Chapter 8: Excitation and Contraction of Smooth Muscle PDF

CHAPTER 8 UNIT II c0040 Excitation and Contraction of Smooth Muscle...

CHAPTER 8 UNIT II c0040 Excitation and Contraction of Smooth Muscle muscle of the eye, the iris muscle of the eye, and the pilo- Contraction of erector muscles that cause erection of the hairs when stim- Smooth Muscle ulated by the sympathetic nervous system. In Chapters 6 and 7, the dis- Unitary Smooth Muscle. This type is also called cussion was concerned with syncytial smooth muscle or visceral smooth muscle. skeletal muscle. We now turn The term “unitary” is confusing because it does not mean to smooth muscle, which is composed of far smaller fibers— single muscle fibers. Instead, it means a mass of hun- usually 1 to 5 micrometers in diameter and only 20 to 500 dreds to thousands of smooth muscle fibers that contract micrometers in length. In contrast, skeletal muscle fibers are together as a single unit. The fibers usually are arranged as much as 30 times greater in diameter and hundreds of in sheets or bundles, and their cell membranes are adher- times as long. Many of the same principles of contraction ent to one another at multiple points so that force gener- apply to smooth muscle as to skeletal muscle. Most impor- ated in one muscle fiber can be transmitted to the next. In tant, essentially the same attractive forces between myosin addition, the cell membranes are joined by many gap junc- and actin filaments cause contraction in smooth muscle as tions through which ions can flow freely from one muscle in skeletal muscle, but the internal physical arrangement of cell to the next so that action potentials or simple ion flow smooth muscle fibers is different. without action potentials can travel from one fiber to the next and cause the muscle fibers to contract together. This Types of Smooth Muscle type of smooth muscle is also known as syncytial smooth The smooth muscle of each organ is distinctive from that muscle because of its syncytial interconnections among of most other organs in several ways: (1) physical dimen- fibers. It is also called visceral smooth muscle because it is sions, (2) organization into bundles or sheets, (3) response found in the walls of most viscera of the body, including to different types of stimuli, (4) characteristics of inner- the gastrointestinal tract, bile ducts, ureters, uterus, and vation, and (5) function. Yet for the sake of simplicity, many blood vessels. 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. Multi-Unit Smooth Muscle. This type of smooth muscle is composed of discrete, separate smooth muscle Adventitia fibers. Each fiber operates independently of the others and often is innervated by a single nerve ending, as occurs for skeletal muscle fibers. Further, the outer surfaces of these fibers, like those of skeletal muscle fibers, are covered by a Medial thin layer of basement membrane–like substance, a mix- muscle ture of fine collagen and glycoprotein that helps insulate the fibers separate fibers from one another. Endothelium The most important characteristic of multi-unit smooth muscle fibers is that each fiber can contract indepen- dently of the others, and their control is exerted mainly Small artery by nerve signals. In contrast, a major share of control of unitary smooth muscle is exerted by non-nervous stimuli. A Multi-unit smooth muscle B Unitary smooth muscle Some examples of multi-unit smooth muscle are the ciliary Figure 8-1 Multi-unit (A) and unitary (B) smooth muscle. 91 Unit II Membrane Physiology, Nerve, and Muscle Contractile Mechanism in Smooth Muscle Chemical Basis for Smooth Muscle Contraction Smooth muscle contains both actin and myosin filaments, having chemical characteristics similar to those of the actin and myosin filaments in skeletal muscle. It does not Actin filaments contain the normal troponin complex that is required in the control of skeletal muscle contraction, so the mecha- nism for control of contraction is different. This is dis- cussed in detail later in this chapter. Dense bodies Chemical studies have shown that actin and myosin filaments derived from smooth muscle interact with each other in much the same way that they do in skeletal mus- cle. Further, the contractile process is activated by calcium ions, and adenosine triphosphate (ATP) is degraded to adenosine diphosphate (ADP) to provide the energy for contraction. Myosin filaments There are, however, major differences between the physical organization of smooth muscle and that of skele- tal muscle, as well as differences in excitation-contraction coupling, control of the contractile process by calcium ions, duration of contraction, and amount of energy required for contraction. Physical Basis for Smooth Muscle Contraction Smooth muscle does not have the same striated arrange- Cell membrane ment of actin and myosin filaments as is found in skel- etal muscle. Instead, electron micrographic techniques suggest the physical organization exhibited in Figure 8-2. This figure shows large numbers of actin filaments attached to so-called dense bodies. Some of these bodies are attached to the cell membrane. 