SMOOTH MUSCLE MORPHOLOGY

Smooth muscle is distinguished anatomically from skeletal

and cardiac muscle because it lacks visible cross-striations.

Actin and myosin-II are present, and they slide on each other

to produce contraction. However, they are not arranged in

regular arrays, as in skeletal and cardiac muscle, and so the

striations are absent. Instead of Z lines, there are dense bodies

in the cytoplasm and attached to the cell membrane, and these

are bound by α-actinin to actin filaments. Smooth muscle also

contains tropomyosin, but troponin appears to be absent. The

isoforms of actin and myosin differ from those in skeletal mus

cle. A sarcoplasmic reticulum is present, but it is less extensive

than those observed in skeletal or cardiac muscle. In general,

smooth muscles contain few mitochondria and depend, to a

large extent, on glycolysis for their metabolic needs.

TYPES
There is considerable variation in the structure and function

of smooth muscle in different parts of the body. In general,

smooth muscle can be divided into unitary (or visceral)

smooth muscle and multiunit smooth muscle. Unitary

smooth muscle occurs in large sheets, has many low-resistance

gap junctional connections between individual muscle cells,

and functions in a syncytial fashion. Unitary smooth muscle

is found primarily in the walls of hollow viscera. The muscula

ture of the intestine, the uterus, and the ureters are examples.

Multiunit smooth muscle is made up of individual units with

few (or no) gap junctional bridges. It is found in structures

such as the iris of the eye, in which fine, graded contractions

occur. It is not under voluntary control, but it has many func

tional similarities to skeletal muscle. Each multiunit smooth

muscle cell has en passant endings of nerve fibers, but in uni

tary smooth muscle there are en passant junctions on fewer

cells, with excitation spreading to other cells by gap junctions.

In addition, these cells respond to hormones and other circu

lating substances. Blood vessels have both unitary and multi

unit smooth muscle in their walls.

ELECTRICAL & MECHANICAL

ACTIVITY
Unitary smooth muscle is characterized by the instability

of its membrane potential and by the fact that it shows

continuous, irregular contractions that are independent of

its nerve supply. This maintained state of partial contraction

is called tonus, or tone. The membrane potential has no

true “resting” value, being relatively low when the tissue is

active and higher when it is inhibited, but in periods of

relative quiescence values for resting potential are on the

order of –20 to –65 mV. Smooth muscle cells can display

divergent electrical activity (eg, Figure 5–18). There are slow

sine wave-like fluctuations a few millivolts in magnitude

and spikes that sometimes overshoot the zero potential line

and sometimes do not. In many tissues, the spikes have a

duration of about 50 ms, whereas in some tissues the action

potentials have a prolonged plateau during repolarization,

like the action potentials in cardiac muscle. As in the other

muscle types, there are significant contributions of K +, Na+,

and Ca2+ channels and Na, K ATPase to this electrical activity.

However, discussion of contributions to individual smooth

muscle types is beyond the scope of this text.

Because of the continuous activity, it is difficult to study

the relation between the electrical and mechanical events in

unitary smooth muscle, but in some relatively inactive prepa

rations, a single spike can be generated. In such preparations,

the excitation–contraction coupling in unitary smooth muscle

can occur with as much as a 500 ms delay. Thus, it is a very slow

process compared with that in skeletal and cardiac muscle,

in which the time from initial depolarization to initiation of

contraction is less than 10 ms. Unlike unitary smooth muscle,

multiunit smooth muscle is nonsyncytial and contractions do

not spread widely through it. Because of this, the contractions

of multiunit smooth muscle are more discrete, fine, and local

ized than those of unitary smooth muscle.

MOLECULAR BASIS
OF CONTRACTION
As in skeletal and cardiac muscle, Ca2+ plays a prominent role

in the initiation of contraction of smooth muscle. However, the

source of Ca2+ increase can be quite different in unitary smooth

muscle. Depending on the activating stimulus, Ca 2+ increase

can be due to influx through voltage- or ligand-gated plasma

membrane channels, efflux from intracellular stores through

the RyR, efflux from intracellular stores through the inositol

trisphosphate receptor (IP3 R) Ca2+ channel, or via a combi

nation of these channels. In addition, the lack of troponin in

smooth muscle prevents Ca2+ activation via troponin binding.

