Guyton 8: Excitation & Contraction of Smooth Muscle PDF

CHAPTER 8 Excitation and Contraction of UNIT II S...

CHAPTER 8 Excitation and Contraction of UNIT II Smooth Muscle CONTRACTION OF SMOOTH MUSCLE Unitary Smooth Muscle. Unitary smooth muscle is also Smooth muscle is composed of small fibers that are usu- called syncytial smooth muscle or visceral smooth muscle. ally 1 to 5 micrometers in diameter and only 20 to 500 The term unitary does not mean single muscle fibers. In- micrometers in length. In contrast, skeletal muscle fibers stead, it means a mass of hundreds to thousands of smooth are as much as 30 times greater in diameter and hundreds muscle fibers that contract together as a single unit. The of times as long. Many of the same principles of contrac- fibers usually are arranged in sheets or bundles, and their tion apply to smooth muscle as to skeletal muscle. Most cell membranes are adherent to one another at multiple important, essentially the same attractive forces between points so that force generated in one muscle fiber can be myosin and actin filaments cause contraction in smooth transmitted to the next. In addition, the cell membranes muscle as in skeletal muscle, but the internal physical are joined by many gap junctions through which ions can arrangement of smooth muscle fibers is different. flow freely from one muscle cell to the next so that ac- tion potentials, or ion flow without action potentials, can travel from one fiber to the next and cause the muscle fib- TYPES OF SMOOTH MUSCLE ers to contract together. This type of smooth muscle is also The smooth muscle of each organ is distinctive from known as syncytial smooth muscle because of its syncyt- that of most other organs in several ways: (1) physical ial interconnections among fibers. It is also called visceral dimensions; (2) organization into bundles or sheets; (3) smooth muscle because it is found in the walls of most vis- response to different types of stimuli; (4) characteristics cera of the body, including the gastrointestinal tract, bile of innervation; and (5) function. Yet, for the sake of sim- ducts, ureters, uterus, and many blood vessels.! plicity, smooth muscle can generally be divided into two major types, which are shown in Figure 8-1, multi-unit smooth muscle and unitary (or single-unit) smooth muscle. CONTRACTILE MECHANISM IN SMOOTH MUSCLE Multi-Unit Smooth Muscle. Multi-unit smooth muscle is composed of discrete, separate, smooth muscle fibers. Chemical Basis for Smooth Muscle Each fiber operates independently of the others and often Contraction is innervated by a single nerve ending, as occurs for skele- Smooth muscle contains both actin and myosin filaments, tal muscle fibers. Furthermore, the outer surfaces of these having chemical characteristics similar to those of the fibers, like those of skeletal muscle fibers, are covered by a actin and myosin filaments in skeletal muscle. It does not thin layer of basement membrane–like substance, a mix- contain the troponin complex that is required for the con- ture of fine collagen and glycoprotein that helps insulate trol of skeletal muscle contraction, and thus the mecha- the separate fibers from one another. nism for controlling contraction is different. This topic is Important characteristics of multi- unit smooth discussed in more detail later in this chapter. muscle fibers are that each fiber can contract indepen- Chemical studies have shown that actin and myo- dently of the others, and their control is exerted mainly sin filaments derived from smooth muscle interact with by nerve signals. In contrast, a major share of control each other in much the same way that they do in skeletal of unitary smooth muscle is exerted by non-nervous muscle. Furthermore, the contractile process is activated stimuli. Some examples of multi- unit smooth muscle by calcium ions, and adenosine triphosphate (ATP) is are the ciliary muscle of the eye, the iris muscle of the degraded to adenosine diphosphate (ADP) to provide the eye, and the piloerector muscles that cause erection of energy for contraction. the hairs when stimulated by the sympathetic nervous There are, however, major differences between the system.! physical organization of smooth muscle and that of 101 UNIT II Membrane Physiology, Nerve, and Muscle Adventitia Actin filaments Medial muscle Dense bodies fibers Endothelium Small artery A Multi-unit smooth muscle B Unitary smooth muscle Myosin filaments Figure 8-1 Multi-unit (A) and unitary (B) smooth muscle. skeletal muscle, as well as differences in excitation- contraction coupling, control of the contractile process by calcium ions, duration of contraction, and the amount of energy required for contraction.! Physical Basis for Smooth Muscle Cell membrane Contraction Smooth muscle does not have the same striated arrange- ment of actin and myosin filaments as is found in skeletal muscle. Instead, electron micrographic techniques sug- gest the physical organization shown in Figure 8-2, which illustrates large numbers of actin filaments attached to dense bodies. Some of these bodies are attached to the cell membrane, and others are dispersed inside the cell. Some