Chapter 8: Excitation and Contraction of Smooth Muscle

Guyton & Hall Textbook of Medical Physiology, 15th Edition

1. CONTRACTION OF SMOOTH MUSCLE - Basic Structure

• Smooth muscle fibers: 1-5 micrometers in diameter, 20-500 micrometers in length
• Skeletal muscle fibers: up to 30 times greater in diameter and hundreds of times as long
• Despite size difference, the same basic principle applies: attractive forces between myosin and actin filaments cause contraction
• However, the internal physical arrangement of smooth muscle fibers is different

2. TYPES OF SMOOTH MUSCLE

A. Multi-Unit Smooth Muscle

• Composed of discrete, separate smooth muscle fibers
• Each fiber operates independently of the others
• Often innervated by a single nerve ending (like skeletal muscle)
• Outer surface covered by a thin layer of basement membrane-like substance (mixture of fine collagen and glycoprotein) that insulates fibers from each other
• Control is exerted mainly by nerve signals
• Examples: ciliary muscle of the eye, iris muscle, piloerector muscles (hair erection)

B. Unitary (Single-Unit) Smooth Muscle

• Also called syncytial smooth muscle or visceral smooth muscle
• A mass of hundreds to thousands of smooth muscle fibers that contract together as a single unit
• Fibers arranged in sheets or bundles
• Cell membranes adhere to each other at multiple points
• Cell membranes joined by many gap junctions - ions flow freely from one cell to the next
• Action potentials or ion flow can travel from one fiber to the next - causes all fibers to contract together
• Called "syncytial" because of its syncytial interconnections
• Found in walls of most viscera: gastrointestinal tract, bile ducts, ureters, uterus, many blood vessels

3. CONTRACTILE MECHANISM IN SMOOTH MUSCLE

A. Chemical Basis for Contraction

• Smooth muscle contains both actin and myosin filaments with similar chemical characteristics to skeletal muscle
• ATP is degraded to ADP to provide energy
• Contractile process activated by Ca²⁺
• Key difference: Smooth muscle does NOT contain the troponin complex - the mechanism for controlling contraction is entirely different

B. Physical Basis for Contraction (Figure 8.2)

• No striated arrangement (unlike skeletal muscle)
• Actin filaments attached to dense bodies
  • Some dense bodies attached to the cell membrane
  • Others dispersed inside the cell
  • Membrane-dense bodies of adjacent cells bonded together by intercellular protein bridges
  • Force of contraction transmitted from one cell to the next through these bonds
  • Dense bodies serve the same role as Z disks in skeletal muscle
• Myosin filaments are interspersed among actin filaments
  • Myosin filaments have diameter more than twice that of actin filaments
  • In electron micrographs: 5 to 10 times as many actin filaments as myosin filaments
• "Side polar" cross-bridges: Myosin filaments have cross-bridges arranged so bridges on one side hinge in the opposite direction to those on the other side (Figure 8.2C)
  • This allows myosin to pull an actin filament in one direction on one side, while simultaneously pulling another actin filament in the opposite direction on the other side
  • Result: Smooth muscle cells can contract as much as 80% of their length (vs. less than 30% for skeletal muscle)

4. COMPARISON OF SMOOTH MUSCLE AND SKELETAL MUSCLE CONTRACTION

A. Slow Cycling of Myosin Cross-Bridges

• Attachment to actin, release, reattachment cycle is much slower than skeletal muscle
• Frequency: as little as 1/10 to 1/300 that of skeletal muscle
• Yet the fraction of time cross-bridges remain attached to actin (which determines force) is greatly increased in smooth muscle
• Reason: Cross-bridge heads have far less ATPase activity - ATP degradation is greatly reduced, slowing cycling rate

B. Low Energy Requirement

• Only 1/10 to 1/300 as much energy needed to sustain the same tension as skeletal muscle
• Results from slow attachment/detachment cycling
• Only one molecule of ATP is required for each cycle, regardless of its duration
• Important for organs like intestines, urinary bladder, gallbladder that maintain tonic contraction almost indefinitely