Rather, myosin in smooth muscle must be phosphorylated

for activation of the myosin ATPase. Phosphorylation and

dephosphorylation of myosin also occur in skeletal muscle, but

phosphorylation is not necessary for activation of the ATPase.

In smooth muscle, Ca2+ binds to calmodulin, and the result

ing complex activates calmodulin-dependent myosin light

chain kinase. This enzyme catalyzes the phosphorylation of

the myosin light chain on serine at position 19, increasing its

ATPase activity.

Myosin is dephosphorylated by myosin light chain

phosphatase in the cell. However, dephosphorylation of

myosin light chain kinase does not necessarily lead to relaxation

of the smooth muscle. Various mechanisms are involved. One

appears to be a latch bridge mechanism by which myosin

cross-bridges remain attached to actin for some time after the

cytoplasmic Ca2+ concentration falls. This produces sustained

contraction with little expenditure of energy, which is especially

important in vascular smooth muscle. Relaxation of the muscle

presumably occurs when the Ca2+-calmodulin complex finally

dissociates or when some other mechanism comes into play.

The events leading to contraction and relaxation of unitary

smooth muscle are summarized in Figure 5–19. The events in

multiunit smooth muscle are generally similar.

Unitary smooth muscle is unique in that, unlike other

types of muscle, it contracts when stretched in the absence of

any extrinsic innervation. Stretch is followed by a decline in

membrane potential, an increase in the frequency of spikes,

and a general increase in tone.

If epinephrine or norepinephrine is added to a preparation

of intestinal smooth muscle arranged for recording of intra

cellular potentials in vitro, the membrane potential usually

becomes larger, the spikes decrease in frequency, and the

muscle relaxes (Figure 5–20). Norepinephrine is the chemical

mediator released at noradrenergic nerve endings, and stimu

lation of the noradrenergic nerves to the preparation produces

inhibitory potentials. Acetylcholine has an effect opposite to

that of norepinephrine on the membrane potential and con

tractile activity of intestinal smooth muscle. If acetylcholine

is added to the fluid bathing a smooth muscle preparation

in vitro, the membrane potential decreases and the spikes

become more frequent. The muscle becomes more active, with

an increase in tonic tension and the number of rhythmic con

tractions. The effect is mediated by phospholipase C, which

produces IP3 and allows for Ca2+ release through IP3 receptors.

In the intact animal, stimulation of cholinergic nerves causes

release of acetylcholine, excitatory potentials, and increased

intestinal contractions.

Like unitary smooth muscle, multiunit smooth muscle

is very sensitive to circulating chemical substances and is

normally activated by chemical mediators (acetylcholine and

norepinephrine) released at the endings of its motor nerves.

Norepinephrine in particular tends to persist in the muscle and

to cause repeated firing of the muscle after a single stimulus

rather than a single action potential. Therefore, the contractile

response produced is usually an irregular tetanus rather than

a single twitch. When a single twitch response is obtained, it

resembles the twitch contraction of skeletal muscle except that

its duration is 10 times long.

RELAXATION
In addition to cellular mechanisms that increase contraction

of smooth muscle, there are cellular mechanisms that lead to

its relaxation (Clinical Box 5–7). This is especially important

in smooth muscle that surrounds the blood vessels to increase

blood flow. It was long known that endothelial cells that line

the inside of blood cells could release a substance that relaxed

smooth muscle (endothelial-derived relaxing factor, EDRF).

EDRF was later identified as the gaseous second messenger

molecule, nitric oxide (NO). NO produced in endothelial cells

is free to diffuse into the smooth muscle for its effects. Once

in muscle, NO directly activates a soluble guanylyl cyclase to

produce another second messenger molecule, cyclic guanosine

monophosphate (cGMP). This molecule can activate cGMP

specific protein kinases that can affect ion channels, Ca 2+

homeostasis, or phosphatases, or all of those mentioned, lead

ing to smooth muscle relaxation (see Chapters 7 and 32).

