Excitation and Contraction of Smooth Muscle

Multi-Unit Smooth Muscle.

Multi-unit smooth muscle is composed of discrete, separate smooth muscle 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 thin layer of basement membrane–like substance, a mixture of fine collagen and glycoprotein that helps insulate the separate fibers from one another.

Important characteristics of multi-unit smooth muscle fibers are that each fiber can contract independently of the others, and their control is exerted mainly by nerve signals. In contrast, a major share of control of unitary smooth muscle is exerted by non-nervous stimuli. Some examples of multi-unit smooth muscle are the ciliary muscle of the eye, the iris muscle of the eye, and the piloerector muscles that cause erection of the hairs when stimulated by the sympathetic nervous system.

Unitary Smooth Muscle.

Unitary smooth muscle is also called syncytial smooth muscle or visceral smooth muscle. The term “unitary” is confusing because it does not mean single muscle fibers. Instead, it means a mass of hundreds to thousands of smooth muscle fibers that contract together as a single unit. The fibers usually are arranged in sheets or bundles, and their cell membranes are adherent to one another at multiple points so that force generated in one muscle fiber can be transmitted to the next. In addition, the cell membranes are joined by many gap junctions through which ions can flow freely from one muscle cell to the next so that action potentials, or simple ion flow without action potentials, can travel from one fiber to the next and cause the muscle fibers to contract together. This type of smooth muscle is also known as syncytial smooth muscle because of its syncytial interconnections among fibers. It is also called visceral smooth muscle because it is found in the walls of most viscera of the body, including the gastrointestinal tract, bile ducts, ureters, uterus, and many blood vessels.

Slow Cycling of the Myosin Cross-Bridges.

The rapidity of cycling of the myosin cross-bridges in smooth muscle—that is, their attachment to actin, then release from the actin, and reattachment for the next cycle—is much slower than in skeletal muscle; in fact, the frequency is as little as 1/10 to 1/300 that in skeletal muscle. Yet, the fraction of time that the cross-bridges remain attached to the actin filaments, which is a major factor that determines the force of contraction, is believed to be greatly increased in smooth muscle. A possible reason for the slow cycling is that the cross-bridge heads have far less ATPase activity than in skeletal muscle, and thus degradation of the ATP that energizes the movements of the cross-bridge heads is greatly reduced, with corresponding slowing of the rate of cycling.

Low Energy Requirement to Sustain Smooth Muscle Contraction.

Only 1/10 to 1/300 as much energy is required to sustain the same tension of contraction in smooth muscle as in skeletal muscle. This, too, is believed to result from the slow attachment and detachment cycling of the cross-bridges and because only one molecule of ATP is required for each cycle, regardless of its duration.

This low energy utilization by smooth muscle is important to the overall energy economy of the body because organs such as the intestines, urinary bladder, gallbladder, and other viscera often maintain tonic muscle contraction almost indefinitely.

Slowness of Onset of Contraction and Relaxation of the Total Smooth Muscle Tissue.

A typical smooth muscle tissue begins to contract 50 to 100 milliseconds after it is excited, reaches full contraction about 0.5 second later, and then declines in contractile force in another 1 to 2 seconds, giving a total contraction time of 1 to 3 seconds. This is about 30 times as long as a single contraction of an average skeletal muscle fiber. However, because there are so many types of smooth muscle, contraction of some types can be as short as 0.2 second or as long as 30 seconds.

The slow onset of contraction of smooth muscle, as well as its prolonged contraction, is caused by the slowness of attachment and detachment of the cross-bridges with the actin filaments. In addition, the initiation of contraction in response to calcium ions is much slower than in skeletal muscle, as will be discussed later.

The Maximum Force of Contraction Is Often Greater in Smooth Muscle Than in Skeletal Muscle.