C. Slowness of Onset and Relaxation

• A typical smooth muscle tissue begins to contract 50-100 ms after excitation
• Reaches full contraction at about 0.5 seconds
• Declines over 1-2 seconds = total contraction time of 1-3 seconds
• This is about 30 times as long as a single skeletal muscle fiber contraction
• Range: as short as 0.2 seconds or as long as 30 seconds depending on type

D. Maximum Force Often Greater Than Skeletal Muscle

• Despite fewer myosin filaments and slow cycling time, maximum force of contraction is often greater
• Can generate 4-6 kg/cm² cross-sectional area (vs. 3-4 kg/cm² for skeletal muscle)
• Due to the prolonged period of attachment of myosin cross-bridges to actin

E. Latch Mechanism - Prolonged Holding with Minimal Energy

• Once full contraction is developed, excitation can be reduced to far less than initial level
• Muscle maintains full force of contraction with miniscule energy consumption
• As little as 1/300 of energy required for comparable sustained skeletal muscle contraction
• This is called the latch mechanism
• Allows smooth muscle to maintain prolonged tonic contraction for hours with minimal energy use

F. Stress-Relaxation of Smooth Muscle

• Important characteristic of visceral unitary smooth muscle - especially in hollow organs
• Ability to return to nearly its original force of contraction seconds or minutes after being elongated or shortened
• Example: sudden increase in fluid volume in urinary bladder - immediate large increase in pressure - but during next 15-60 seconds, pressure returns almost to original level despite continued stretch
• This is called stress-relaxation (when stretched) and reverse stress-relaxation (when volume decreases)
• These responses allow a hollow organ to maintain about the same amount of pressure inside despite sustained large changes in volume

5. REGULATION OF CONTRACTION BY CALCIUM IONS

• Nerve stimulation of the smooth muscle fiber
• Hormonal stimulation
• Stretch of the fiber
• Changes in the chemical environment

Ca²⁺-Calmodulin-Myosin Kinase Pathway (Figure 8.3)

• Influx of Ca²⁺ from extracellular fluid through Ca²⁺ channels
• Release of Ca²⁺ from the sarcoplasmic reticulum

• When NOT phosphorylated: attachment-detachment cycling of myosin head with actin does NOT occur
• When phosphorylated: the myosin head gains the capability of binding repetitively with actin and proceeding through the entire cycling process - causing muscle contraction

Most Ca²⁺ Comes from Extracellular Fluid

• The sarcoplasmic reticulum is only slightly developed in most smooth muscle
• Unlike skeletal muscle (where SR provides virtually all Ca²⁺), smooth muscle Ca²⁺ mainly enters from extracellular fluid at time of action potential
• Extracellular Ca²⁺ concentration > 10⁻³ molar vs. less than 10⁻⁷ molar inside - rapid diffusion when channels open
• Latent period: Time for Ca²⁺ diffusion averages 200-300 milliseconds - about 50 times as great as for skeletal muscle

Role of Sarcoplasmic Tubules and Caveolae (Figure 8.4)

• Some larger smooth muscle cells have slightly developed sarcoplasmic tubules
• Small invaginations of cell membrane called caveolae lie near the tubules
• Caveolae = rudimentary analog of transverse tubule system of skeletal muscle
• When action potential transmitted into caveolae, believed to excite Ca²⁺ release from abutting sarcoplasmic tubules
• The more extensive the sarcoplasmic reticulum, the more rapidly smooth muscle contracts

Smooth Muscle Contraction Depends on Extracellular Ca²⁺

• When extracellular Ca²⁺ concentration decreases to 1/10 normal, smooth muscle contraction usually ceases
• Therefore, force of smooth muscle contraction is highly dependent on extracellular fluid Ca²⁺ concentration