of the membrane-dense bodies of adjacent cells are bonded together by intercellular protein bridges. It is mainly through these bonds that the force of contraction Figure 8-2 Physical structure of smooth muscle. The fiber on the up- is transmitted from one cell to the next. per left shows actin filaments radiating from dense bodies. The fiber Interspersed among the actin filaments in the muscle on the lower left and at right demonstrate the relation of myosin filaments to actin filaments. fiber are myosin filaments. These filaments have a diam- eter more than twice that of the actin filaments. In elec- tron micrographs, 5 to 10 times as many actin filaments as on one side while simultaneously pulling another actin fila- myosin filaments are usually found. ment in the opposite direction on the other side. The value To the right in Figure 8-2 is a postulated structure of an of this organization is that it allows smooth muscle cells to individual contractile unit in a smooth muscle cell, show- contract as much as 80% of their length instead of being ing large numbers of actin filaments radiating from two limited to less than 30%, as occurs in skeletal muscle.! dense bodies; the ends of these filaments overlap a myosin filament located midway between the dense bodies. This Comparison of Smooth Muscle contractile unit is similar to the contractile unit of skeletal Contraction and Skeletal Muscle muscle, but without the regularity of the skeletal muscle Contraction structure. In fact, the dense bodies of smooth muscle Although most skeletal muscles contract and relax rap- serve the same role as the Z disks in skeletal muscle. idly, most smooth muscle contraction is prolonged tonic Another difference is that most of the myosin filaments contraction, sometimes lasting hours or even days. have “side polar” cross-bridges arranged so that the bridges Therefore, it is to be expected that both the physical and on one side hinge in one direction, and those on the other chemical characteristics of smooth muscle versus skeletal side hinge in the opposite direction. This configuration muscle contraction would differ. Some of the differences allows the myosin to pull an actin filament in one direction are noted in the following sections. 102  Chapter 8 Excitation and Contraction of Smooth Muscle Slow Cycling of the Myosin Cross-Bridges. The rapid- longed period of attachment of the myosin cross-bridges ity of cycling of the myosin cross-bridges in smooth mus- to the actin filaments.! cle—that is, their attachment to actin, then release from the actin, and reattachment for the next cycle—is much Latch Mechanism Facilitates Prolonged Holding of slower than in skeletal muscle. The frequency is as little Contractions of Smooth Muscle. Once smooth muscle as 1/10 to 1/300 that in skeletal muscle. Yet, the fraction has developed full contraction, the amount of continu- UNIT II of time that the cross-bridges remain attached to the ac- ing excitation can usually be reduced to far less than the tin filaments, which is a major factor that determines the initial level, even though the muscle maintains its full force of contraction, is believed to be greatly increased in force of contraction. Furthermore, the energy consumed smooth muscle. A possible reason for the slow cycling is to maintain contraction is often minuscule, sometimes that the cross-bridge heads have far less ATPase activ- as little as 1/300 of the energy required for comparable ity than in skeletal muscle; thus, degradation of the ATP sustained skeletal muscle contraction. This mechanism is that energizes the movements of the cross-bridge heads called the latch mechanism. is greatly reduced, with corresponding slowing of the rate The importance of the latch mechanism is that it can of cycling.! maintain prolonged tonic contraction in smooth muscle for hours, with little use of energy. Little continued excit- Low Energy Requirement to Sustain Smooth Mus- atory signal is required from nerve fibers or hormonal cle Contraction. Only 1/10 to 1/300 as much energy is sources.! required to sustain the same tension of contraction in smooth muscle as in skeletal muscle. This, too, is believed Stress-Relaxation of Smooth Muscle. Another im- to result from the slow attachment and detachment cy- portant characteristic of smooth muscle, especially the cling of the cross-bridges, and because only one molecule visceral unitary type of smooth muscle of many hollow of ATP is required for each cycle, regardless of its dura- organs, is its ability to return to nearly its original force tion. of contraction seconds or minutes after it has been This low energy utilization by smooth muscle is impor- elongated or shortened. For example, a sudden increase tant to the overall energy economy of the body because in fluid volume in the urinary bladder, thus stretching organs such as the intestines, urinary bladder, gallbladder, the smooth muscle in the bladder wall, causes an im- and other viscera often maintain tonic muscle contraction mediate large increase in pressure in the bladder. How- almost indefinitely.! ever, during about the next 15 to 60 seconds, despite continued stretch of the