PHYSIOLOGICAL PROPERTIES OF HEART
CARDIAC MUSCLE PHYSIOLOGY
Cardiac Muscle
Some aspects of the structure and function of cardiac muscle have already been described in the Histology and Heart lectures. These notes repeat many of these basic details, but the lecture itself will only briefly review subjects that have already been covered. The action potentials of cardiac myocytes were extensively covered in the Membrane Physiology lectures. Notes that summarize some of the most important characteristics of these action potentials and the underlying ionic channels are presented here, but will only be briefly touched on in lecture.
CARDIAC MUSCLE STRUCTURE:
Cardiac muscle is similar in structure to skeletal muscle in many ways; however, there are several important differences that can be discerned at the structural level (and the electrical activity of cardiac muscle is very different from that of skeletal muscle, see below).
Ø Like skeletal muscle, cardiac muscle is striated. It contains the same basic contractile proteins forming thick and thin filaments that are organized into sarcomeres as they are in skeletal muscle, and the same sliding filament mechanism applies.
Ø Cardiac muscle fibers or cardiac cells (i.e. myocytes) also contain myofibrils, a network of T tubules, and SR. Force generation and its control by Ca2+ are also very similar to skeletal muscle, although cardiac muscle is less dependent on the release of Ca2+ from the SR, and the mechanism of SR Ca2+ release is different (i.e., calcium-induced calcium release, see below).
Ø In some respects, cardiac muscle cells are similar to type I (slow oxidative) skeletal muscle fibers. Cardiac muscle cells depend primarily on oxidative phosphorylation to generate ATP. They are highly resistant to fatigue, but are also highly dependent on a continuous supply of oxygen.
Ø Cardiac muscle cells are much shorter than skeletal muscle fibers and they are sometimes branched. A typical ventricular muscle cell is roughly 100 microns long and about 20 microns in diameter.
Ø Individual cardiac muscle cells are joined together by structures called intercalated discs. This is a very important distinction between cardiac and skeletal muscle. There are two types of membrane junctions in the intercalated discs. These are:
a) desmosomes, which are mechanical adhering junctions which hold the cells together.
b) gap junctions, which are low resistance electrical connections between adjacent cells. Gap junctions allow electrical activity (e.g., action potentials) of one cell to spread to adjacent cells. Cardiac muscle cells are electrically coupled to one another, which allows the heart to contract as a unit.
CARDIAC MUSCLE ELECTRICAL ACTIVITY
The Cardiac Action Potential.
The Ventricular Muscle Cell Action Potential:
The action potential that occurs in ventricular muscle is similar to that which occurs in other contractile cells of the heart (see atrial action potential below).
The resting potential of a ventricular cell is typically about ‑90 mV. The action potential threshold is about ‑70 mV. The resting potential is determined primarily by the membrane’s permeability to K+, which is higher than the permeability to other ions when the cell is at rest.
However, the cardiac action potential is of very much longer duration than the skeletal muscle action potential and displays a prominent plateau. While the skeletal muscle action potential has a duration of only 1‑2 msec, the ventricular action potential has a duration of about 250 msec. The duration of contraction in the two types of muscle is also shown in this figure (dashed lines).
Membrane permeability changes underlying the ventricular action potential. What follows is a very basic summary; many more details have already been presented in the Membrane Physiology lecture.
Ø The initial rapid upstroke of the ventricular action potential is the result of the opening of voltage‑dependent Na+ channels. These channels are essentially the same in their behavior as those of skeletal muscle and nerve. They open in response to membrane depolarization, and their opening causes the membrane potential to move toward the Na+ equilibrium potential. The Na+ channels also spontaneously inactivate within a few msec, just as is the case in skeletal muscle and nerve.
Ø The rapid inactivation of Na+ channels causes the membrane potential to begin to fall from its early peak near +30 mV. The transient outward K+ current also contributes to this phase of the action potential.