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 is transmitted from one cell to the next. Interspersed among the actin filaments in the muscle Figure 8-2 Physical structure of smooth muscle. The upper left- fiber are myosin filaments. These have a diameter more hand fiber shows actin filaments radiating from dense bodies. than twice that of the actin filaments. In electron micro- The lower left-hand fiber and the right-hand diagram demonstrate graphs, one usually finds 5 to 10 times as many actin fila- the relation of myosin filaments to actin filaments. ments as myosin filaments. To the right in Figure 8-2 is a postulated structure of allows smooth muscle cells to contract as much as 80 per- an individual contractile unit within a smooth muscle cell, cent of their length instead of being limited to less than showing large numbers of actin filaments radiating from 30 percent, as occurs in skeletal muscle. two dense bodies; the ends of these filaments overlap a myosin filament located midway between the dense bod- Comparison of Smooth Muscle Contraction and ies. This contractile unit is similar to the contractile unit of Skeletal Muscle Contraction skeletal muscle, but without the regularity of the skeletal Although most skeletal muscles contract and relax rapidly, muscle structure; in fact, the dense bodies of smooth mus- most smooth muscle contraction is prolonged tonic con- cle serve the same role as the Z discs in skeletal muscle. traction, sometimes lasting hours or even days. Therefore, There is another difference: Most of the myosin fila- it is to be expected that both the physical and the chemi- ments have what are called “sidepolar” cross-bridges cal characteristics of smooth muscle versus skeletal mus- arranged so that the bridges on one side hinge in one cle contraction would differ. Following are some of the direction and those on the other side hinge in the oppo- differences. site direction. This allows the myosin to pull an actin fila- Slow Cycling of the Myosin Cross-Bridges. The rapid- ment in one direction on one side while simultaneously ity of cycling of the myosin cross-bridges in smooth mus- pulling another actin filament in the opposite direction cle—that is, their attachment to actin, then release from the on the other side. The value of this organization is that it actin, and reattachment for the next cycle—is much slower 92  Chapter 8 Excitation and Contraction of Smooth Muscle than in skeletal muscle; in fact, the frequency is as little as The importance of the latch mechanism is that it can 1/10 to 1/300 that in skeletal muscle. Yet the fraction of maintain prolonged tonic contraction in smooth muscle for time that the cross-bridges remain attached to the actin fil- hours with little use of energy. Little continued excitatory aments, which is a major factor that determines the force signal is required from nerve fibers or hormonal sources. of contraction, is believed to be greatly increased in smooth Stress-Relaxation of Smooth Muscle. Another impor- UNIT II muscle. A possible reason for the slow cycling is that the tant characteristic of smooth muscle, especially the visceral cross-bridge heads have far less ATPase activity than in unitary type of smooth muscle of many hollow organs, is skeletal muscle, so degradation of the ATP that energizes its ability to return to nearly its original force of contrac- the movements of the cross-bridge heads is greatly reduced, tion seconds or minutes after it has been elongated or with corresponding slowing of the rate of cycling. shortened. For example, a sudden increase in fluid volume Low Energy Requirement to Sustain Smooth Muscle in the urinary bladder, thus stretching the smooth muscle Contraction. Only 1/10 to 1/300 as much energy is in the bladder wall, causes an immediate large increase in required to sustain the same tension of contraction in pressure in the bladder. However, during the next 15 sec- smooth muscle as in skeletal muscle. This, too, is believed onds to a minute or so, despite continued stretch of the to result from the slow attachment and detachment cycling bladder wall, the pressure returns almost exactly back to of the cross-bridges and because only one molecule of ATP the original level. Then, when the volume is increased by is required for each cycle, regardless of its duration. another step, the same effect occurs again. This sparsity of energy utilization by smooth muscle is Conversely, when the volume is suddenly decreased, exceedingly important to the overall energy economy of the pressure falls drastically at first but then rises in the body