6. Ca²⁺ PUMP IS REQUIRED FOR RELAXATION

• Transports Ca²⁺ out of the smooth muscle fiber back into extracellular fluid
• Or transports Ca²⁺ into the sarcoplasmic reticulum if present (Figure 8.5)
• This pump requires ATP and is slow acting compared to fast-acting SR pump in skeletal muscle
• Therefore, a single smooth muscle contraction often lasts seconds rather than hundredths to tenths of a second (as in skeletal muscle)

Myosin Phosphatase Is Important in Cessation of Contraction (Figure 8.5)

• Relaxation occurs when Ca²⁺ channels close and Ca²⁺ pump transports Ca²⁺ out
• When Ca²⁺ concentration falls below critical level, processes automatically reverse, except for phosphorylation of the myosin head
• Dephosphorylation requires another enzyme: myosin phosphatase
  • Located in the cytosol of smooth muscle cell
  • Splits the phosphate from the regulatory light chain
  • Then cycling stops and contraction ceases
• Time required for relaxation is determined largely by amount of active myosin phosphatase in the cell

Possible Mechanism for the Latch Phenomenon

• When both myosin kinase and myosin phosphatase are strongly activated: cycling frequency and velocity of contraction are great
• As activation of both enzymes decreases: cycling frequency decreases BUT deactivation allows myosin heads to remain attached to actin for a longer proportion of the cycling period
• Therefore, number of heads attached to actin at any given time remains large
• Since the number of heads attached determines the static force of contraction, tension is maintained (latched) yet little energy is used
• ATP is not degraded to ADP except on the rare occasion when a head detaches

7. NERVOUS AND HORMONAL CONTROL OF SMOOTH MUSCLE CONTRACTION

• Skeletal muscle is stimulated exclusively by the nervous system
• Smooth muscle can be stimulated by: nervous signals, hormonal stimulation, stretch, and several other ways
• Key reason: Smooth muscle membrane contains many types of receptor proteins that can initiate the contractile process
• Additional receptor proteins can inhibit smooth muscle contraction (unlike skeletal muscle)

8. NEUROMUSCULAR JUNCTIONS OF SMOOTH MUSCLE

Physiologic Anatomy of Smooth Muscle Neuromuscular Junctions

• Highly structured junctions (like motor end plates) do NOT occur in smooth muscle
• Instead, autonomic nerve fibers that innervate smooth muscle generally branch diffusely on top of a sheet of muscle fibers (Figure 8.6)
• In most cases, nerve fibers do NOT make direct contact with smooth muscle cell membranes
• Instead, they form diffuse junctions that secrete transmitter substance into the matrix coating of the smooth muscle - a few nanometers to a few micrometers from the muscle cells
• Transmitter substance then diffuses to the cells
• Where many layers of muscle cells exist, nerve fibers often innervate only the outer layer - muscle excitation travels inward by action potential conduction in the muscle mass or by additional diffusion

Varicosities

• Axons innervating smooth muscle do NOT have typical branching end feet (like motor end plates)
• Instead, fine terminal axons have multiple varicosities distributed along their axes
• At these points, Schwann cells are interrupted so transmitter can be secreted through the walls of the varicosities
• Varicosities contain vesicles with transmitter substances
• In some fibers: acetylcholine; in others: norepinephrine; occasionally other substances

Contact Junctions

• In multi-unit smooth muscle especially, varicosities are separated from muscle cell membrane by only 20-30 nanometers - the same width as the synaptic cleft in skeletal muscle junctions
• These are called contact junctions and function much like the skeletal muscle neuromuscular junction
• Contraction of these smooth muscle fibers is considerably faster than diffuse junction fibers