bladder wall, the pressure re- Slowness of Onset of Contraction and Relaxation turns almost exactly back to the original level. Then, of the Total Smooth Muscle Tissue. A typical smooth when the volume is increased by another step, the same muscle tissue begins to contract 50 to 100 milliseconds effect occurs again. after it is excited, reaches full contraction about 0.5 sec- Conversely, when the volume is suddenly decreased, ond later, and then declines in contractile force in another the pressure falls drastically at first but then rises in 1 to 2 seconds, giving a total contraction time of 1 to 3 another few seconds or minutes to or near the original seconds. This is about 30 times as long as a single contrac- level. These phenomena are called stress-relaxation and tion of an average skeletal muscle fiber. However, because reverse stress-relaxation. Their importance is that except there are so many types of smooth muscle, contraction of for short periods, they allow a hollow organ to main- some types can be as short as 0.2 second or as long as 30 tain about the same amount of pressure inside its lumen seconds. despite sustained large changes in volume.! The slow onset of contraction of smooth muscle, as well as its prolonged contraction, is caused by the slow- REGULATION OF CONTRACTION BY ness of attachment and detachment of the cross-bridges CALCIUM IONS with the actin filaments. In addition, the initiation of con- traction in response to calcium ions is much slower than As is true for skeletal muscle, the initiating stimulus for in skeletal muscle, as will be discussed later.! most smooth muscle contraction is an increase in intra- cellular calcium ions. This increase can be caused in dif- Maximum Force of Contraction Is Often Greater in ferent types of smooth muscle by nerve stimulation of Smooth Muscle Than in Skeletal Muscle. Despite the the smooth muscle fiber, hormonal stimulation, stretch of the relatively few myosin filaments in smooth muscle, and fiber, or even changes in the chemical environment of despite the slow cycling time of the cross-bridges, the the fiber. maximum force of contraction of smooth muscle is often Smooth muscle does not contain troponin, the regu- greater than that of skeletal muscle, as much as 4 to 6 kg/ latory protein that is activated by calcium ions to cause cm2 cross-sectional area for smooth muscle in compari- skeletal muscle contraction. Instead, smooth muscle con- son with 3 to 4 kilograms for skeletal muscle. This great traction is activated by an entirely different mechanism, force of smooth muscle contraction results from the pro- as described in the next section. 103 UNIT II Membrane Physiology, Nerve, and Muscle Extracellular fluid Ca2+ Sarcoplasmic reticulum Ca2+ Ca2+ CaM Caveolae Ca2+ CaM Inactive MLCK Active MLCK Sarcoplasmic ATP reticulum P ADP + P Inactive myosin Phosphorylated myosin Figure 8-4 Sarcoplasmic tubules in a large smooth muscle fiber showing their relation to invaginations in the cell membrane called caveolae. Actin cycling of the myosin head with the actin filament does not occur. However, when the regulatory chain Muscle contraction is phosphorylated, the head has the capability of binding repetitively with the actin filament and pro- ceeding through the entire cycling process of inter- Figure 8-3 Intracellular calcium ion (Ca2+) concentration increases when Ca2+ enters the cell through calcium channels in the cell mem- mittent pulls, the same as what occurs for skeletal brane or is released from the sarcoplasmic reticulum. The Ca2+ binds muscle, thus causing muscle contraction.! to calmodulin (CaM) to form a Ca2+-CaM complex, which then acti- vates myosin light chain kinase (MLCK). The active MLCK phospho- Source of Calcium Ions That Cause rylates the myosin light chain, leading to attachment of the myosin Contraction head with the actin filament and contraction of the smooth muscle. ADP, Adenosine diphosphate; ATP, adenosine triphosphate; P, phos- Although the contractile process in smooth muscle, as in phate. skeletal muscle, is activated by calcium ions, the source of the calcium ions differs. An important difference is Calcium Ions Combine with Calmodulin to Cause Ac- that the sarcoplasmic reticulum, which provides virtu- tivation of Myosin Kinase and Phosphorylation of ally all the calcium ions for skeletal muscle contraction, is the Myosin Head. In place of troponin, smooth muscle only slightly developed in most smooth muscle. Instead, cells contain a large amount of another regulatory protein most of the calcium ions that cause contraction enter the called calmodulin (Figure 8-3). Although this protein is muscle cell from the extracellular fluid at the time of the similar to troponin, it is different in the manner in which it action potential or other stimulus. That is, the concentra- initiates contraction. Calmodulin initiates contraction by tion of calcium ions in the extracellular fluid is greater activating the myosin cross-bridges. This activation and than 10−3 molar, in comparison with less than 10−7 molar subsequent contraction occur in the following sequence: inside the smooth muscle cell; this causes rapid diffusion 1. The calcium concentration in the cytosolic fluid of of the calcium ions into the cell from the extracellular the smooth muscle increases as a result of the influx fluid when the calcium channels open. The time required of calcium from the extracellular fluid through cal- for this diffusion to occur averages 200 to 300 millisec- cium channels and/or release of calcium from the onds and is called the latent period before contraction sarcoplasmic reticulum. begins. This latent period is about 50 times as great for 2. The calcium ions bind reversibly with calmodulin. smooth muscle as for skeletal muscle contraction. 