because organs such as the intestines, urinary another few seconds or minutes to or near to the original bladder, gallbladder, and other viscera often maintain level. These phenomena are called stress-relaxation and tonic muscle contraction almost indefinitely. reverse stress-relaxation. Their importance is that, except Slowness of Onset of Contraction and Relaxation of for short periods of time, they allow a hollow organ to the Total Smooth Muscle Tissue. A typical smooth mus- maintain about the same amount of pressure inside its cle tissue begins to contract 50 to 100 milliseconds after it lumen despite long-term, large changes in volume. is excited, reaches full contraction about 0.5 second later, and then declines in contractile force in another 1 to 2 Regulation of Contraction by Calcium Ions seconds, giving a total contraction time of 1 to 3 seconds. As is true for skeletal muscle, the initiating stimulus for This is about 30 times as long as a single contraction of most smooth muscle contraction is an increase in intracel- an average skeletal muscle fiber. But because there are so lular calcium ions. This increase can be caused in different many types of smooth muscle, contraction of some types types of smooth muscle by nerve stimulation of the smooth can be as short as 0.2 second or as long as 30 seconds. muscle fiber, hormonal stimulation, stretch of the fiber, The slow onset of contraction of smooth muscle, as or even change in the chemical environment of the fiber. well as its prolonged contraction, is caused by the slow- Yet smooth muscle does not contain troponin, the reg- ness of attachment and detachment of the cross-bridges ulatory protein that is activated by calcium ions to cause with the actin filaments. In addition, the initiation of con- skeletal muscle contraction. Instead, smooth muscle con- traction in response to calcium ions is much slower than traction is activated by an entirely different mechanism, in skeletal muscle, as discussed later. as follows. Maximum Force of Contraction Is Often Greater in Smooth Muscle Than in Skeletal Muscle. Despite the Calcium Ions Combine with Calmodulin to Cause relatively few myosin filaments in smooth muscle, and Activation of Myosin Kinase and Phosphorylation of despite the slow cycling time of the cross-bridges, the the Myosin Head. In place of troponin, smooth muscle maximum force of contraction of smooth muscle is often cells contain a large amount of another regulatory protein greater than that of skeletal muscle—as great as 4 to 6 kg/ called calmodulin (Figure 8-3). Although this protein is cm2 cross-sectional area for smooth muscle, in compari- similar to troponin, it is different in the manner in which son with 3 to 4 kilograms for skeletal muscle. This great it initiates contraction. Calmodulin does this by activating force of smooth muscle contraction results from the pro- the myosin cross-bridges. This activation and subsequent longed period of attachment of the myosin cross-bridges contraction occur in the following sequence: to the actin filaments. 1. The calcium ions bind with calmodulin. “Latch” Mechanism Facilitates Prolonged Holding of Contractions of Smooth Muscle. Once smooth muscle 2. The calmodulin-calcium complex then joins with and has developed full contraction, the amount of continuing activates myosin light chain kinase, a phosphorylating excitation can usually be reduced to far less than the initial enzyme. level yet the muscle maintains its full force of contraction. 3. One of the light chains of each myosin head, called Further, the energy consumed to maintain contraction is the regulatory chain, becomes phosphorylated in often minuscule, sometimes as little as 1/300 the energy response to this myosin kinase. When this chain is not required for comparable sustained skeletal muscle con- phosphorylated, the attachment-detachment cycling of traction. This is called the “latch” mechanism. the myosin head with the actin filament does not occur. 93 Unit II Membrane Physiology, Nerve, and Muscle been made to explain it. Among the many mechanisms that Outside Ca++ have been postulated, one of the simplest is the following. When the myosin kinase and myosin phosphatase enzymes are both strongly activated, the cycling frequency of the myosin heads and the velocity of contraction are great. Then, as the activation of the enzymes decreases, the cycling frequency decreases, but at the same time, the SR Ca++ Ca++ deactivation of these enzymes allows the myosin heads to Calmodulin remain attached to the actin filament for a longer and lon- ger proportion of the cycling period. Therefore, the num- ber of heads attached to the actin filament at any given time remains large. Because the number of heads attached Ca++ - Calmodulin to the actin determines the static force of contraction, ten- sion is maintained, or “latched”; yet little