Ø However, the membrane potential does not return to its resting value, but instead remains depolarized near 0 to +10 mV for about 200 msec. This plateau is primarily caused by two voltage‑dependent permeability changes, both of which are initiated by membrane depolarization:
a) Cardiac muscle cell membranes also contain voltage‑dependent Ca2+ channels (here we are considering L-type Ca2+ channels or DHP receptors). These channels open in response to depolarization. Like Na+ channels, they activate and then spontaneously inactivate. Their activation is slower than that of Na+ channels, and their inactivation is very much slower than that of Na+ channels.
b) In addition, during part of the plateau phase of the cardiac action potential the membrane permeability to K+ is reduced below its level when the cell is at rest. This enhances the effect of the increased Ca2+ permeability.
Ø After a period of about 250 msec the ventricular cell membrane potential returns to its original resting value (i.e., to ‑90 mV). This return is fairly rapid, but not nearly as rapid as the initial upstroke of the action potential. The gradual decline of the plateau phase and the more rapid falling phase of the action potential is brought about by the inactivation of Ca2+ channels and the delayed activation of K+ channels (these are the delayed rectifier K+ channels listed in the Heart lectures and in the Membrane Physiology lectures, although it should be remembered that they are not the same as channels in skeletal muscle and nerve that often go by the same name). You should not forget the role of IK1 (“inward rectifier”) K+ channels in the process of final repolarization (see Membrane Physiology).
The Atrial Action Potential:
The atrial action potential is similar to the ventricular action potential in most respects and the membrane permeability changes, which underlie it, are generally the same as those just described. However, the action potential of atrial muscle cells is of significantly shorter duration than the ventricular action potential, lasting only about 150 msec (versus about 250 msec for ventricular cells).
Pacemaker Activity and the Action Potential of Pacemaker Cells.
Ø In addition to the contractile cells of the atria and ventricles (which comprise about 99% of the muscle cells of the heart), the heart also contains specialized autorhythmic cells that do not contract. These cells are specialized for spontaneously initiating action potentials, which then spread to the rest of the heart. This is referred to as pacemaker activity.
Ø Pacemaker cells are located in:
a) The sinoatrial (SA) node
b) The atrioventricular (AV) node
c) The bundle of His
d) Purkinje fibers
Normally SA node activity dominates due to its higher spontaneous rate of action potential generation.
Ø The membrane potential of pacemaker cells is not constant between successive action potentials, but instead undergoes spontaneous depolarization leading to periodic action potentials. These action potentials spread throughout the rest of the heart. The basis for pacemaker depolarization is still being investigated, but appears to primarily result from continuously decreasing K+ permeability (recall the characteristics of IK1 K+ channels), and the gradual opening of pacemaker channels (If, which allow both Na+ and K+ to cross the membrane); a small unchanging ‘leak’ conductance to Na+ is apparently also involved.
Ø When the membrane potential rises to roughly ‑40 mV an action potential is generated. The permeability changes underlying the action potential of pacemaker cells differ from those of the other cells of the heart. In particular, the pacemaker cells of the SA and AV nodes lack significant numbers of voltage‑dependent Na+ channels. In pacemaker cells, the upstroke of the action potential is caused by the opening of voltage‑dependent Ca2+ channels (L‑type Ca2+ channels are of greatest importance, but note that T‑type Ca2+ channels also are functional in cardiac pacemaker cells). The rising phase of the resulting action potential is much more gradual than that which occurs in contractile cells. The falling phase of the action potential results from increased K+ permeability and from the inactivation (and deactivation) of Ca2+ channels.
Ø After the end of the falling phase of the action potential, K+ permeability again begins to fall (relative to a fixed Na+ leak), and pacemaker channels begin to open. The result is gradual depolarization that eventually leads to another action potential. As described in the Membrane Physiology lectures, the opening of T-type Ca2+ channels (which open at more negative potentials than L-type Ca2+ channels) gives an added ‘boost’ to the initiation of the action potential in SA and AV nodal cells.