3. The calmodulin-calcium complex then joins with and activates myosin light chain kinase, a phospho- Role of the Smooth Muscle Sarcoplasmic Reticulum. rylating enzyme. Figure 8-4 shows a few slightly developed sarcoplasmic 4. One of the light chains of each myosin head, called tubules that lie near the cell membrane in some larger the regulatory chain, becomes phosphorylated in smooth muscle cells. Small invaginations of the cell mem- response to this myosin kinase. When this chain is brane, called caveolae, abut the surfaces of these tubules. not phosphorylated, the attachment-detachment The caveolae suggest a rudimentary analog of the trans- 104  Chapter 8 Excitation and Contraction of Smooth Muscle verse tubule system of skeletal muscle. When an action Ca2+ Ca2+ Na+ potential is transmitted into the caveolae, this is believed Extracellular fluid to excite calcium ion release from the abutting sarcoplas- mic tubules in the same way that action potentials in skel- ATP etal muscle transverse tubules cause release of calcium Sarcoplasmic reticulum ions from the skeletal muscle longitudinal sarcoplasmic UNIT II Na+ tubules. In general, the more extensive the sarcoplasmic Ca2+ ATP Ca2+ reticulum in the smooth muscle fiber, the more rapidly it contracts.! CaM Smooth Muscle Contraction Is Dependent on Extra- cellular Calcium Ion Concentration. Whereas chang- Ca2+ CaM ing the extracellular fluid calcium ion concentration from normal has little effect on the force of contraction of Myosin skeletal muscle, this is not true for most smooth muscle. P P phosphatase When the extracellular fluid calcium ion concentration decreases to about 1/3 to 1/10 normal, smooth muscle P P contraction usually ceases. Therefore, the force of con- traction of smooth muscle is usually highly dependent on Inactive myosin Phosphorylated myosin the extracellular fluid calcium ion concentration.! decreases A Calcium Pump Is Required to Cause Smooth Muscle Relaxation. To cause relaxation of smooth muscle after it Muscle has contracted, the calcium ions must be removed from relaxation the intracellular fluids. This removal is achieved by a cal- cium pump that pumps calcium ions out of the smooth Figure 8-5 Relaxation of smooth muscle occurs when the calcium muscle fiber back into the extracellular fluid, or into a ion (Ca2+) concentration decreases below a critical level as Ca2+ is sarcoplasmic reticulum, if it is present (Figure 8-5). This pumped out of the cell or into the sarcoplasmic reticulum. Ca2+ is pump requires ATP and is slow acting in comparison with then released from calmodulin (CaM), and myosin phosphatase the fast-acting sarcoplasmic reticulum pump in skeletal removes phosphate from the myosin light chain, causing detach- ment of the myosin head from the actin filament and relaxation of muscle. Therefore, a single smooth muscle contraction of- the smooth muscle. ADP, Adenosine diphosphate; ATP, adenosine ten lasts for seconds rather than hundredths to tenths of a triphosphate; Na+, sodium; P, phosphate. second, as occurs for skeletal muscle.! Myosin Phosphatase Is Important in Cessation of Con- When the myosin kinase and myosin phosphatase traction. Relaxation of the smooth muscle occurs when enzymes are both strongly activated, the cycling frequency the calcium channels close and the calcium pump trans- of the myosin heads and the velocity of contraction are ports calcium ions out of the cytosolic fluid of the cell. great. Then, as activation of the enzymes decreases, the When the calcium ion concentration falls below a critical cycling frequency decreases but, at the same time, the level, the aforementioned processes automatically reverse, deactivation of these enzymes allows the myosin heads to except for the phosphorylation of the myosin head. Re- remain attached to the actin filament for a longer and lon- versal of this situation requires another enzyme, myosin ger proportion of the cycling period. Therefore, the num- phosphatase (see Figure 8-5), located in the cytosol of the ber of heads attached to the actin filament at any given smooth muscle cell, which splits the phosphate from the time remains large. Because the number of heads attached regulatory light chain. Then the cycling stops, and contrac- to the actin determines the static force of contraction, ten- tion ceases. The time required for the relaxation of muscle sion is maintained, or latched, yet little energy is used by contraction, therefore, is determined to a great extent by the muscle because ATP is not degraded to ADP, except the