energy is used by Active Inactive MLCK MLCK the muscle because ATP is not degraded to ADP except on the rare occasion when a head detaches. Phosphatase MLC MLC Nervous and Hormonal Control Phosphorylated Dephosphorylated of Smooth Muscle Contraction Although skeletal muscle fibers are stimulated exclusively by the nervous system, smooth muscle can be stimulated Contraction Relaxation to contract by multiple types of signals: by nervous sig- Figure 8-3 Intracellular calcium ion (Ca++) concentration increases nals, by hormonal stimulation, by stretch of the muscle, when Ca++ enters the cell through calcium channels in the cell membrane or the sarcoplasmic reticulum (SR). The Ca++ binds to and in several other ways. The principal reason for the calmodulin to form a Ca++-calmodulin complex, which then acti- difference is that the smooth muscle membrane con- vates myosin light chain kinase (MLCK). The MLCK phosphorylates tains many types of receptor proteins that can initiate the the myosin light chain (MLC) leading to contraction of the smooth contractile process. Still other receptor proteins inhibit muscle. When Ca++ concentration decreases, due to pumping of smooth muscle contraction, which is another difference Ca++ out of the cell, the process is reversed and myosin phos- phatase removes the phosphate from MLC, leading to relaxation. from skeletal muscle. Therefore, in this section, we dis- cuss nervous control of smooth muscle contraction, fol- lowed by hormonal control and other means of control. But when the regulatory chain is phosphorylated, the head has the capability of binding repetitively with the Neuromuscular Junctions of Smooth Muscle actin filament and proceeding through the entire cycling Physiologic Anatomy of Smooth Muscle Neu- process of intermittent “pulls,” the same as occurs for romuscular Junctions. Neuromuscular junctions of skeletal muscle, thus causing muscle contraction. the highly structured type found on skeletal muscle fibers do not occur in smooth muscle. Instead, the auto- nomic nerve fibers that innervate smooth muscle gener- Myosin Phosphatase Is Important in Cessation of ally branch diffusely on top of a sheet of muscle fibers, Contraction. When the calcium ion concentration falls as shown in Figure 8-4. In most instances, these fibers below a critical level, the aforementioned processes auto- matically reverse, except for the phosphorylation of the myosin head. Reversal of this requires another enzyme, myosin phosphatase (see Figure 8-3), located in the cytosol Gap junctions of the smooth muscle cell, which splits the phosphate from the regulatory light chain. Then the cycling stops and con- traction ceases. The time required for relaxation of muscle contraction, therefore, is determined to a great extent by the amount of active myosin phosphatase in the cell. Possible Mechanism for Regulation Varicosities of the Latch Phenomenon Because of the importance of the latch phenomenon in smooth muscle, and because this phenomenon allows long- term maintenance of tone in many smooth muscle organs Visceral Multi-unit without much expenditure of energy, many attempts have Figure 8-4 Innervation of smooth muscle. 94  Chapter 8 Excitation and Contraction of Smooth Muscle do not make direct contact with the smooth muscle causing the excitation or inhibition. These receptors are fiber cell membranes but instead form so-called diffuse discussed in more detail in Chapter 60 in relation to func- junctions that secrete their transmitter substance into tion of the autonomic nervous system. the matrix coating of the smooth muscle often a few nanometers to a few micrometers away from the mus- Membrane Potentials and Action Potentials UNIT II cle cells; the transmitter substance then diffuses to the in Smooth Muscle cells. Furthermore, where there are many layers of mus- Membrane Potentials in Smooth Muscle. The cle cells, the nerve fibers often innervate only the outer quantitative voltage of the membrane potential of smooth layer. Muscle excitation travels from this outer layer to muscle depends on the momentary condition of the mus- the inner layers by action potential conduction in the cle. In the normal resting state, the intracellular potential muscle mass or by additional diffusion of the transmit- is usually about −50 to −60 millivolts, which is about 30 ter substance. millivolts less negative than in skeletal muscle. The axons that innervate smooth muscle fibers do not have typical branching end feet of the type in the motor Action Potentials in Unitary Smooth Muscle. Action end plate on skeletal muscle fibers. Instead, most of the potentials occur in unitary smooth muscle (such as vis- fine terminal axons have multiple varicosities distributed ceral muscle) in the same way that they occur in skeletal along their axes. At these points the Schwann cells that muscle. They do not normally occur