Despite the relatively few myosin filaments in smooth muscle, and despite the slow cycling time of the cross-bridges, the maximum force of contraction of smooth muscle is often greater than that of skeletal muscle—as great as 4 to 6 kg/cm² cross-sectional area for smooth muscle, in comparison with 3 to 4 kilograms for skeletal muscle. This great force of smooth muscle contraction results from the prolonged period of attachment of the myosin cross-bridges to the actin filaments.

The “Latch” Mechanism Facilitates Prolonged Holding of Contractions of Smooth Muscle.

Once smooth muscle has developed full contraction, the amount of continuing excitation can usually be reduced to far less than the initial level even though the muscle maintains its full force of contraction. Further, the energy consumed to maintain contraction is often minuscule, sometimes as little as 1/300 the energy required for comparable sustained skeletal muscle contraction. This mechanism is called the “latch” mechanism.

The importance of the latch mechanism is that it can maintain prolonged tonic contraction in smooth muscle for hours with little use of energy. Little continued excitatory signal is required from nerve fibers or hormonal sources.

Stress-Relaxation of Smooth Muscle.

Another important characteristic of smooth muscle, especially the visceral unitary type of smooth muscle of many hollow organs, is its ability to return to nearly its original force of contraction seconds or minutes after it has been elongated or shortened. For example, a sudden increase in fluid volume in the urinary bladder, thus stretching the smooth muscle in the bladder wall, causes an immediate large increase in pressure in the bladder. However, during the next 15 seconds to a minute or so, despite continued stretch of the bladder wall, the pressure returns almost exactly back to the original level. Then, when the volume is increased by another step, the same effect occurs again.

Conversely, when the volume is suddenly decreased, the pressure falls drastically at first but then rises in another few seconds or minutes to or near to the original level. These phenomena are called stress-relaxation and reverse stress-relaxation. Their importance is that, except for short periods, they allow a hollow organ to maintain about the same amount of pressure inside its lumen despite sustained, large changes in volume.

Role of the Smooth Muscle Sarcoplasmic Retic­ulum.

Figure 8-4 shows a few slightly developed sarcoplasmic tubules that lie near the cell membrane in some larger smooth muscle cells. Small invaginations of the cell membrane, called caveolae, abut the surfaces of these tubules. The caveolae suggest a rudimentary analog of the transverse tubule system of skeletal muscle. When an action potential is transmitted into the caveolae, this is believed to excite calcium ion release from the abutting sarcoplasmic tubules in the same way that action potentials in skeletal muscle transverse tubules cause release of calcium ions from the skeletal muscle longitudinal sarcoplasmic tubules. In general, the more extensive the sarcoplasmic reticulum in the smooth muscle fiber, the more rapidly it contracts.

Smooth Muscle Contraction Is Dependent on Extra­cellular Calcium Ion Concentration.

Although changing the extracellular fluid calcium ion concentration from normal has little effect on the force of contraction of skeletal muscle, this is not true for most smooth muscle. When the extracellular fluid calcium ion concentration decreases to about 1/3 to 1/10 normal, smooth muscle contraction usually ceases. Therefore, the force of contraction of smooth muscle is usually highly dependent on the extracellular fluid calcium ion concentration.

A Calcium Pump Is Required to Cause Smooth Muscle Relaxation.

To cause relaxation of smooth muscle after it has contracted, the calcium ions must be removed from the intracellular fluids. This removal is achieved by a calcium pump that pumps calcium ions out of the smooth muscle fiber back into the extracellular fluid, or into a sarcoplasmic reticulum, if it is present (Figure 8-5). This pump requires ATP and is slow acting in comparison with the fast-acting sarcoplasmic reticulum pump in skeletal muscle. Therefore, a single smooth muscle contraction often lasts for seconds rather than hundredths to tenths of a second, as occurs for skeletal muscle.

Myosin Phosphatase Is Important in Cessation of Contraction.