amount of active myosin phosphatase in the cell.! on the rare occasion when a head detaches.! Possible Mechanism for Regulating the Latch Phe- NERVOUS AND HORMONAL CONTROL nomenon. Because of the importance of the latch phe- OF SMOOTH MUSCLE CONTRACTION nomenon in smooth muscle, and because this phenom- enon allows for the long-term maintenance of tone in Although skeletal muscle fibers are stimulated exclusively many smooth muscle organs without much expenditure by the nervous system, smooth muscle can be stimulated of energy, many attempts have been made to explain it. to contract by nervous signals, hormonal stimulation, Among the many mechanisms that have been postulated, stretch of the muscle, and several other ways. The prin- one of the simplest is the following. cipal reason for the difference is that the smooth muscle 105 UNIT II Membrane Physiology, Nerve, and Muscle Visceral most of the fine terminal axons have multiple varicosi- Autonomic neuron ties distributed along their axes. At these points, the varicosity Schwann cells that envelop the axons are interrupted so Neurotransmitter that transmitter substance can be secreted through the Receptor walls of the varicosities. In the varicosities are vesicles similar to those in the skeletal muscle end plate that con- Gap junction tain transmitter substance. However, in contrast to the vesicles of skeletal muscle junctions, which always con- tain acetylcholine, the vesicles of the autonomic nerve Multi-unit fiber endings contain acetylcholine in some fibers and norepinephrine in others and occasionally other sub- stances as well. In a few cases, particularly in the multi-unit type of smooth muscle, the varicosities are separated from the muscle cell membrane by as little as 20 to 30 nanome- ters—the same width as the synaptic cleft that is found Autonomic neuron in the skeletal muscle junction. These are called contact varicosity junctions, and they function in much the same way as Figure 8-6 Innervation of smooth muscle by autonomic nerve fib- the skeletal muscle neuromuscular junction. The rapidity ers that branch diffusely and secrete neurotransmitter from multiple of contraction of these smooth muscle fibers is consid- varicosities. Unitary (visceral) smooth muscle cells are connected by erably faster than that of fibers stimulated by the diffuse gap junctions so that depolarization can rapidly spread from one cell to another, permitting the muscle cells to contract as a single unit. In junctions.! multi-unit smooth muscle, each cell is stimulated independently by a neurotransmitter released from closely associated autonomic nerve Excitatory and Inhibitory Transmitter Substances Se- varicosities. creted at the Smooth Muscle Neuromuscular Junc- tion. The most important transmitter substances secret- membrane contains many types of receptor proteins that ed by the autonomic nerves innervating smooth muscle can initiate the contractile process. Still other recep- are acetylcholine and norepinephrine, but they are never tor proteins inhibit smooth muscle contraction, which secreted by the same nerve fibers. Acetylcholine is an ex- is another difference from skeletal muscle. Therefore, in citatory transmitter substance for smooth muscle fibers this section, we discuss nervous control of smooth mus- in some organs but an inhibitory transmitter for smooth cle contraction, followed by hormonal control and other muscle in other organs. When acetylcholine excites a means of control. muscle fiber, norepinephrine ordinarily inhibits it. Con- versely, when acetylcholine inhibits a fiber, norepineph- rine usually excites it. NEUROMUSCULAR JUNCTIONS OF Why are these responses different? The answer is that SMOOTH MUSCLE both acetylcholine and norepinephrine excite or inhibit Physiologic Anatomy of Smooth Muscle Neuromus- smooth muscle by first binding with a receptor protein cular Junctions. Neuromuscular junctions of the highly on the surface of the muscle cell membrane. Some of the structured type found on skeletal muscle fibers do not oc- receptor proteins are excitatory receptors, whereas others cur in smooth muscle. Instead, the autonomic nerve fibers are inhibitory receptors. Thus, the type of receptor deter- that innervate smooth muscle generally branch diffusely mines whether the smooth muscle is inhibited or excited on top of a sheet of muscle fibers, as shown in Figure 8-6. and also determines which of the two transmitters, ace- In most cases, these fibers do not make direct contact with tylcholine or norepinephrine, is effective in causing the the smooth muscle fiber cell membranes but instead form excitation or inhibition. These receptors are discussed diffuse junctions that secrete their transmitter substance in more detail in Chapter 61 in regard to function of the into the matrix coating of the smooth muscle, often a few autonomic nervous system.! nanometers to a few micrometers away from the muscle cells. The transmitter substance then diffuses to the cells. MEMBRANE POTENTIALS AND ACTION Furthermore, where there are many layers of muscle cells, POTENTIALS IN SMOOTH MUSCLE the nerve fibers often innervate only the outer layer. Mus- cle excitation travels from this outer layer to the inner lay- Membrane Potentials in Smooth Muscle. The quanti- ers by action potential conduction in the muscle mass or tative voltage of the membrane potential of smooth mus- by additional diffusion of the transmitter substance. cle depends on the momentary condition of the muscle. The axons that innervate smooth muscle fibers do not In the normal resting state, the intracellular potential is have the typical branching end feet of the type found in usually about −50 to −60 millivolts, which is about 30 mil- the motor end plate on skeletal muscle fibers. Instead, livolts less negative than in skeletal muscle.! 