more rapid calcium retrapping by the SR, there is also a norepinephrine-induced decrease in the action potential duration. This effect is achieved by a potassium channel alteration, occurring in response to the elevated intracellular[Ca²⁺], that increases potassium permeability, terminates the plateau phase of the action potential and contributes to the early relaxation. Such shortening of the systolic interval is helpful in the presence of elevated heart rates that might otherwise significantly compromise diastolic filling time.

Enhanced parasympathetic activity has been shown to have a small negative inotropic effect upon the heart. In the atria, where this effect is most pronounced, the negative inotropic effect is thought to be due to a shortening of the action potential and a decrease in the amount of Ca²⁺ that enters the cell during the action potential.

Changes in heart rate also influence cardiac contractility. Recall that a small amount of extracellular Ca²⁺ enters the cell during the plateau phase of each action potential. As the heart rate increases, more Ca²⁺ enters the cells per minute. There is a buildup of intracellular Ca²⁺ and a greater amount of Ca²⁺ is released into the sarcoplasm with each action potential. Thus, a sudden increase in beating rate is followed by a progressive increase in contractile force to a higher plateau. This behavior is called the staircase phenomenon (or treppe). Changes in contractility produced by this intrinsic mechanism are sometimes referred to as homeometric autoregulation. The importance of such rate-dependent modulation of contractility in normal ventricular function is not clear at present.

The contractility of isolated cardiac muscle is often assessed by first determining the peak velocity of shortening of the preparation during isotonic contractions against several different total loads. The data obtained are used to construct what is known as the muscle force-velocity relationship as shown in Figure 2 11A. The force-velocity relationship indicates the trade-off between force development and shortening velocity, which is inherent in the contractile machinery of all muscle. The isometric force generating capability of the muscle is indicated by the point where the curve intersects the force axis. The point where the force-velocity curve intersects the velocity axis is called V_max. This V_max point has been shown to be closely correlated with the actin-myosin ATPase activity of the muscle and is thought to indicate the maximum possible rate of interaction between thick and thin filaments within the sarcomere. The V_max value is commonly used as an index of the contractility of isolated cardiac muscle. Figure 2 11B shows the effect of norepinephrine (or other inotropic agents) on the force-velocity relationship. Note that both peak isometric tension and V_max become elevated with increases in the contractility of the preparation.

Relating Cardiac Muscle Cell Mechanics to Ventricular Function

Certain geometric factors dictate how the length-tension relationships of cardiac muscle fibers in the ventricular wall determine the volume and pressure relationships of the ventricular chamber. The actual relationships are complex because the shape of the ventricle is complex. The ventricle is often modeled as either a cylinder or a sphere, although its actual shape lies somewhere between the two. Because cardiac muscle cells are oriented circumferentially in the ventricular wall, either model can be used to illustrate three important functional points:

1. An increase in ventricular volume causes an increase in ventricular circumference and therefore an increase in the length of the individual cardiac muscle cells (and vice-versa).

2. At any given ventricular volume, an increase in the tension of individual cardiac muscle cells in the wall causes an increase in intraventricular pressure (and vice versa).

3. As ventricular volume increases (ie, as the ventricular radius increases), a greater force is required from each individual muscle cell to produce any given intraventricular pressure.

The last point is a reflection of the law of Laplace, which is a statement of the relationship that exists between forces within the walls of any curved fluid container and pressure of its contents. If the ventricle is modeled as a cylinder where changes in ventricular volume occur only by changes in radius, the law of Laplace states that the tension on the muscle of the ventricular wall (T) depends both on the intraventricular pressure (P) and the intraventricular radius (r) as T = P x r.

The importance of these relationships will become more apparent in the subsequent chapter as we consider how cardiac muscle cell behavior determines how the heart functions as a pump.

Key Concepts

Cardiac myocyte membrane potentials are a result of the relative permeability of the membrane to various ions and their concentration differences across the membrane.

Action potentials of cardiac myocytes are a result of changes in the membrane permeability to various ions.

Action potentials of cardiac myocytes have long plateau phases that generate long refractory periods and preclude summated or tetanic contractions.

Action potentials are spontaneously generated by pacemaker cells in the SA node and are conducted from cell to cell via gap junctions throughout the entire heart.

The rate of spontaneous diastolic depolarization of the SA nodal cells (and thus the heart rate) is modulated by the autonomic nervous system.

Excitation of the cardiac myocyte initiates contraction by increasing the cytostolic calcium level that activates the contractile apparatus.

Mechanical response of the myocyte depends on preload (determined by the initial resting length), afterload (determined by the tension that needs to be developed) and contractility (the degree of activation of the contractile apparatus dependent upon the amount of calcium released upon activation).

The cardiac myocyte length-tension relationships are correlated with changes in volume and pressure in the intact ventricle.

Study Questions

2 1. Small changes in extracellular potassium ion concentrations have major effects on cell membrane potentials.

a. What will happen to the potassium equilibrium potential of cardiac muscle cells when interstitial [K⁺] (ie, [K⁺]_O) is elevated?

b. What effect will this have on the cells' resting membrane potential?

c. What effect will this have on the cells' excitability?

2 2. Cardiac survival during cardiac transplantation is improved by perfusing donor hearts with cardioplegic solutions containing

20 mM KCl. Why is this high potassium concentration helpful?

2 3. There are several classes of drugs that are useful for treating various cardiac arrhythmias. Identify the primary effects of each of the following classes of drugs on cardiac myocyte characteristics.

a. What are the effects of sodium channel blockers on the PR interval of the ECG? On the duration of the QRS complex?

b. What are the effects of calcium channel blockers on the rate of firing of SA nodal cells? On the rate of conduction of the action potential through the AV node? On myocardial contractility?

c. What are the effects of potassium channel blockers on action potential duration? On refractory periods?

2 4. Very high sympathetic neural activity to the heart can lead to tetanic concentration of the cardiac muscle. True or false?

2 5. An increase in which of the following (with the others held constant) will result in an increase in the amount of active shortening of a cardiac muscle cell?

a. Preload

b. Afterload

c. Contractility

See answers.