in most multi-unit envelop the axons are interrupted so that transmitter sub- types of smooth muscle, as discussed in a subsequent stance can be secreted through the walls of the varicosi- section. ties. In the varicosities are vesicles similar to those in the The action potentials of visceral smooth muscle occur skeletal muscle end plate that contain transmitter sub- in one of two forms: (1) spike potentials or (2) action stance. But in contrast to the vesicles of skeletal muscle potentials with plateaus. junctions, which always contain acetylcholine, the vesi- cles of the autonomic nerve fiber endings contain acetyl- Spike Potentials. Typical spike action potentials, choline in some fibers and norepinephrine in others—and such as those seen in skeletal muscle, occur in most types occasionally other substances as well. of unitary smooth muscle. The duration of this type of In a few instances, particularly in the multi-unit type action potential is 10 to 50 milliseconds, as shown in of smooth muscle, the varicosities are separated from Figure 8-5A. Such action potentials can be elicited in the muscle cell membrane by as little as 20 to 30 nano- many ways, for example, by electrical stimulation, by the meters—the same width as the synaptic cleft that occurs in the skeletal muscle junction. These are called contact junctions, and they function in much the same way as 0 the skeletal muscle neuromuscular junction; the rapidity of contraction of these smooth muscle fibers is consid- erably faster than that of fibers stimulated by the diffuse –20 Millivolts junctions. –40 Excitatory and Inhibitory Transmitter Substances Secreted at the Smooth Muscle Neuromuscular Junction. The most important transmitter substances –60 Slow waves secreted by the autonomic nerves innervating smooth muscle are acetylcholine and norepinephrine, but they are never secreted by the same nerve fibers. Acetylcholine 0 50 100 0 10 20 30 is an excitatory transmitter substance for smooth mus- A Milliseconds B Seconds cle fibers in some organs but an inhibitory transmitter for smooth muscle in other organs. When acetylcholine 0 excites a muscle fiber, norepinephrine ordinarily inhibits Millivolts it. Conversely, when acetylcholine inhibits a fiber, norepi- –25 nephrine usually excites it. But why are these responses different? The answer –50 is that both acetylcholine and norepinephrine excite or inhibit smooth muscle by first binding with a receptor 0 0.1 0.2 0.3 0.4 C Seconds protein on the surface of the muscle cell membrane. Some of the receptor proteins are excitatory receptors, whereas Figure 8-5 A, Typical smooth muscle action potential (spike others are inhibitory receptors. Thus, the type of recep- potential) elicited by an external stimulus. B, Repetitive spike potentials, elicited by slow rhythmical electrical waves that tor determines whether the smooth muscle is inhibited occur spontaneously in the smooth muscle of the intestinal or excited and also determines which of the two trans- wall. C, Action potential with a plateau, recorded from a smooth mitters, acetylcholine or norepinephrine, is effective in muscle fiber of the uterus. 95 Unit II Membrane Physiology, Nerve, and Muscle action of hormones on the smooth muscle, by the action brane; that is, the membrane potential becomes more of transmitter substances from nerve fibers, by stretch, or negative when sodium is pumped rapidly and less nega- as a result of spontaneous generation in the muscle fiber tive when the sodium pump becomes less active. Another itself, as discussed subsequently. suggestion is that the conductances of the ion channels increase and decrease rhythmically. Action Potentials with Plateaus. Figure 8-5C The importance of the slow waves is that, when they shows a smooth muscle action potential with a plateau. are strong enough, they can initiate action potentials. The onset of this action potential is similar to that of the The slow waves themselves cannot cause muscle contrac- typical spike potential. However, instead of rapid repo- tion. However, when the peak of the negative slow wave larization of the muscle fiber membrane, the repolariza- potential inside the cell membrane rises in the positive tion is delayed for several hundred to as much as 1000 direction from −60 to about −35 millivolts (the approxi- milliseconds (1 second). The importance of the plateau mate threshold for eliciting action potentials in most vis- is that it can account for the prolonged contraction that ceral smooth muscle), an action potential develops and occurs in some types of smooth muscle, such as the spreads over the muscle mass and contraction occurs. ureter, the uterus under some conditions, and certain Figure 8-5B demonstrates this effect, showing that at types of vascular smooth muscle. (Also, this is the type each peak of the slow wave, one or more action poten- of action