106  Chapter 8 Excitation and Contraction of Smooth Muscle some conditions, and certain types of vascular smooth 0 muscle. Also, this is the type of action potential seen in cardiac muscle fibers that have a prolonged period of con- traction, as discussed in Chapters 9 and 10.! –20 Millivolts Calcium Channels Are Important in Generating the UNIT II –40 Smooth Muscle Action Potential. The smooth muscle cell membrane has far more voltage-gated calcium chan- nels than skeletal muscle but few voltage-gated sodium –60 Slow waves channels. Therefore, sodium does not participate much in the generation of the action potential in most smooth 0 50 100 0 10 20 30 muscle. Instead, the flow of calcium ions to the interior of the fiber is mainly responsible for the action potential. A Milliseconds B Seconds This flow occurs in the same self-regenerative way as oc- curs for the sodium channels in nerve fibers and in skel- 0 etal muscle fibers. However, the calcium channels open many times more slowly than sodium channels, and they Millivolts –25 also remain open much longer. These characteristics largely account for the prolonged plateau action poten- –50 tials of some smooth muscle fibers. 0 0.1 0.2 0.3 0.4 Another important feature of calcium ion entry into C Seconds the cells during the action potential is that the calcium ions act directly on the smooth muscle contractile mech- Figure 8-7 A, Typical smooth muscle action potential (spike poten- tial) elicited by an external stimulus. B, Repetitive spike potentials, anism to cause contraction. Thus, the calcium performs elicited by slow rhythmical electrical waves that occur spontaneously two tasks at once.! in the smooth muscle of the intestinal wall. C, Action potential with a plateau, recorded from a smooth muscle fiber of the uterus. Slow Wave Potentials in Unitary Smooth Muscle Can Lead to Spontaneous Generation of Action Poten- Action Potentials in Unitary Smooth Muscle. Action tials. Some smooth muscle is self-excitatory—that is, ac- potentials occur in unitary smooth muscle (e.g., visceral tion potentials arise within the smooth muscle cells with- muscle) in the same way that they occur in skeletal mus- out an extrinsic stimulus. This activity is often associated cle. They do not normally occur in most multi-unit types with a basic slow wave rhythm of the membrane potential. of smooth muscle, as discussed in a subsequent section. A typical slow wave in a visceral smooth muscle of the gut The action potentials of visceral smooth muscle occur is shown in Figure 8-7B. The slow wave is not the action in one of two forms—(1) spike potentials or (2) action potential. That is, it is not a self-regenerative process that potentials with plateaus.! spreads progressively over the membranes of the muscle fibers. Instead, it is a local property of the smooth muscle Spike Potentials. Typical spike action potentials, such fibers that make up the muscle mass. as those seen in skeletal muscle, occur in most types of The cause of the slow wave rhythm is unknown. One unitary smooth muscle. The duration of this type of ac- suggestion is that the slow waves are caused by waxing tion potential is 10 to 50 milliseconds, as shown in Fig- and waning of the pumping of positive ions (presumably ure 8-7A. Such action potentials can be elicited in many sodium ions) outward through the muscle fiber mem- ways—for example, by electrical stimulation, by the ac- brane. That is, the membrane potential becomes more tion of hormones on the smooth muscle, by the action of negative when sodium is pumped rapidly and less nega- transmitter substances from nerve fibers, by stretch, or tive when the sodium pump becomes less active. Another as a result of spontaneous generation in the muscle fiber suggestion is that the conductances of the ion channels itself, as discussed subsequently.! increase and decrease rhythmically. The importance of the slow waves is that when they Action Potentials with Plateaus. Figure 8-7C shows a are strong enough, they can initiate action potentials. smooth muscle action potential with a plateau. The onset The slow waves themselves cannot cause muscle contrac- of this action potential is similar to that of the typical spike tion. However, when the peak of the negative slow wave potential. However, instead of rapid repolarization of the potential inside the cell membrane rises in the positive muscle fiber membrane, the repolarization is delayed for direction, from −60 to about −35 millivolts (the approxi- several hundred