Factors that Alter the Cardiac Action Potential
External K+ concentration: Increased extracellular K+ (hyperkalemia) depolarizes the resting membrane potential. This will inactivate some Na+ channels, and (with somewhat larger depolarizations) will also inactivate some Ca2+ channels. The peak amplitude of the action potential will be reduced and its duration will decrease. Less Ca2+ will enter the cell (and as a result less Ca2+ will be released from the SR) and the force and duration of contraction will be decreased.
Clinical Correlation: Hyperkalemia can be very dangerous and can lead to cardiac arrhythmias and death.
Acetylcholine (ACh) hyperpolarizes pacemaker cells and slows the spontaneous rate of action potential generation at the SA node. ACh (from parasympathetic nerves) binds to M2 muscarinic receptors in the SA node, producing effects introduced in the Heart lectures and depicted below.
Catecholamines (norepinephrine, epinephrine) act on b1 adrenergic receptors in the cardiac muscle cell membrane. They facilitate Ca2+ channels, causing increased inward Ca2+ current. At pacemaker cells this increases the rate of spontaneous action potential generation, likely due to facilitation of ‘pacemaker’ channels. For contractile cardiac muscle cells the increased Ca2+ influx increases the force of contraction. The duration of the action potential of contractile cells will decrease due to facilitation of delayed rectifier K+ channels and the opening of cAMP-dependent Cl– channels.
Some other factors which alter the action potential (and the force with which cardiac muscle contracts) include:
External Ca2+ concentration.
Ø Ca2+ channel blockers reduce Ca2+ current. This shortens the action potential, decreases contractility (or inotropic state as you will better understand soon), and reduces the rate of action potential firing by pacemaker cells.
Ø Cardiac glycosides inhibit the Na+‑K+ pump causing an increase in internal Na+ concentration. There are several effects. One important effect is the reduction of Na+/Ca2+ exchange which results in less Ca2+ being removed from the myoplasm to the extracellular space during each cardiac cycle. This Ca2+ is sequestered into the SR (by the SR Ca2+ pump) resulting in more Ca2+ being stored in the SR and more Ca2+ being released during each action potential. This will increase contractility, producing more forceful contractions.
EXCITATION‑CONTRACTION COUPLING IN CARDIAC MUSCLE
Despite the functional differences between skeletal and cardiac muscle, the ultrastructural organization of the cardiac intracellular membrane systems involved in the excitation-contraction coupling is generally similar to that in skeletal muscle. Nevertheless, some ultrastructural differences exist between these types of muscle. These differences include: sarcoplasmic reticulum (SR) is a bit sparser; T-tubes are positioned near the Z line versus A-I band junction; T-tubes are larger in diameter (200 nm vs. 30 nm in skeletal muscle). In cardiac muscle, the SR terminal cisternae make junctional couplings with the T-tubes, as well with the plasma membrane (sarcolemma), that are called dyads (vs. triad in skeletal muscle). The dyad is where the transduction of the electrical signal (action potential) into contraction takes place.
Ø The action potential that propagates on the sarcolemma also spreads into the T tubular membrane. In both locations voltage‑dependent L-type Ca2+ channels (DHPRs) are opened as described above. A significant portion (about 20%) of the Ca2+ that triggers contraction enters the cardiac muscle cell from the extracellular space via these Ca2+ channels. This is different from skeletal muscle where Ca2+ currents across the sarcolemma are insignificant. Cardiac muscle can NOT contract in the absence of extracellular Ca2+, unlike skeletal muscle.
Ø The trigger that causes Ca2+ release from the SR is different in cardiac muscle and skeletal muscle. In cardiac muscle, the rise in myoplasmic Ca2+ caused by influx from the extracellular space triggers the release of SR calcium. This is called Ca2+‑induced Ca2+ release
RELAXATION OF CARDIAC MUSCLE.
In cardiac muscle, relaxation results from active pumping of Ca2+ back into the SR via SR Ca2+ pumps (SERCA) and from transport of Ca2+ from the cytoplasm back into the extracellular space primarily via the sarcolemmal Na+‑Ca2+ exchanger (Na-Ca antiporter).