Relaxation of the smooth muscle occurs when the calcium channels close and the calcium pump transports calcium ions out of the cytosolic fluid of the cell. When the calcium ion concentration falls below a critical level, the aforementioned processes automatically reverse, except for the phosphorylation of the myosin head. Reversal of this situation requires another enzyme, myosin phosphatase (Figure 8-5), located in the cytosol of the smooth muscle cell, which splits the phosphate from the regulatory light chain. Then the cycling stops and contraction 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 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 without much expenditure of energy, many attempts have been made to explain it. Among the many mechanisms that 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 deactivation of these enzymes allows the myosin heads to remain attached to the actin filament for a longer and longer proportion of the cycling period. Therefore, the number of heads attached to the actin filament at any given time remains large. Because the number of heads attached to the actin determines the static force of contraction, tension is maintained, or “latched,” yet little energy is used by the muscle because ATP is not degraded to ADP except on the rare occasion when a head detaches.

Physiologic Anatomy of Smooth Muscle Neuro­muscular Junctions.

Neuromuscular junctions of the highly structured type found on skeletal muscle fibers do not occur in smooth muscle. Instead, the autonomic nerve fibers that innervate smooth muscle generally branch diffusely on top of a sheet of muscle fibers, as shown in Figure 8-6. In most instances, these fibers do not make direct contact with the smooth muscle fiber cell membranes but instead form diffuse junctions that secrete their transmitter substance into the matrix coating of the smooth muscle often a few nanometers to a few micro­meters away from the muscle cells; the transmitter substance then diffuses to the cells. Furthermore, where there are many layers of muscle cells, the nerve fibers often innervate only the outer layer. Muscle excitation travels from this outer layer to the inner layers by action potential conduction in the muscle mass or by additional diffusion of the transmitter substance.

The axons that innervate smooth muscle fibers do not have typical branching end feet of the type found in the motor end plate on skeletal muscle fibers. Instead, most of the fine terminal axons have multiple varicosities distributed along their axes. At these points the Schwann cells that envelop the axons are interrupted so that transmitter substance can be secreted through the walls of the varicosities. In the varicosities are vesicles similar to those in the skeletal muscle end plate that contain transmitter substance. But in contrast to the vesicles of skeletal muscle junctions, which always contain acetylcholine, the vesicles of the autonomic nerve fiber endings contain acetylcholine in some fibers and norepinephrine in others, and occasionally other substances as well.

In a few instances, 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 nanometers—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 the skeletal muscle neuromuscular junction; the rapidity of contraction of these smooth muscle fibers is consider­ably faster than that of fibers stimulated by the diffuse junctions.

Excitatory and Inhibitory Transmitter Substances Secreted at the Smooth Muscle Neuromuscular Junction.

The most important transmitter substances secreted by the autonomic nerves innervating smooth muscle are acetylcholine and norepinephrine, but they are never secreted by the same nerve fibers. Acetylcholine is an excitatory transmitter substance for smooth muscle fibers in some organs but an inhibitory transmitter for smooth muscle in other organs. When acetylcholine excites a muscle fiber, norepinephrine ordinarily inhibits it. Conversely, when acetylcholine inhibits a fiber, norepinephrine usually excites it.

Why are these responses different? The answer is that both acetylcholine and norepinephrine excite or inhibit smooth muscle by first binding with a receptor protein on the surface of the muscle cell membrane. Some of the receptor proteins are excitatory receptors, whereas others are inhibitory receptors. Thus, the type of receptor determines whether the smooth muscle is inhibited or excited and also determines which of the two transmitters, acetylcholine or norepinephrine, is effective in causing the excitation or inhibition. These receptors are discussed in more detail in Chapter 61 in relation to function of the autonomic nervous system.

Membrane Potentials in Smooth Muscle.

The quantitative voltage of the membrane potential of smooth muscle depends on the momentary condition of the muscle. In the normal resting state, the intracellular potential is usually about −50 to −60 millivolts, which is about 30 millivolts less negative than in skeletal muscle.

Action Potentials in Unitary Smooth Muscle.

