Cardiopulmonary Physiology Millersville University Dr.

Larry Reinking

Chapter 4 - Characteristics of Cardiac Muscle Cells. This chapter deals with the properties of heart muscle cells and will serve as background information for future laboratory and lecture sessions. In previous courses, you have learned about the mechanical and electrical properties of skeletal muscle. We will review these concepts and use them as a foundation for learning about heart muscle. As you will see, there are similarities as well as vast differences between these two types of striated muscle. General Terminology and Structure The prefixes myo- and sarco- are frequently used when referring to striated muscle cells and their organelles. Hence, we speak of the sarcoplasm (cytoplasm) or sarcoplasmic reticulum (endoplasmic reticulum). Heart muscle is also called cardiac muscle or myocardium. Skeletal muscle is a syncytium, that is, the individual cells are fused and form a long, multinucleate fiber (called a myofiber). This arrangement of cells seems to enhance communication and coordination within the muscle. Cardiac myofibers have distinct boundaries between the cells called the intercalated discs. These cell boundaries are very permeable and offer little resistance to cell-cell communication. Hence, cardiac muscle is a functional rather than an anatomical syncytium. The histological appearance of cardiac muscle is also distinct from skeletal muscle in that it is highly branched and has centrally located nuclei:
irtd nai ta s eec cd l ns u c l e u

ccc am ru ds i l ae

st u km e s ll c e l ae Figure 4.1 Striated Muscle

Contraction of Striated Muscle As seen above, skeletal muscle and cardiac muscle have a characteristic striated appearance. This appearance is due to a regularly repeating pattern of contractile proteins within the muscle cells. Each contractile unit, known as the sarcomere, is about 2 m in length and can be depicted as follows:

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actin Z-line

myosin
= Ca2+ actin cross-bridge myosin resting contracting

sarcomere Figure 4.2 Sarcomere Contraction of striated muscle involves cross-bridging between the protein filaments, actin and myosin. Repeated cross-bridging causes these filaments to slide past one another and results in muscle shortening (i.e., the Sliding Filament Theory). The trigger that promotes cross-bridging is a sudden rise in intracellular calcium levels; at rest there is almost no free calcium in the cytoplasm. Be aware that other regulatory proteins are involved in this process but are not shown in the diagram. ATP, of course, is needed for muscle contraction and appears to be involved in breaking cross-bridges and re-energizing these broken cross-bridges. Calcium and Muscle Contraction In resting muscle, almost all intracellular calcium is unavailable because it is sequestered in the sarcoplasmic reticulum. The following diagram illustrates the sarcoplasmic reticulum and its relationship to contractile proteins; note the extensions from the cell membrane (T tubules) that penetrate into the cells interior:
cell membrane contractile proteins sarcoplasmic reticulum contractile proteins

{ x y

T tubule = Ca
2+

skeletal muscle cardiac muscle Figure 4.3 Calcium and the Sarcoplasmic Reticulm During excitation of a skeletal muscle, neurotransmitter from a nerve signal will initiate an action potential (defined below) that is propagated along the cell surface and down the T tubule membrane. The T tubule action potential, in turn, will cause the sarcoplasmic reticulum to release stored calcium; cross-bridges then form and the muscle contracts. Calcium pumps (i.e., active transport) re-sequester calcium and the muscle returns to the resting state. Skeletal muscle is not affected by extracellular calcium. In contrast, cardiac muscle has a complex calcium circulation and is greatly affected by external calcium concentrations. Note in the above diagram that the T tubules of cardiac cells

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are large and enhance contact with extracellular calcium. The following steps are hypothesized for cardiac muscle: Following arrival of the T tubule action potential, calcium enters from the extracellular fluid . Most of the entering calcium triggers a large (heavy arrow) release of stored calcium from the sarcoplasmic reticulum . This released calcium, plus a small portion of the entering, extracellular calcium , promote cross-bridging and muscle contraction. Following contraction, most of the calcium is pumped back into the sarcoplasmic reticulum . The remaining free calcium is ejected from the cell to the exterior by either a cell membrane calcium pump or a membrane carrier that exchanges external sodium for internal calcium . Action of Cardiac Glycosides Cardiac glycosides such as digitalis increase cardiac contractility. The major action of these drugs is the inhibition of membrane sodium pumps (which pump Na out of the cell). The resulting accumulation of intracellular sodium inhibits the sodium-calcium exchanger , depicted in the above diagram. The ultimate result is more free intracellular calcium, more cross-bridging and thus, more contraction. Electrical Activity of Muscle Cells Like other excitable cells, striated muscle has a resting electrical potential and propagates signals via an action potential.