to as much as 1000 milliseconds (1 sec- mate threshold for eliciting action potentials in most vis- ond). The importance of the plateau is that it can account ceral smooth muscle), an action potential develops and for the prolonged contraction that occurs in some types spreads over the muscle mass and contraction occurs. of smooth muscle, such as the ureter, the uterus under Figure 8-7B demonstrates this effect, showing that at 107 UNIT II Membrane Physiology, Nerve, and Muscle each peak of the slow wave, one or more action poten- tle or no nervous supply. Yet, the smooth muscle is highly tials occur. These repetitive sequences of action potentials contractile, responding rapidly to changes in local chemi- elicit rhythmical contraction of the smooth muscle mass. cal conditions in the surrounding interstitial fluid and to Therefore, the slow waves are called pacemaker waves. In stretch caused by changes in blood pressure. Chapter 63, we see that this type of pacemaker activity In the normal resting state, many of these small blood controls the rhythmical contractions of the gut.! vessels remain contracted. However, when extra blood flow to the tissue is necessary, multiple factors can relax Excitation of Visceral Smooth Muscle by Muscle the vessel wall, thus allowing for increased flow. In this Stretch. When visceral (unitary) smooth muscle is way, a powerful local feedback control system controls the stretched sufficiently, spontaneous action potentials are blood flow to the local tissue area. Some of the specific usually generated. They result from a combination of the control factors are as follows: following: (1) the normal slow wave potentials; and (2) a 1. Lack of oxygen in the local tissues causes smooth decrease in overall negativity of the membrane potential muscle relaxation and, therefore, vasodilation. caused by the stretch. This response to stretch allows the 2. Excess carbon dioxide causes vasodilation. gut wall, when excessively stretched, to contract auto- 3. Increased hydrogen ion concentration causes vaso- matically and rhythmically. For example, when the gut is dilation. overfilled by intestinal contents, local automatic contrac- Adenosine, lactic acid, increased potassium ions, nitric tions often set up peristaltic waves that move the contents oxide, and increased body temperature can all cause away from the overfilled intestine, usually in the direction local vasodilation. Decreased blood pressure, by caus- of the anus.! ing decreased stretch of the vascular smooth muscle, also causes these small blood vessels to dilate.! DEPOLARIZATION OF MULTI-UNIT SMOOTH Effects of Hormones on Smooth Muscle Contraction. MUSCLE WITHOUT ACTION POTENTIALS Many circulating hormones in the blood affect smooth The smooth muscle fibers of multi-unit smooth muscle muscle contraction to some degree, and some have pro- (e.g., the muscle of the iris of the eye or the piloerector found effects. Among the more important of these hor- muscle of each hair) normally contract mainly in response mones are norepinephrine, epinephrine, angiotensin II, en- to nerve stimuli. The nerve endings secrete acetylcholine in dothelin, vasopressin, oxytocin, serotonin, and histamine. the case of some multi-unit smooth muscles and norepi- A hormone causes contraction of a smooth muscle nephrine in the case of others. In both cases, the transmit- when the muscle cell membrane contains hormone-gated ter substances cause depolarization of the smooth muscle excitatory receptors for the respective hormone. Con- membrane, and this depolarization in turn elicits contrac- versely, the hormone causes inhibition if the membrane tion. Action potentials usually do not develop because the contains inhibitory receptors for the hormone rather than fibers are too small to generate an action potential. (When excitatory receptors.! action potentials are elicited in visceral unitary smooth muscle, 30 to 40 smooth muscle fibers must depolarize Mechanisms of Smooth Muscle Excitation or Inhibi- simultaneously before a self-propagating action potential tion by Hormones or Local Tissue Factors. Some hor- ensues.) However, in small smooth muscle cells, even with- mone receptors in the smooth muscle membrane open out an action potential, the local depolarization (called the sodium or calcium ion channels and depolarize the mem- junctional potential) caused by the nerve transmitter sub- brane, the same as after nerve stimulation. Sometimes, stance spreads “electrotonically” over the entire fiber and is action potentials result, or action potentials that are al- all that is necessary to cause muscle contraction. ready occurring may be enhanced. In other cases, depo- larization occurs without action potentials, and this depo- Local Tissue Factors and Hormones larization allows for calcium ion entry into the cell, which Can Cause Smooth Muscle Contraction promotes the contraction. Without Action Potentials Inhibition, in contrast, occurs when the hormone (or Approximately half of all smooth muscle contraction is other tissue factor) closes the sodium and calcium chan- likely initiated by stimulatory factors acting directly on nels to prevent entry of