Action potentials occur in unitary smooth muscle (such as visceral muscle) in the same way that they occur in skeletal muscle. They do not normally occur in most multi-unit types of smooth muscle, as discussed in a subsequent section.

The action potentials of visceral smooth muscle occur in one of two forms: (1) spike potentials or (2) action potentials with plateaus.

Spike Potentials.

Typical spike action potentials, such as those seen in skeletal muscle, occur in most types of unitary smooth muscle. The duration of this type of action potential is 10 to 50 milliseconds, as shown in Figure 8-7A. Such action potentials can be elicited in many ways—for example, by electrical stimulation, by the action of hormones on the smooth muscle, by the action of transmitter substances from nerve fibers, by stretch, or as a result of spontaneous generation in the muscle fiber itself, as discussed subsequently.

Action Potentials with Plateaus.

Figure 8-7C shows a smooth muscle action potential with a plateau. The onset of this action potential is similar to that of the typical spike potential. However, instead of rapid repolarization of the muscle fiber membrane, the repolarization is delayed for several hundred to as much as 1000 milliseconds (1 second). The importance of the plateau is that it can account for the prolonged contraction that occurs in some types of smooth muscle, such as the ureter, the uterus under some conditions, and certain types of vascular smooth muscle. (Also, this is the type of action potential seen in cardiac muscle fibers that have a prolonged period of contraction, as discussed in Chapters 9 and 10.)

Calcium Channels Are Important in Generating the Smooth Muscle Action Potential.

The smooth muscle cell membrane has far more voltage-gated calcium channels than does skeletal muscle but few voltage-gated sodium channels. Therefore, sodium participates little in the generation of the action potential in most smooth muscle. Instead, flow of calcium ions to the interior of the fiber is mainly responsible for the action potential. This flow occurs in the same self-regenerative way as occurs for the sodium channels in nerve fibers and in skeletal muscle fibers. However, the calcium channels open many times more slowly than do sodium channels, and they also remain open much longer. These characteristics largely account for the prolonged plateau action potentials of some smooth muscle fibers.

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 mechanism to cause contraction. Thus, the calcium performs two tasks at once.

Slow Wave Potentials in Unitary Smooth Muscle Can Lead to Spontaneous Generation of Action Poten­tials.

Some smooth muscle is self-excitatory—that is, action potentials arise within the smooth muscle cells without an extrinsic stimulus. This activity is often associated with a basic slow wave rhythm of the membrane potential. A typical slow wave in a visceral smooth muscle of the gut is shown in Figure 8-7B. The slow wave itself is not the action potential. That is, it is not a self-regenerative process that spreads progressively over the membranes of the muscle fibers. Instead, it is a local property of the smooth muscle fibers that make up the muscle mass.

The cause of the slow wave rhythm is unknown. One suggestion is that the slow waves are caused by waxing and waning of the pumping of positive ions (presumably sodium ions) outward through the muscle fiber membrane; that is, the membrane potential becomes more negative when sodium is pumped rapidly and less negative when the sodium pump becomes less active. Another suggestion is that the conductances of the ion channels increase and decrease rhythmically.

The importance of the slow waves is that, when they are strong enough, they can initiate action potentials. The slow waves themselves cannot cause muscle contraction. However, when the peak of the negative slow wave potential inside the cell membrane rises in the positive direction from −60 to about −35 millivolts (the approximate threshold for eliciting action potentials in most visceral smooth muscle), an action potential develops and spreads over the muscle mass and contraction occurs. Figure 8-7B demonstrates this effect, showing that at each peak of the slow wave, one or more action potentials occur. These repetitive sequences of action potentials elicit rhythmical contraction of the smooth muscle mass. Therefore, the slow waves are called pacemaker waves. In Chapter 63, we see that this type of pacemaker activity controls the rhythmical contractions of the gut.

Excitation of Visceral Smooth Muscle by Muscle Stretch.