FUNCTION OF THE NERVE SUPPLY

TO SMOOTH MUSCLE
The effects of acetylcholine and norepinephrine on unitary

smooth muscle serve to emphasize two of its important prop

erties: (1) its spontaneous activity in the absence of nervous

stimulation and (2) its sensitivity to chemical agents released

from nerves locally or brought to it in the circulation. In

mammals, unitary muscle usually has a dual nerve supply

from the two divisions of the autonomic nervous system. The

function of the nerve supply is not to initiate activity in the

muscle but rather to modify it. Stimulation of one division of

the autonomic nervous system usually increases smooth

muscle activity, whereas stimulation of the other decreases

it. In some organs, noradrenergic stimulation increases and

cholinergic stimulation decreases smooth muscle activity; in

others, the reverse is true.

FORCE GENERATION &

PLASTICITY OF SMOOTH MUSCLE
Smooth muscle displays a unique economy when compared

to skeletal muscle. Despite approximately 20% of the myosin

content and a 100-fold difference in ATP use when compared

with skeletal muscle, they can generate similar force per cross

sectional area. One of the tradeoffs of obtaining force under

these conditions is the noticeably slower contractions when

compared to skeletal muscle. There are several known reasons

for these noticeable changes, including unique isoforms of

myosin and contractile-related proteins expressed in smooth

muscle and their distinct regulation (discussed above). The

unique architecture of the smooth cell and its coordinated

units also likely contribute to these changes.

Another special characteristic of smooth muscle is the

variability of the tension it exerts at any given length. If a uni

tary smooth muscle is stretched, it first exerts increased ten

sion. However, if the muscle is held at the greater length after

stretching, the tension gradually decreases. Sometimes the

tension falls to or below the level exerted before the muscle

was stretched. It is consequently impossible to correlate length

and developed tension accurately, and no resting length can

be assigned. In some ways, therefore, smooth muscle behaves

more like a viscous mass than a rigidly structured tissue, and

it is this property that is referred to as the plasticity of smooth

muscle.

The consequences of plasticity can be demonstrated

in humans. For example, the tension exerted by the smooth

muscle walls of the bladder can be measured at different

degrees of distension as fluid is infused into the bladder via a

catheter. Initially, tension increases relatively little as volume

is increased because of the plasticity of the bladder wall.

However, a point is eventually reached at which the bladder

contracts forcefully

Smooth muscle cells are small and unstriated.

Most smooth muscle cells are found in the walls of hollow

organs and tubes. Their contraction exerts pressure on and

regulates forward movement of the contents of these structures.

Both smooth and skeletal muscle cells are elongated, but in

contrast to their large, cylindrical skeletal muscle counterparts,

smooth muscle cells are spindle shaped (tapered at both ends),

have a single nucleus, and are considerably smaller (2 to 10 µm

in diameter and 50 to 400 µm long). Also unlike skeletal muscle

cells, a single smooth muscle cell does not extend the full length

of a muscle. Instead, groups of smooth muscle cells are typically

arranged in sheets (see ❙Figure 8-1c).

A smooth muscle cell has three types of filaments: (1) thick

myosin filaments, which are longer than those in skeletal mus

cle; (2) thin actin filaments, which contain tropomyosin but

lack troponin; and (3) filaments of intermediate size, which do

not directly participate in contraction but are part of the cyto

skeletal framework that supports the cell shape. Smooth muscle

filaments do not form myofibrils and are not arranged in the

sarcomere pattern found in skeletal muscle. Thus, smooth

muscle cells do not show the banding or striation of skeletal

muscle, hence the term smooth for this muscle type.