these positive ions; inhibition the smooth muscle contractile machinery and without also occurs if the normally closed potassium channels are action potentials. Two types of non-nervous and nonac- opened, allowing positive potassium ions to diffuse out of tion potential stimulating factors often involved are (1) the cell. Both these actions increase the degree of negativ- local tissue chemical factors and (2) various hormones. ity inside the muscle cell, a state called hyperpolarization, which strongly inhibits muscle contraction. Smooth Muscle Contraction in Response to Local Tis- Sometimes, smooth muscle contraction or inhibition is sue Chemical Factors. In Chapter 17, we discuss control initiated by hormones without directly causing any change of contraction of the arterioles, meta-arterioles, and pre- in the membrane potential. In these cases, the hormone capillary sphincters. The smallest of these vessels have lit- may activate a membrane receptor that does not open 108  Chapter 8 Excitation and Contraction of Smooth Muscle any ion channels but, instead, causes an internal change Brozovich FV, Nicholson CJ, Degen CV, Gao YZ, Aggarwal M, Mor- in the muscle fiber, such as release of calcium ions from gan KG: Mechanisms of vascular smooth muscle contraction and the basis for pharmacologic treatment of smooth muscle disorders. the intracellular sarcoplasmic reticulum; the calcium then Pharmacol Rev 68:476, 2016. induces contraction. To inhibit contraction, other recep- Burnstock G. Purinergic signaling in the cardiovascular system. Circ tor mechanisms are known to activate the enzyme ade- Res 120:207, 2017. nylate cyclase or guanylate cyclase in the cell membrane. Cheng H, Lederer WJ: Calcium sparks. Physiol Rev 88:1491, 2008. UNIT II The portions of the receptors that protrude to the interior Davis MJ: Perspective: physiological role(s) of the vascular myogenic response. Microcirculation 19:99, 2012. of the cells are coupled to these enzymes, causing the for- Dopico AM, Bukiya AN, Jaggar JH. Calcium- and voltage-gated BK mation of cyclic adenosine monophosphate (cAMP) or channels in vascular smooth muscle. Pflugers Arch 470:1271, cyclic guanosine monophosphate (cGMP), so-called sec- 2018. ond messengers. cAMP or cGMP has many effects, one Dora KA. Endothelial-smooth muscle cell interactions in the regulation of of which is to change the degree of phosphorylation of vascular tone in skeletal muscle. Microcirculation 23:626, 2016. Drummond HA, Grifoni SC, Jernigan NL: A new trick for an old several enzymes that indirectly inhibit contraction. The dogma: ENaC proteins as mechanotransducers in vascular smooth pump that moves calcium ions from the sarcoplasm into muscle. Physiology (Bethesda) 23:23, 2008. the sarcoplasmic reticulum is activated, as well as the cell Hill MA, Meininger GA. Small artery mechanobiology: roles of cellular membrane pump that moves calcium ions out of the cell; and non-cellular elements. Microcirculation 23:611, 2016. these effects reduce the calcium ion concentration in the Huizinga JD, Lammers WJ: Gut peristalsis is governed by a multitude of cooperating mechanisms. Am J Physiol Gastrointest Liver Physiol sarcoplasm, thereby inhibiting contraction. 296:G1, 2009. Smooth muscles have considerable diversity in how Kauffenstein G, Laher I, Matrougui K, et al: Emerging role of G they initiate contraction or relaxation in response to protein-coupled receptors in microvascular myogenic tone. Cardio- different hormones, neurotransmitters, and other sub- vasc Res 95:223, 2012. stances. In some cases, the same substance may cause Lacolley P, Regnault V, Segers P, Laurent S. Vascular smooth muscle cells and arterial stiffening: relevance in development, aging, and either relaxation or contraction of smooth muscles in disease. Physiol Rev 97:1555, 2017. different locations. For example, norepinephrine inhibits Morgan KG, Gangopadhyay SS: Cross-bridge regulation by thin contraction of smooth muscle in the intestine but stimu- filament-associated proteins. J Appl Physiol 91:953, 2001. lates contraction of smooth muscle in blood vessels. Ratz PH. Mechanics of vascular smooth muscle. Compr Physiol 6:111, 2015. Sanders KM, Kito Y, Hwang SJ, Ward SM. Regulation of gastroin- testinal smooth muscle function by interstitial cells. Physiology Bibliography (Bethesda) 31:316, 2016. Also see the bibliography for Chapters 5 and 6. Somlyo AP, Somlyo AV: Ca2+ sensitivity of smooth muscle and non- Behringer EJ, Segal SS: Spreading the signal for vasodilatation: im- muscle myosin II: modulated by G proteins, kinases, and myosin plications for skeletal muscle blood flow control and the effects of phosphatase. Physiol Rev 83:1325, 2003. aging. J Physiol 590:6277, 2012. Tykocki NR, Boerman EM, Jackson WF. Smooth muscle ion channels Berridge MJ: Smooth muscle cell calcium activation mechanisms. J and regulation of vascular tone in resistance arteries and arterioles. Physiol 586:5047, 2008. Compr Physiol 7:485, 2017. Blaustein MP, Lederer WJ: Sodium/calcium exchange: its physiological Webb RC: Smooth muscle contraction and relaxation. Adv Physiol implications. Physiol Rev 79:763, 1999. Educ 27:201, 2003. 109