When visceral (unitary) smooth muscle is stretched sufficiently, spontaneous action potentials are usually generated. They result from a combination of (1) the normal slow wave potentials and (2) a decrease in overall negativity of the membrane potential caused by the stretch. This response to stretch allows the gut wall, when excessively stretched, to contract automatically and rhythmically. For instance, when the gut is overfilled by intestinal contents, local automatic contractions often set up peristaltic waves that move the contents away from the overfilled intestine, usually in the direction of the anus.

Smooth Muscle Contraction in Response to Local Tissue Chemical Factors.

In Chapter 17, we discuss control of contraction of the arterioles, meta-arterioles, and precapillary sphincters. The smallest of these vessels have little or no nervous supply. Yet the smooth muscle is highly contractile, responding rapidly to changes in local chemical conditions in the surrounding inter­stitial fluid and to stretch caused by changes in blood pressure.

In the normal resting state, many of these small blood vessels remain contracted. However, when extra blood flow to the tissue is necessary, multiple factors can relax the vessel wall, thus allowing for increased flow. In this way, a powerful local feedback control system controls the blood flow to the local tissue area. Some of the specific control factors are as follows:

Adenosine, lactic acid, increased potassium ions, diminished calcium ion concentration, and increased body temperature can all cause local vasodilation. Decreased blood pressure, by causing decreased stretch of the vascular smooth muscle, also causes these small blood vessels to dilate.

Effects of Hormones on Smooth Muscle Contrac­tion.

Many circulating hormones in the blood affect smooth muscle contraction to some degree, and some have profound effects. Among the more important of these hormones are norepinephrine, epinephrine, angiotensin II, endothelin, vasopressin, oxytocin, serotonin, and histamine.

A hormone causes contraction of a smooth muscle when the muscle cell membrane contains hormone-gated excitatory receptors for the respective hormone. Conversely, the hormone causes inhibition if the membrane contains inhibitory receptors for the hormone rather than excitatory receptors.

Mechanisms of Smooth Muscle Excitation or Inhi­bition by Hormones or Local Tissue Factors.

Some hormone receptors in the smooth muscle membrane open sodium or calcium ion channels and depolarize the membrane, the same as after nerve stimulation. Sometimes action potentials result, or action potentials that are already occurring may be enhanced. In other cases, depolarization occurs without action potentials, and this depolarization allows calcium ion entry into the cell, which promotes the contraction.

Inhibition, in contrast, occurs when the hormone (or other tissue factor) closes the sodium and calcium channels to prevent entry of these positive ions; inhibition also occurs if the normally closed potassium channels are opened, allowing positive potassium ions to diffuse out of the cell. Both of these actions increase the degree of negativity inside the muscle cell, a state called hyperpolarization, which strongly inhibits muscle contraction.

Sometimes smooth muscle contraction or inhibition is initiated by hormones without directly causing any change in the membrane potential. In these instances, the hormone may activate a membrane receptor that does not open any ion channels but instead causes an internal change in the muscle fiber, such as release of calcium ions from the intracellular sarcoplasmic reticulum; the calcium then induces contraction. To inhibit contraction, other receptor mechanisms are known to activate the enzyme adenylate cyclase or guanylate cyclase in the cell membrane; the portions of the receptors that protrude to the interior of the cells are coupled to these enzymes, causing the formation of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP), so-called second messengers. The cAMP or cGMP has many effects, one of which is to change the degree of phosphorylation of several enzymes that indirectly inhibit contraction. The pump that moves calcium ions from the sarcoplasm into the sarcoplasmic reticulum is activated, as well as the cell membrane pump that moves calcium ions out of the cell itself; these effects reduce the calcium ion concentration in the sarcoplasm, thereby inhibiting contraction.

Smooth muscles have considerable diversity in how they initiate contraction or relaxation in response to different hormones, neurotransmitters, and other substances. In some instances, the same substance may cause either relaxation or contraction of smooth muscles in different locations. For example, norepinephrine inhibits contraction of smooth muscle in the intestine but stimulates contraction of smooth muscle in blood vessels.