Excitatory and Inhibitory Transmitter Substances

• Most important transmitters from autonomic nerves: acetylcholine and norepinephrine
• They are never secreted by the same nerve fibers
• Acetylcholine: excitatory for smooth muscle in some organs; inhibitory in other organs
• Norepinephrine: ordinarily inhibits when acetylcholine excites; excites when acetylcholine inhibits
• Why? Both bind with receptor proteins on the smooth muscle cell membrane
  • Some receptors are excitatory receptors
  • Others are inhibitory receptors
• The type of receptor determines whether the smooth muscle is inhibited or excited

9. MEMBRANE POTENTIALS AND ACTION POTENTIALS IN SMOOTH MUSCLE

Membrane Potentials in Smooth Muscle

• Resting intracellular potential: -50 to -60 millivolts
• About 30 millivolts less negative than in skeletal muscle

Action Potentials in Unitary (Visceral) Smooth Muscle

• Occur in unitary smooth muscle (e.g., visceral muscle) in the same way as in skeletal muscle
• Do NOT normally occur in most multi-unit smooth muscle
• Two forms of action potentials:

• Typical spike action potentials occur in most types of unitary smooth muscle
• Duration: 10 to 50 milliseconds (Figure 8.7A)
• Can be elicited by: electrical stimulation, action of hormones, transmitter substances from nerve fibers, stretch, or spontaneous generation in the muscle fiber itself

• Onset similar to typical spike potential
• Instead of rapid repolarization, the repolarization is delayed for several hundred to 1000 milliseconds (1 second) (Figure 8.7C)
• Accounts for prolonged contraction in some smooth muscles: ureter, uterus under some conditions, certain vascular smooth muscles
• Also the type seen in cardiac muscle (discussed in Chapters 9 and 10)

Calcium Channels Are Important in Generating the Smooth Muscle Action Potential

• Smooth muscle cell membrane has far more voltage-gated Ca²⁺ channels than skeletal muscle
• Few voltage-gated sodium channels - so sodium does NOT participate much in action potential generation
• The flow of Ca²⁺ to the interior of the fiber is mainly responsible for the action potential
• Ca²⁺ channels open many times more slowly than sodium channels and remain open much longer - these characteristics account for the prolonged plateau action potentials
• Important feature: Ca²⁺ entering during action potential acts directly on the smooth muscle contractile mechanism to cause contraction - Ca²⁺ performs two tasks at once (triggers AP and causes contraction)

10. SLOW WAVE POTENTIALS AND PACEMAKER ACTIVITY

Slow Wave Potentials (Figure 8.7B)

• Some smooth muscle is self-excitatory - action potentials arise within smooth muscle without extrinsic stimulation
• Associated with a basic slow wave rhythm of the membrane potential
• The slow wave is NOT the action potential - it does not self-regenerate or spread progressively
• It is a local property of the smooth muscle fibers making up the muscle mass
• Cause of slow wave rhythm is uncertain - possible suggestion: caused by waxing and waning of the pumping of positive ions (sodium) outward through the muscle fiber membrane
  • Membrane potential becomes more negative when sodium pump is rapid
  • Less negative when sodium pump becomes less active
  • Another suggestion: conductances of ion channels increase and decrease rhythmically

Slow Waves as Pacemakers

• When slow waves are strong enough, they can initiate action potentials
• When peak of negative slow wave potential rises in positive direction - from -60 to about -35 millivolts (approximate threshold for visceral smooth muscle) - action potential develops and spreads over the muscle mass
• Figure 8.7B shows: at each peak of slow wave, one or more action potentials occur
• These repetitive sequences of action potentials elicit rhythmical contraction of smooth muscle mass
• Therefore, slow waves are called pacemaker waves
• In Chapter 63, 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 generated
• Result from: (1) normal slow wave potentials and (2) a decrease in overall negativity of the membrane potential caused by the stretch
• This response allows the gut wall, when excessively stretched, to contract automatically and rhythmically to move intestinal contents toward the anus (peristaltic waves)