Resting Potential At rest, muscle cells have an unequal distribution of positive and negative ions across the membrane. This results is an electrical potential, called the resting potential that has a typical value of -90 mV in striated muscle (an exception will be cardiac nodal tissue):
+ + + + + + + + + + + + +- - - - - - - - - - - - - - + + - -+ + - + - - - - - - - - - - - + + + + + + + + - + + + + +

D is tr ib u tio n o f c h a rg e s in a r e s tin g c a rd ia c m u s c le c e ll. T h e re su ltin g e s tin g p o te n t ia l r h a s a v a lu e o f - 9 0 m V .

Figure 4.4 Resting Cardiac Cell

An increase in the resting potential (i.e., a more negative value such as -100 mV) is called an hyperpolarization. The opposite, a decrease in the resting potential is a depolarization. A repolarization is the return to the resting potential after the depolarization of an action potential. In cells such as nerve and muscle, the resting potential sets the stage for excitability, that is, the initiation of an action potential. A cell that has lost the resting potential will no longer be excitable while a hyperpolarized cell will be more difficult to stimulate. The basis of the resting potential is a combination of factors that include the sodium-potassium pump (Na/KATPase), chemical and electrostatic forces and membrane permeabilities to a variety of ions (Na, K, Ca, Cl, and nondiffusible anions). The bottom line, for our purposes is the following - The major cause of the resting potential is the potassium gradient and the resting membranes

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permeabilty to K+. Potassium ion concentration is high within cells ( 135 mM) and is low in the extracellular fluid ( 4 mM, see p.4, chapter 2). Extracellular Potassium and Cardiac Function Excess potassium in the extracellular fluid causes the heart to become weak and flaccid. The reduction of the potassium gradient induces a depolarization that, in turn, results in a weak cardiac action potential (the magnitude of the cardiac action potential is related to the strength of contraction). An elevation of serum potassium to only 8-12 mM is sufficient to induce abnormal cardiac function and death. For this reason there is extreme clinical concern for patients with renal failure; renal failure is accompanied by a rapid rise in serum potassium. During bypass surgery, a common way to stop the heart is to simply pour a cold solution of potassium chloride into the thoracic cavity. The heart immediately stops beating due to the combination of cold and the loss of the potassium gradient. Action Potential The action potential is a nondegradatory, self propagating wave of depolarization. In skeletal muscle, the duration of an action potential is limited to several msec while a cardiac action potential may last for hundreds of msec. Figure 4.5 depictions action potentials and the associated ionic events for skeletal and cardiac muscle. Cardiac nodal tissue differs from either of these patterns and will be examined later in this chapter.

Figure 4.5 Muscle Action Potentials (heavy arrows = fast current; light arrow = slow current)

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Na in

K out +

K out Na in Cl in Ca in K out + + + +

membrane potential (mV)

+30

skeletal muscle

resting potential

resting potential

cardiac muscle 4 0 1 2 3 4

-90 10 msec 400 msec

The skeletal muscle action potential has two basic phases. Upon achieving a threshold stimulus (recall the all-or-none principle), sodium gates in the membrane open, sodium ions rush in, the membrane rapidly depolarizes and 'overshoots' to about +30 mV. A rapid repolarization follows that is due to closure of the Na+ gates and to outward moving potassium ions. As a result, the membrane returns to the resting potential. In contrast, the cardiac action potential takes much longer, has five phases (0-4), a variety of ionic events and varies in characteristics from one region of the heart to another. Its nature will also change depending on the type of stimulation: if threshold is achieved swiftly, a large, rapidly rising action potential occurs but if the stimulus gradually reaches threshold, then a slowly rising, small action potential results. Phase 0 (the upstroke) is caused by an opening of the sodium gates and an entry of sodium ions. These gates open fully with rapid stimulation or open only partially with a gradual stimulus. Phase 1 (early repolarization) is caused by a brief outward movement of K+ and a simultaneous inward movement of Cl-. Phase 2 (the plateau) is most notable since it creates a prolonged refractory period (time during which a muscle cannot be re-excited). The plateau is maintained, primarily, by a slow inward movement of calcium ions. In addition to contributing to the plateau, these entering calcium ions interact with the contractile proteins to form cross-bridges. Drugs Effects and the Plateau - Catecholamines (epinephrine and norepinephrine) increase the slow, inward calcium current of phase 2. This action seems to be the primary mechanism for increased cardiac contractility caused by epinephrine and norepinephrine (remember, more internal Ca, more cross-bridging). Calcium channel blockers (e.g. verapamil, nifedipine, dilitiazem) impede this slow, inward calcium current and, thus, decrease the strength of cardiac contraction. Calcium channel blockers also have antiarrhythmic actions. One cause of heart arrhythmia is a reentry current that is, a flow of electrical current that inappropriately restimulates some area in the heart. Normal heart stimulation, of course, is initiated by the Chapter 4 5