potential seen in cardiac muscle fibers that tials occur. These repetitive sequences of action potentials have a prolonged period of contraction, as discussed in elicit rhythmical contraction of the smooth muscle mass. Chapters 9 and 10.) Therefore, the slow waves are called pacemaker waves. In Chapter 62, we see that this type of pacemaker activity Calcium Channels Are Important in Generating controls the rhythmical contractions of the gut. the Smooth Muscle Action Potential. The smooth muscle cell membrane has far more voltage-gated calcium Excitation of Visceral Smooth Muscle by Muscle channels than does skeletal muscle but few voltage-gated Stretch. When visceral (unitary) smooth muscle is sodium channels. Therefore, sodium participates little stretched sufficiently, spontaneous action potentials in the generation of the action potential in most smooth are usually generated. They result from a combination muscle. Instead, flow of calcium ions to the interior of of (1) the normal slow wave potentials and (2) decrease the fiber is mainly responsible for the action potential. in overall negativity of the membrane potential caused This occurs in the same self-regenerative way as occurs by the stretch itself. This response to stretch allows the for the sodium channels in nerve fibers and in skeletal gut wall, when excessively stretched, to contract auto- muscle fibers. However, the calcium channels open many matically and rhythmically. For instance, when the gut times more slowly than do sodium channels, and they also is overfilled by intestinal contents, local automatic con- remain open much longer. This accounts in large mea- tractions often set up peristaltic waves that move the sure for the prolonged plateau action potentials of some contents away from the overfilled intestine, usually in smooth muscle fibers. the direction of the anus. Another important feature of calcium ion entry into the cells during the action potential is that the calcium ions act directly on the smooth muscle contractile mech- Depolarization of Multi-Unit Smooth Muscle anism to cause contraction. Thus, the calcium performs Without Action Potentials two tasks at once. The smooth muscle fibers of multi-unit smooth muscle (such as the muscle of the iris of the eye or the piloerector Slow Wave Potentials in Unitary Smooth Muscle muscle of each hair) normally contract mainly in response Can Lead to Spontaneous Generation of Action to nerve stimuli. The nerve endings secrete acetylcho- Potentials. Some smooth muscle is self-excitatory. That line in the case of some multi-unit smooth muscles and is, action potentials arise within the smooth muscle cells norepinephrine in the case of others. In both instances, themselves without an extrinsic stimulus. This is often the transmitter substances cause depolarization of the associated with a basic slow wave rhythm of the mem- smooth muscle membrane, and this in turn elicits con- brane potential. A typical slow wave in a visceral smooth traction. Action potentials usually do not develop; the muscle of the gut is shown in Figure 8-5B. The slow wave reason is that the fibers are too small to generate an action itself is not the action potential. That is, it is not a self- potential. (When action potentials are elicited in visceral regenerative process that spreads progressively over the unitary smooth muscle, 30 to 40 smooth muscle fibers membranes of the muscle fibers. Instead, it is a local must depolarize simultaneously before a self-propagating property of the smooth muscle fibers that make up the action potential ensues.) Yet in small smooth muscle cells, muscle mass. even without an action potential, the local depolariza- The cause of the slow wave rhythm is unknown. One tion (called the junctional potential) caused by the nerve suggestion is that the slow waves are caused by waxing transmitter substance itself spreads “electrotonically” over and waning of the pumping of positive ions (presumably the entire fiber and is all that is necessary to cause muscle sodium ions) outward through the muscle fiber mem- contraction. 96  Chapter 8 Excitation and Contraction of Smooth Muscle Effect of Local Tissue Factors and Hormones Inhibition, in contrast, occurs when the hormone (or to Cause Smooth Muscle Contraction Without other tissue factor) closes the sodium and calcium chan- Action Potentials nels to prevent entry of these positive ions; inhibition Probably half of all smooth muscle contraction is initiated also occurs if the normally closed potassium channels are by stimulatory factors acting directly on the smooth mus- opened, allowing positive potassium ions to diffuse out of UNIT II cle contractile machinery and without action potentials. the cell. Both of these actions increase the degree of nega- Two types of non-nervous and nonaction potential stim- tivity inside the muscle cell, a state