MECHANICAL PROPERTIES OF CARDIAC MUSCLE
The molecular basis of cardiac contraction and relaxation is very similar to that in skeletal muscle. The similarities include:
Ø Excitation leads to a rise in intracellular Ca2+
Ø Ca2+ binds to troponin
Ø Ca2+‑troponin complex with tropomyosin unblocks actin-binding sites for crossbridge attachment.
Ø Myosin cross-bridges attach to actin and utilize ATP to generate active force. The same basic sliding filament mechanism applies to cardiac muscle.
Ø The SR pumps Ca2+ back out of the cytoplasm to end contraction (but see below).
The differences include:
Ø Calcium-induced calcium release from the SR in cardiac muscle.
Ø Na+‑Ca2+ exchanger of the sarcolemma moves Ca2+ from the cytoplasm to the extracellular space and contributes to relaxation in cardiac muscle.
Ø Under normal circumstances, the amount of Ca2+ that enters the cytoplasm during an action potential is not sufficient to saturate troponin. This is important to cardiac muscle since it allows contractility (inotropic state) to be changed by a variety of mechanisms that are unavailable to skeletal muscle.
CARDIAC MUSCLE LACKS SUMMATION:
As already described, the cardiac action potential is much longer than that of skeletal muscle. The period of contraction in cardiac muscle is much more comparable in duration to the duration of the action potential than is the case in skeletal muscle. In cardiac muscle the mechanical response is almost complete by the end of the refractory period.
Ø In addition, the intracellular rise in Ca2+ concentration (and therefore the rise in contractile force) is slower than in skeletal muscle. This is primarily due to the dependence of cardiac muscle on Ca2+ currents, which cross the surface and T tubular membrane.
Ø Because cardiac muscle cannot produce a second action potential until its contraction is almost complete and because of the relatively slow rise in tension of cardiac muscle, temporal summation of tension and tetanic contraction do not occur in cardiac muscle.
INTRINSIC MODULATION OF CARDIAC CONTRACTION.
Length‑tension relationship for cardiac muscle:
Ø The basic shape of the length‑tension relationship for cardiac muscle fibers is essentially the same as that already described for skeletal muscle. In addition, the underlying mechanisms in terms of thick and thin filament overlap (etc.) are essentially the same as in skeletal muscle.
Ø The major difference is in the normal operating range of the two types of muscle. As already seen, skeletal muscle normally operates near the peak of its length‑tension curve. On the other hand, cardiac muscle normally works at lengths that are shorter than the length at which maximum tension can be developed.
Ø This is important to the normal operation of the healthy heart. Additional stretch leads to the generation of additional force. Thus if for whatever reason the heart fills with more blood than ‘usual’ (which stretches the muscle fibers more than usual), the force generated by the next heartbeat will automatically be increased, resulting in increased ejection of blood. This mechanism of intrinsic regulation is referred to as Frank-Starling’s Law of the Heart.
Ø The length-tension relationship for single myocardial cells can be extrapolated to the ventricles.
Ø The mechanism underlying such a stretch-induced increase in force of contraction appears to involve an increase in Ca2+ sensitivity of actin-myosin interactions. There is also evidence that Ca2+ sensitivity of active force is under the strong influence of titin-based lattice spacing modulation. Therefore, titin is a self-adjustable and multi-functional spring that is indispensable for proper heart functions.
CARDIAC CONTRACTILE FORCE.
Extrinsic modulation of cardiac contractility (or inotropic state).
Contractility of cardiac muscle is a measure of the force developed by the muscle fibers when the initial fiber length remains constant. This is also called inotropic state. At the cellular level it is a function of the rate of cycling of cross-bridges between actin and myosin filaments (more cycling = increased contractility = increased force). Increased intracellular Ca2+ concentration leads to increased contractility. The contractility (inotropic state) of cardiac muscle can be altered by nervous and hormonal inputs as well as by many drugs. The effects of several agents have already been briefly described. The effects of such agents on cardiac contractility should now be easier to understand, for example:
Catecholamines. Norepinephrine and epinephrine increase contractility (FIGURE 15). The primary effect is a facilitation of Ca2+ channels leading to increased Ca2+ influx. Heart rate is also increased.