11. DEPOLARIZATION OF MULTI-UNIT SMOOTH MUSCLE WITHOUT ACTION POTENTIALS

• Multi-unit smooth muscle (e.g., iris of eye, piloerector muscles) normally contracts mainly in response to nerve stimuli
• Nerve endings secrete acetylcholine (some) or norepinephrine (others)
• These transmitters cause depolarization of the smooth muscle membrane, which elicits contraction
• Action potentials usually do NOT develop because fibers are too small to generate an action potential
• In small smooth muscle cells, the local depolarization (called the junctional potential) caused by the nerve transmitter substance spreads "electrotonically" over the entire fiber - sufficient to cause muscle contraction

12. LOCAL TISSUE FACTORS AND HORMONES CAN CAUSE SMOOTH MUSCLE CONTRACTION WITHOUT ACTION POTENTIALS

• Approximately half of all smooth muscle contraction is likely initiated by stimulatory factors acting directly on smooth muscle contractile machinery WITHOUT action potentials
• Two types of non-nervous, non-action potential stimulators:
  1. Local tissue chemical factors
  2. Various hormones

Smooth Muscle Contraction in Response to Local Tissue Chemical Factors

• The smallest blood vessels (arterioles, metarterioles, precapillary sphincters) have little or no nervous supply
• Yet smooth muscle is highly contractile, responding rapidly to local chemical conditions and to stretch caused by changes in blood pressure
• In normal resting state, many small blood vessels remain contracted
• When extra blood flow to tissue is necessary, multiple factors can relax the vessel wall
• Local control factors causing vasodilation:
  1. Lack of oxygen in local tissues causes smooth muscle relaxation - vasodilation
  2. Excess carbon dioxide causes vasodilation
  3. Increased hydrogen ion concentration causes vasodilation
  4. Adenosine, lactic acid, increased potassium ions, nitric oxide, increased body temperature can all cause local vasodilation
  5. Decreased blood pressure (decreased stretch of vascular smooth muscle) also causes these small blood vessels to dilate

Effects of Hormones on Smooth Muscle Contraction

• Many circulating hormones affect smooth muscle contraction
• Important hormones: norepinephrine, epinephrine, angiotensin II, endothelin, vasopressin, oxytocin, serotonin, histamine
• A hormone causes contraction when the muscle cell membrane contains hormone-gated excitatory receptors
• A hormone causes inhibition if the membrane contains inhibitory receptors

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

• Some hormone receptors open sodium or Ca²⁺ channels and depolarize the membrane (same as after nerve stimulation)
• Sometimes action potentials result, or already occurring action potentials may be enhanced
• In other cases, depolarization occurs without action potentials - this allows Ca²⁺ entry which promotes contraction

• Inhibition occurs when the hormone closes sodium and Ca²⁺ channels to prevent entry of positive ions
• Inhibition also occurs if normally closed potassium channels are opened - allowing positive potassium ions to diffuse out
• Both actions increase negativity inside the muscle cell = hyperpolarization - strongly inhibits muscle contraction

• Sometimes smooth muscle contraction or inhibition is initiated by hormones without directly altering membrane potential
• Hormone activates a membrane receptor that does not open ion channels but instead causes an internal change in the muscle fiber
• Examples:
  • Some receptors release Ca²⁺ from intracellular sarcoplasmic reticulum - Ca²⁺ then induces contraction
  • To inhibit contraction, other receptor mechanisms activate adenylate cyclase or guanylate cyclase in the cell membrane
  • These produce cAMP (cyclic adenosine monophosphate) or cGMP (cyclic guanosine monophosphate) - "second messengers"
  • cAMP or cGMP has many effects including:
    • Changing the degree of phosphorylation of several enzymes that indirectly inhibit contraction
    • Activating the pump that moves Ca²⁺ from sarcoplasm into the sarcoplasmic reticulum
    • Activating the cell membrane pump that moves Ca²⁺ out of the cell
    • Both effects reduce Ca²⁺ concentration in the sarcoplasm, thereby inhibiting contraction

SUMMARY TABLE