Lacking sarcomeres, smooth muscle does not have Z lines,

but it does have dense bodies containing the same protein con

stituent found in Z lines (❙Figure 8-28). Dense bodies are posi

tioned throughout the smooth muscle cell, as well as attached to

the internal surface of the plasma membrane. Dense bodies are

held in place by a scaffold of intermediate filaments. The actin

filaments are anchored to the dense bodies. Considerably more

actin is present in smooth muscle cells than in skeletal muscle

cells, with 10 to 15 thin filaments for each thick myosin filament

in smooth muscle compared to 2 thin filaments for each thick

filament in skeletal muscle.

The thick- and thin-filament contractile units are oriented

slightly diagonally from side to side within the smooth muscle

cell in an elongated, diamond-shaped lattice, rather than run

ning parallel with the long axis as myofibrils do in skeletal

muscle (❙Figure 8-29a). Relative sliding of the thin filaments

past the thick filaments during contraction causes the filament

lattice to shorten and expand from side to side. As a result, the

whole cell shortens and bulges out between the points where

the thin filaments are attached to the inner surface of the

plasma membrane (❙Figure 8-29b).

Unlike in skeletal muscle, myosin molecules are arranged in

a smooth-muscle thick filament so that cross bridges are pres

ent along the entire filament length (that is, there is no bare

portion in the center of a smooth-muscle thick filament). As a

result, the surrounding thin filaments can be pulled along the

thick filaments for longer distances than in skeletal muscle.

Also dissimilar to skeletal muscle (in which all thin filaments

surrounding a thick filament are pulled toward the center of the

stationary thick filament), the myosin proteins in smooth

muscle thick filaments are organized so that half of the sur

rounding thin filaments are pulled toward one end of the sta

tionary thick filament and the other half are pulled toward the

opposite end (❙Figure 8-29b).

Smooth muscle cells are turned on by Ca21

-
dependent phosphorylation of myosin.
The thin filaments of smooth muscle cells do not contain tro

ponin, and tropomyosin does not block actin’s cross-bridge

binding sites. What, then, prevents actin and myosin from

binding at the cross bridges in the resting state, and how is

cross-bridge activity switched on in the excited state? Light

weight chains of proteins are attached like “necklaces” to the

heads of myosin molecules, near the “neck” region. These so

called light chains are only of secondary importance in skel

etal muscle, but they have a crucial regulatory function in

smooth muscle. Smooth muscle myosin can interact with

actin only when the light chain is phosphorylated (that is, has
an inorganic phosphate from ATP attached to it). During exci

tation, the increased cytosolic Ca21

acts as an intracellular

messenger, initiating a chain of biochemical events that results

in phosphorylation of the myosin light chain ( ❙ Figure 8-30).

Smooth muscle Ca21

binds with calmodulin, an intracellular

protein found in most cells that is structurally similar to tro

ponin (see p. 124). This Ca21

–calmodulin complex binds to

and activates another protein, myosin light chain kinase

(MLC kinase), which in turn phosphorylates the myosin light

chain. This phosphate on the myosin light chain is in addition

to the phosphate accompanying ADP on the myosin cross

bridge ATPase site during the energy-supplying cycle that

powers cross-bridge bending. The Pi on the light chain per

mits the myosin cross bridge to bind with actin so that cross

bridge cycling can begin. Therefore, smooth muscle is trig

gered to contract by a rise in cytosolic Ca21

, similar to what

happens in skeletal muscle, but in smooth muscle, Ca 21

ulti

mately turns on the cross bridges by inducing a chemical

change in myosin in the thick filaments (phosphorylation),

whereas in skeletal muscle it exerts its effects by causing a

physical change at the thin filaments (moving troponin and

tropomyosin from their blocking positions) (❙ Figure 8-31).