pacemaker of the SA node. Reentry currents are likely to happen when isolated areas of the heart remains depolarized for too long. Calcium channel blockers will decrease the time an area is depolarized by shortening phase 2. Phase 3 (repolarization) is caused by a net outward movement of potassium ions which rapidly returns the cardiac cell to its original resting potential. The repolarization that takes place during this phase involves an interplay of several different types of potassium channels. Phase 4 is the resting potential. Types of Cardiac Muscle Cardiac muscle can be categorized into different types of specialized cells. Basically, there are cells that are specialized for contraction and those that are specialized for signal conduction. Unlike many organs, the heart uses specialized muscle cells rather than neurons for signal conduction. Consult your lab handouts for diagrams and further information dealing with cardiac cell types. This chapter also should be used in conjunction with the transcript from the program Electrical Anatomy of the Heart, Part I. 1. Working Myocardium. These are the cells that make up the vast majority of the atrial muscle, ventricular muscle and the intraventricular septum. They are highly striated and are comprised mostly of contractile proteins and mitochondria (48% and 36%, by volume). Consistent with the high density of mitochondria, these cells rely heavily on aerobic metabolism. Within the atrial myocardial cells are dense granules that contain peptide hormones. When the atria are stretched, these hormones are released and alter kidney and vascular function. Thus, the heart is also an endocrine organ! 2. Conduction System. These cells are modified for rapid signal conduction and only exhibit weak contractions. Correspondingly, the contractile proteins (20%) and mitochondria (10%) are reduced in volume and cellular metabolism is mostly anaerobic. This type of cell is found in the bundle of His (also known as the AV bundle or common bundle), the bundle branches and the Purkinje fibers. 3. Nodal Cells. The sinoatrial node (SA node) and atrioventricular node (AV node) are comprised of small, pale cells that are only slightly striated. They are responsible for pacemaker activity and regulate conduction from the atria to the ventricles. The electrical properties of these cells differ from the other types of myocardium (see below). 4. Transitional Cells. These cells are the interface between the Purkinje fibers and the working myocardium. Their histological appearance is intermediate between these two cell types. It has been speculated that this type of cell may also form conductive tracts within the atria. Electrical Properties of Nodal Cells Nodal tissue has a resting potential value that is less than other myocardium, has an action potential upstroke of slow velocity, has no plateau and repolarizes slowly. Depicted, below, is an action potential for the SA node: Figure 5.6 Electrical Activity of Cardiac Nodal Tissue

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membrane potential (mV)