called hyperpolariza- ulating factors often involved are (1) local tissue chemical tion, which strongly inhibits muscle contraction. factors and (2) various hormones. Sometimes smooth muscle contraction or inhibition is initiated by hormones without directly causing any Smooth Muscle Contraction in Response to Local change in the membrane potential. In these instances, the Tissue Chemical Factors. In Chapter 17, we discuss hormone may activate a membrane receptor that does control of contraction of the arterioles, meta-arterioles, not open any ion channels but instead causes an inter- and precapillary sphincters. The smallest of these vessels nal change in the muscle fiber, such as release of calcium have little or no nervous supply. Yet the smooth muscle is ions from the intracellular sarcoplasmic reticulum; the highly contractile, responding rapidly to changes in local calcium then induces contraction. To inhibit contraction, chemical conditions in the surrounding interstitial fluid. other receptor mechanisms are known to activate the In the normal resting state, many of these small blood enzyme adenylate cyclase or guanylate cyclase in the cell vessels remain contracted. But when extra blood flow membrane; the portions of the receptors that protrude to the tissue is necessary, multiple factors can relax the to the interior of the cells are coupled to these enzymes, vessel wall, thus allowing for increased flow. In this way, causing the formation of cyclic adenosine monophosphate a powerful local feedback control system controls the (cAMP) or cyclic guanosine monophosphate (cGMP), so- blood flow to the local tissue area. Some of the specific called second messengers. The cAMP or cGMP has many control factors are as follows: effects, one of which is to change the degree of phospho- rylation of several enzymes that indirectly inhibit con- 1. Lack of oxygen in the local tissues causes smooth mus- traction. The pump that moves calcium ions from the cle relaxation and, therefore, vasodilatation. sarcoplasm into the sarcoplasmic reticulum is activated, 2. Excess carbon dioxide causes vasodilatation. as well as the cell membrane pump that moves calcium 3. Increased hydrogen ion concentration causes vaso- ions out of the cell itself; these effects reduce the calcium dilatation. ion concentration in the sarcoplasm, thereby inhibiting contraction. Adenosine, lactic acid, increased potassium ions, Smooth muscles have considerable diversity in how diminished calcium ion concentration, and increased they initiate contraction or relaxation in response to body temperature can all cause local vasodilatation. different hormones, neurotransmitters, and other sub- Effects of Hormones on Smooth Muscle stances. In some instances, the same substance may cause Contraction. Many circulating hormones in the blood either relaxation or contraction of smooth muscles in dif- affect smooth muscle contraction to some degree, and ferent locations. For example, norepinephrine inhibits some have profound effects. Among the more important contraction of smooth muscle in the intestine but stimu- of these are norepinephrine, epinephrine, acetylcholine, lates contraction of smooth muscle in blood vessels. angiotensin, endothelin, vasopressin, oxytocin, serotonin, Source of Calcium Ions That Cause Contraction and histamine. Through the Cell Membrane and from the A hormone causes contraction of a smooth mus- Sarcoplasmic Reticulum cle when the muscle cell membrane contains hormone- gated excitatory receptors for the respective hormone. Although the contractile process in smooth muscle, as in Conversely, the hormone causes inhibition if the mem- skeletal muscle, is activated by calcium ions, the source of brane contains inhibitory receptors for the hormone rather the calcium ions differs. An important difference is that than excitatory receptors. the sarcoplasmic reticulum, which provides virtually all the calcium ions for skeletal muscle contraction, is only Mechanisms of Smooth Muscle Excitation or slightly developed in most smooth muscle. Instead, most Inhibition by Hormones or Local Tissue Factors. Some of the calcium ions that cause contraction enter the mus- hormone receptors in the smooth muscle membrane open cle cell from the extracellular fluid at the time of the action sodium or calcium ion channels and depolarize the mem- potential or other stimulus. That is, the concentration of brane, the same as after nerve stimulation. Sometimes calcium ions in the extracellular fluid is greater than 10−3 action potentials result, or action potentials that are molar, in comparison with less than 10−7 molar inside the already occurring may be enhanced. In other cases, depo- smooth muscle cell; this causes rapid diffusion of the cal- larization occurs without action potentials and this depo- cium ions into the cell from the extracellular fluid when larization