Cardiac glycosides like ouabain, digoxin, inhibit the Na+‑K+ pump. This increases internal Na+ which in turn decreases the rate of the Na+‑Ca2+ exchanger. This results in more Ca2+ being stored within the SR and more Ca2+ released from the SR during the cardiac action potential.
Ca2+ channel blockers decrease contractility.
At the level of the whole heart other factors may also affect contractility as it is broadly defined. These include the number of functional myocytes in the heart and the coronary blood supply.
Note that increased force due to additional stretch of cardiac muscle (i.e., Frank-Starling’s Law) is different from increased force due to increased myoplasmic Ca2+ (i.e., increased contractility or inotropic state). In both cases, the force developed increases. However, in the case of Frank-Starling’s Law this takes place due to increased initial fiber length (at constant myoplasmic Ca2+). At the cellular level, increased contractility is due to increased myoplasmic Ca2+ with muscle fibers at the same initial fiber length. These two mechanisms can work simultaneously.
A reasonable index of myocardial contractility can be obtained from the contour of ventricular pressure curves. A hypodynamic heart (such as in cardiac failure) is characterized by an elevated end-diastolic pressure (EDP), a slowly rising ventricular pressure, and a somewhat reduced ejection phase. A hyperdynamic heart (such as heart stimulated by norepinephrine) shows reduced EDP, fast rising ventricular pressure, and a brief ejection phase. The slope of the ascending limb of the ventricular pressure curve indicates the maximal rate of force development by the ventricle (maximal rate of change in pressure with time; Max dP/dt). At any given degree of ventricular filling, the slope provides an index of the initial contraction velocity, and hence of contractility.
AUTONOMIC NERVOUS SYSTEM CONTROL OF THE HEART
The effects of the autonomic nervous system on the heart were introduced during the Heart lectures. These effects have also been described in the Autonomic Nervous System lectures. The major effects of increased sympathetic activity (via b1 receptor activation) are:
a) Increased heart rate, produced by facilitation (via phosphorylation) of L-type Ca2+ and pacemaker channels.
b) Increased conduction velocity at the AV node, probably also resulting from facilitation of Ca2+ channels
c) Increased force of contraction (increased contractility or inotropic state) in both the ventricles and atria. This results from facilitation of Ca2+ channels causing more Ca2+ to enter the myoplasm from the extracellular fluid and also resulting in more Ca2+‑induced Ca2+ release from the SR. b1 receptor activation also decreases the sensitivity of the contractile machinery of heart muscle to Ca2+ (by phosphorylating troponin). This helps to shorten the duration of contraction (consistent with tachycardia); contractions are shorter but stronger. The SR Ca2+ pump also is stimulated, which causes increased storage of Ca2+ by the SR and hence increased Ca2+ release during the cardiac action potential.
d) The facilitation of delayed rectifier K+ channels and the opening of cAMP dependent Cl– channels causes the duration of the cardiac action potential to decrease.
e) Sympathetic nerves, innervate the ventricles, atria, SA node and AV node.
THE MAJOR EFFECTS OF PARASYMPATHETIC ACTIVITY (VIA M2 MUSCARINIC RECEPTORS) ON THE HEART ARE:
a) Decreased heart rate, due to facilitation of ACh activated K+ channels in SA node and to inhibition of Ca2+ channels and pacemaker channels.
b) Decreased action potential conduction velocity at the AV node (probably due to inhibition of Ca2+ channels and facilitation of K+ channels).
c) Decreased contractility or inotropic state of the atria only.
d) parasympathetic nerves (via the vagus nerve) innervate the atria, SA node and AV node. There are essentially no effects on the ventricles.