Phasic smooth muscle contracts in bursts;

tonic smooth muscle maintains tone.
Smooth muscle can be grouped into two categories depending

on its pattern of contractile activity and how its cytosolic Ca 21

concentration increases: phasic smooth muscle and tonic smooth

muscle. Phasic smooth muscle contracts in bursts, triggered by

action potentials that lead to increased cytosolic Ca 21

. These

bursts in contraction are characterized by pronounced increases

in contractile activity. Phasic smooth muscle is most abundant

in the walls of hollow organs that push contents through them,

such as digestive organs. Phasic digestive contractions mix food

with digestive juices and propel the mass forward for further

processing. Tonic smooth muscle is usually partially con

tracted at all times; that is, it exhibits smooth muscle tone. Tone

exists because this type of smooth muscle has a relatively low

resting potential of 255 to 240 mV. Some surface

membrane voltage-gated Ca21

channels are open at these

potentials. The resultant Ca21

entry maintains a state of

partial contraction, or tone, in the absence of action potentials.

Tonic smooth muscle does not display bursts of contractile

activity but instead incrementally varies its extent of contrac

tion above or below this tonic level in response to regulatory

factors, which alter the cytosolic Ca21

concentration. The

smooth muscle in walls of arterioles is an example of tonic

smooth muscle. The ongoing tonic contraction in these small

blood vessels squeezes down on the blood flowing through

them and is one of the major contributing factors to mainte

nance of blood pressure.

A smooth muscle cell has no T tubules and a poorly

developed SR. In phasic smooth muscle, the increased cyto

solic Ca21
that triggers contraction comes from two sources:

Most Ca21

enters from the extracellular fluid (ECF), but

some is released intracellularly from the sparse SR stores.

Unlike their role in skeletal muscle cells, voltage-sensitive

dihydropyridine receptors in the plasma membrane of

smooth muscle cells function as Ca21

channels. When these

surface-membrane channels are opened in response to an

action potential, Ca21

enters down its concentration gradi

ent from the ECF. The entering Ca21

triggers the opening of

Ca21

channels in the SR so that small additional amounts of

Ca21

are released intracellularly from this meager source.

Because smooth muscle cells are so much smaller in diame

ter than skeletal muscle fibers, most Ca21

entering from the

ECF can influence cross-bridge activity, even in the central

portions of the cell, without requiring an elaborate T tubule–

SR mechanism.

One of the major means of increasing cytosolic Ca21

con

centration and thus increasing contractile activity in tonic

smooth muscle is binding of an extracellular chemical mes

senger, such as norepinephrine or various hormones, to a

G-protein-coupled receptor, which activates the IP3–Ca21

second-messenger pathway (see p. 124). The membrane of the

SR in tonic smooth muscle has IP3 receptors, which like

ryanodine receptors, are Ca21

-release channels. IP3 binding

leads to release of contractile-inducing Ca21

from this intra

cellular store into the cytosol. This is how norepinephrine

released from the sympathetic nerve endings acts on arterioles

to increase blood pressure.

Relaxation in smooth muscle is accomplished by removal of

Ca21

as it is actively transported out across the plasma mem

brane or back into the SR, depending on its source. When Ca 21

is removed, myosin is dephosphorylated (the phosphate is

removed) and can no longer interact with actin, so the muscle

relaxes.

We still have not addressed the question of how action

potentials are initiated in smooth muscle. Smooth muscle is

grouped in another way into two categories—multiunit and

single-unit smooth muscle—based on differences in how the

muscle fibers become excited. Let us compare them.

Multiunit smooth muscle is neurogenic.

Multiunit smooth muscle exhibits properties partway between

those of skeletal muscle and those of single-unit smooth mus

cle. As the name implies, a multiunit smooth muscle consists of

multiple discrete units that function independently of one

another and must be separately stimulated by nerves to undergo

action potentials and contract, similar to skeletal muscle motor

units. Thus, contractile activity in both skeletal muscle and

multiunit smooth muscle is neurogenic (“nerve produced”).

That is, contraction in these muscle types is initiated only in

response to stimulation by the nerves supplying the muscle. All

multiunit smooth muscle is phasic, contracting only when neu

rally stimulated. Whereas skeletal muscle is innervated by the

voluntary somatic nervous system (motor neurons), multiunit

(as well as single-unit) smooth muscle is supplied by the invol

untary autonomic nervous system.