-70

pacemaker potential

slope

SA node

threshold 100 msec

slope

Note the slow upstroke which indicates the that fast sodium channels are not operating. This is probably due to the low initial resting potential since partial, slow depolarization is known to inactivate fast sodium channels. In nodal tissue, the upstroke is due mostly to an inward movement of calcium ions. Heart muscle is myogenic, that is the signal that initiates contraction comes from within the muscle, not from a nerve impulse. The nervous input to the heart will, however, modify the rate and strength of contraction. In the above diagram, note the unstable resting potential which gradually depolarizes until it reaches threshold. This type of resting potential is called a pacemaker potential. The gradual depolarization of the pacemaker potential is due to a least three factors: 1) a slow decline in outward potassium movement, 2) a slow inward calcium leak and, most importantly, 3) a slow inward current of sodium ions. Control of heart rate, by the autonomic nervous system, is achieved primarily by increasing or decreasing the slope of the pacemaker potential. Sympathetic Stimulation (Norepinephrine) Sympathetic stimulation (via cardiac nerves) of the SA node is mediated by -adrenergic receptors and causes an increase in heart rate (tachycardia). This effect is brought about by an increased inward movement of calcium and sodium ions, thus increasing the pacemaker potential slope. -adrenergic antagonists (beta blockers) slow the heart by preventing binding to the adrenergic receptors. Parasympathetic Stimulation (Acetylcholine) Vagal stimulation of the SA node causes a slowing of the heart rate (bradycardia). Acetycholines effect is mediated by muscarinic type receptors which bring about a decrease in the inward movement of sodium and calcium, thus decreasing the slope of the pacemaker potential. Also, acetylcholine alters the heart rate by hyperpolarizing the resting potential. Since the new starting point is farther away from threshold, it will take longer initiate an action potential. This second effect is the result of an increased outward movement of potassium ions. Calcium Channel Blockers These agents slow heart rate by binding to calcium channels which will reduce the inward leak of calcium. Hyperkalemia (elevated serum K+) The SA node especially sensitive to extracellular potassium. As noted previously, the resting potential depends primarily on the transmembrane potassium gradient. Elevated serum potassium causes a depolarization of the SA node and slow conduction velocity. Severe hyperkalemia will bring about SA block. Chapter 4 7

Cardiac Glycosides Digitalis and related compounds slow the heart rate by inhibiting the sodium pump which, like hyperkalemia (above) depolarizes the cell thus depressing SA nodal function. AV node The action potential of the AV node looks similar to that of the SA node, however, the resting potential is much more stable. The AV node has the slowest rate of electrical conduction of all types of myocardium; this is due to the very small size of the AV nodal cells. Slow conduction through this part of the heart allows completion of atrial pumping before the initiation of ventricular contraction. Autonomic input to this node will slow (parasympathetic) or facilitate (sympathetic) the rate of conduction. Heart Rate and Action Potential Duration As the heart rate increases the duration of time between beats becomes shorter. Obviously, the prolonged action potential that is characteristic of most types of myocardium must be shortened during high heart rates. During rapid heart rates, more calcium channels are open and intracellular calcium levels rise. This rise in intracellular calcium stimulates an outward movement of potassium via calcium activated potassium channels. This outward movement of K+ rapidly repolarizes the myocardial cells, thus shortening the duration of the action potential. More on Myocardial Resting Potentials The preceding discussion may leave you with the impression that the SA node is the only portion of the heart that is capable of autorhythmicity. In actuality, all types of myocardial cells have unstable resting potentials and therefore are capable of initiating their own action potentials. If a piece of working myocardium, for example, is placed in a beaker of warm Ringers solution it will begin rhythmically contracting, although at a slow rate. The SA node has the most unstable resting potential (steepest slope), the fastest rate of firing and, therefore, is the pacemaker. If the SA node is damaged some other region in the heart will become the center of pacemaker activity and is called an ectopic pacemaker. Summary Tables This chapter contains a good deal of related information in different sections. The following tables may help in pulling together some of the concepts: Table 4.1 Properties of Skeletal Muscle vs. Cardiac Muscle Difference response duration stimulus T-tubules syncytium Skeletal Muscle stereotyped few msec nerve small true anatomical Cardiac Muscle variable 100+ msec myogenic large functional

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substrates

lipid, CHO

lipid, CHO, lactate

Table 4.2 Drug and Ion Effects on the Heart Drug cardiac glycosides cardiac glycosides catecholamines catecholamines acetylcholine Mechanism of Action Na pump intracellular Ca Na pump depolarizes SA & AV node inward Ca current during plateau Na & Ca leak slope of pacemaker pot. Na & Ca leak slope of pacemaker pot. outward K current hyperpolarization Ca channel blockers decreased contractility inward Ca current during plateau Ca channel blockers antiarrhythmic Ca shortens plateau prevents reentry Ca channel blockers slows heart rate inward Ca leak slope of pacemaker pot. hyperkalemia contractility, SA block loss of K gradient depolarization Effect increase contractility heart rate / cond. vel. increase contractility increase heart rate decrease heart rate

Chapter 4