allows calcium ion entry into the cell, which the calcium channels open. The time required for this promotes the contraction. diffusion to occur averages 200 to 300 milliseconds and 97 Unit II Membrane Physiology, Nerve, and Muscle is called the latent period before contraction begins. A Calcium Pump Is Required to Cause Smooth This latent period is about 50 times as great for smooth Muscle Relaxation. To cause relaxation of smooth muscle as for skeletal muscle contraction. muscle after it has contracted, the calcium ions must be removed from the intracellular fluids. This removal Role of the Smooth Muscle Sarcoplasmic Retic- is achieved by a calcium pump that pumps calcium ions ulum. Figure 8-6 shows a few slightly developed sarco- out of the smooth muscle fiber back into the extracellu- plasmic tubules that lie near the cell membrane in some lar fluid, or into a sarcoplasmic reticulum, if it is present. larger smooth muscle cells. Small invaginations of the This pump is slow-acting in comparison with the fast- cell membrane, called caveolae, abut the surfaces of these acting sarcoplasmic reticulum pump in skeletal muscle. tubules. The caveolae suggest a rudimentary analog of the Therefore, a single smooth muscle contraction often lasts transverse tubule system of skeletal muscle. When an action for seconds rather than hundredths to tenths of a second, potential is transmitted into the caveolae, this is believed as occurs for skeletal muscle. to excite calcium ion release from the abutting sarcoplas- mic tubules in the same way that action potentials in skel- etal muscle transverse tubules cause release of calcium ions Bibliography from the skeletal muscle longitudinal sarcoplasmic tubules. Also see references for Chapters 5 and 6. In general, the more extensive the sarcoplasmic reticulum Andersson KE, Arner A: Pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence, Physiol Rev in the smooth muscle fiber, the more rapidly it contracts. 84:935, 2004. Berridge MJ: Smooth muscle cell calcium activation mechanisms, J Physiol Smooth Muscle Contraction Is Dependent on 586:5047, 2008. Extracellular Calcium Ion Concentration. Although Blaustein MP, Lederer WJ: Sodium/calcium exchange: its physiological changing the extracellular fluid calcium ion concentration implications, Physiol Rev 79:763, 1999. Cheng H, Lederer WJ: Calcium sparks, Physiol Rev 88:1491, 2008. from normal has little effect on the force of contraction of Davis MJ, Hill MA: Signaling mechanisms underlying the vascular myogenic skeletal muscle, this is not true for most smooth muscle. response, Physiol Rev 79:387, 1999. When the extracellular fluid calcium ion concentration Drummond HA, Grifoni SC, Jernigan NLA: New trick for an old dogma: falls to about 1/3 to 1/10 normal, smooth muscle contrac- ENaC proteins as mechanotransducers in vascular smooth muscle, tion usually ceases. Therefore, the force of contraction of Physiology (Bethesda) 23:23, 2008. Harnett KM, Biancani P: Calcium-dependent and calcium-independent smooth muscle is usually highly dependent on extracellu- contractions in smooth muscles, Am J Med 115(Suppl 3A):24S, 2003. lar fluid calcium ion concentration. Hilgers RH, Webb RC: Molecular aspects of arterial smooth muscle contrac- tion: focus on Rho, Exp Biol Med (Maywood) 230:829, 2005. House SJ, Potier M, Bisaillon J, Singer HA, Trebak M: The non-excitable smooth muscle: calcium signaling and phenotypic switching during vas- cular disease, Pflugers Arch 456:769, 2008. Huizinga JD, Lammers WJ: Gut peristalsis is governed by a multitude of cooperating mechanisms, Am J Physiol Gastrointest Liver Physiol 296:G1, 2009. Kuriyama H, Kitamura K, Itoh T, Inoue R: Physiological features of visceral smooth muscle cells, with special reference to receptors and ion chan- nels, Physiol Rev 78:811, 1998. Morgan KG, Gangopadhyay SS: Cross-bridge regulation by thin filament- associated proteins, J Appl Physiol 91:953, 2001. Somlyo AP, Somlyo AV: Ca2+ sensitivity of smooth muscle and nonmuscle Caveolae myosin II: modulated by G proteins, kinases, and myosin phosphatase, Physiol Rev 83:1325, 2003. Stephens NL: Airway smooth muscle, Lung 179:333, 2001. Touyz RM: Transient receptor potential melastatin 6 and 7 channels, mag- nesium transport, and vascular biology: implications in hypertension, Am J Physiol Heart Circ Physiol 294:H1103, 2008. Sarcoplasmic Walker JS, Wingard CJ, Murphy RA: Energetics of crossbridge phosphoryla- reticulum tion and contraction in vascular smooth muscle, Hypertension 23:1106, 1994. Wamhoff BR, Bowles DK, Owens GK: Excitation-transcription coupling in Figure 8-6 Sarcoplasmic tubules in a large smooth muscle fiber arterial smooth muscle, Circ Res 98:868, 2006. showing their relation to invaginations in the cell membrane called Webb RC: Smooth muscle contraction and relaxation, Adv Physiol Educ caveolae. 27:201, 2003. 98