Multiunit smooth muscle is found (1) in the walls of large

blood vessels; (2) in small airways to the lungs; (3) in the muscle

of the eye that adjusts the lens for near or far vision; (4) in the

iris of the eye, which alters the pupil size to adjust the amount

of light entering the eye; and (5) at the base of hair follicles,

contraction of which causes “goose bumps.

Single-unit smooth muscle cells form

functional syncytia.
Most smooth muscle is single-unit smooth muscle, alterna

tively called visceral smooth muscle, because it is found in the

walls of the hollow organs or viscera (for example, the digestive,

reproductive, and urinary tracts and small blood vessels). The

term single-unit smooth muscle derives from the muscle fibers

that make up this type of muscle becoming excited and con

tracting as a single unit. The muscle fibers in single-unit smooth

muscle are electrically linked by gap junctions (see p. 62). When

an action potential occurs anywhere within a sheet of single

unit smooth muscle, it is quickly propagated via these special

points of electrical contact throughout the entire group of inter

connected cells, which then contract as a single, coordinated

unit. Such a group of interconnected muscle cells that function

electrically and mechanically as a unit is known as a functional

syncytium (plural, syncytia; syn means “together”; cyt means

“cell”).

Thinking about the role of the uterus during labor can help

you appreciate the significance of this arrangement. Muscle

cells composing the uterine wall act as a functional syncytium.

They repetitively become excited and contract as a unit during

labor, exerting a series of coordinated “pushes” that eventually

deliver the baby. Independent, uncoordinated contractions of

individual muscle cells in the uterine wall could not exert the

uniformly applied pressure needed to expel the baby.

Single-unit smooth muscle is myogenic.

Single-unit smooth muscle is self-excitable, so it does not

require nervous stimulation for contraction. Single-unit smooth

muscle may be of the phasic or tonic type. In phasic single-unit

smooth muscle, clusters of specialized cells within a functional

syncytium display spontaneous electrical activity; that is, they

can undergo action potentials without any external stimulation.

In contrast to the other excitable cells we have been discussing

(such as neurons, skeletal muscle fibers, and multiunit smooth

muscle), the self-excitable cells of phasic single-unit smooth

muscle do not maintain a constant resting potential. Instead,

their membrane potential inherently fluctuates without any

influence by factors external to the cell. Two major types of

spontaneous depolarizations displayed by self-excitable cells are

pacemaker potentials and slow-wave potentials.

Pacemaker Potentials With pacemaker potentials, the

membrane potential gradually depolarizes on its own because

of shifts in passive ionic fluxes accompanying automatic changes

in ion channel permeability (❙Figure 8-32a). When the mem

brane has depolarized to threshold, an action potential is initi

ated. After repolarizing, the membrane potential again depolar

izes to threshold, cyclically continuing in this manner to

repetitively self-generate action potentials.

Self-excitable smooth muscle pacemaker cells are special

ized to initiate action potentials, but they are not equipped to

contract. Only a few of all the cells in a functional syncytium

are noncontractile, pacemaker cells. Most smooth muscle cells

are specialized to contract but cannot self-initiate action poten

tials. However, once an action potential is initiated by a self

excitable pacemaker cell, it is conducted to the remaining con

tractile, nonpacemaker cells of the functional syncytium via gap

junctions, so the entire group of connected cells contracts as a

unit without any nervous input. Such nerve-independent con

tractile activity initiated by the muscle itself is called myogenic

activity (“muscle-produced” activity), in contrast to the neuro

genic activity of skeletal muscle and multiunit smooth muscle.

Slow-Wave Potentials Slow-wave potentials are spontane

ous, gradually alternating depolarizing and hyperpolarizing

swings in potential (❙Figure 8-32b) brought about by unknown

means. They occur only in smooth muscle of the digestive tract.

Slow-wave potentials are initiated by specialized clusters of

nonmuscle pacemaker cells within the digestive tract wall and

spread to the adjacent smooth muscle cells via gap junctions. If

threshold is reached at the peak of a depolarizing swing, a burst

of action potentials occurs. These action potentials bring about

myogenically induced contraction. Threshold is not always