1. Physiology of Smooth Muscle
Dr. Shafali Singh

2. Learning Objectives
Basic structure,functions and types of smooth muscles
Excitation contraction coupling in smooth muscles
Relaxation
Properties of smooth muscle

4. Smooth muscle
Muscle lining vessels & hollow organs, such as the gastrointestinal tract, the bladder, and the uterus, the ureters and the bronchioles.
Sheets of small spindle-shaped (fusiform) cells, connected by special junctions.
Single nucleus (mononucleate).
Contractile units randomly arranged
2 basic functions:
To produce motility (e.g., to propel chyme along the gastrointestinal tract or to propel urine along the ureter)
To maintain tension (e.g., smooth muscle in the walls of blood vessels).

5. Special features of Smooth Muscle
Not striated.
Contractile units randomly arranged
NO Z line ( Instead Dense Bodies present in the cytoplasm & in the cell membrane )
Lots of actin, some myosin
T –Tubule absent, hence triads also absent
Caveoli – Analog of T –Tubule
Sarcoplasmic reticulum is poorly developed
Troponin is absent, instead calmodulin is present

7. “Sidepolar” cross bridges
Most of the Myosin filaments have arranged so that the bridges on one side hinge in one direction & those on the other side hinge in the opposite direction that it allows smooth muscle cells to contract as much as 80 per cent of their length
● Contractions have longer duration and less tension

8. Structure of Smooth Muscle

9. The fibrillar contractile apparatus
● Dense bodies serve as an attachment points for the thin filaments
●Intermediate filaments form a cytoskeletal network between them
mechanical
junctions
intermediate
filament
contractile
proteins
dense
bodies
gap
junctions

10. Smooth Muscle Organisation

11. Gap junctions assure contraction as “single unit.”
Unitary Smooth Muscle
has gap junctions between cells, which allow for the fast spread of electrical activity throughout the organ, followed by a coordinated contraction.
present in the gastrointestinal tract, bladder, uterus, and ureter.
E.g. - action potentials occur simultaneously in the smooth muscle cells of the bladder so that contraction (and emptying) of the entire organ can occur at once.
Gap junctions assure contraction as “single unit.”

12. Types of Smooth Muscle Single unit (most):
Clusters of smooth cells, connected by gap junctions.
Activity in one cell spreads to other cells and acts as a single functional unit.
e.g. gut, uterus, bladder.
Multi-unit: Acts as individual units , no syncytium
e.g. Intrinsic muscles of eye (iris), skin piloerectors, large blood vessels .

13. Fewer gap junctions assure independent
contraction and more precise control.

14. Single unit & Multi unit SM - Differences
1. Large sheets
2. Low resistance
bridges
3. Syncytium
Seen in: uterus, urethra, intestine, ureter, urinary bladder
5. Pace maker activity
present
Multi unit
Individual units
No bridges
Non- syncytial
Iris, Ciliary muscles of the eye, piloerector muscle of skin, blood vessels
No pace maker activity
A third type, a combination of unitary and multiunit smooth muscle, is found in vascular smooth muscle

15. Single unit
6. Rhythmic contraction and relaxations are independent of innervation
7.Stretch causes contraction
8.No tetanic contracton
Multi unit
Contractions are stimulated only by ANS
Stretch cannot cause contraction
Irregular tetanic contractions present

16. Basic steps in contraction of SM
Depolarisation of muscle fibres ↓
Release of Ca++ from sarcoplasmic reticulum & from ECF
Ca++ combines with calmodulin
Activation of myosin light chain kinase
Phosphorylation of myosin
Sliding of actin over myosin

17. Mechanisms for increasing intracellular Ca
Depolarization of the cell membrane opens voltage-gated Ca2+ channels and Ca2+ flows into the cell down its electrochemical gradient, increasing the intracellular [Ca2+].
Two other mechanisms for increasing intracellular Ca2+ are:
Ligand gated Ca channels: Hormones and neurotransmitters may open ligand-gated Ca2+ channels in the cell membrane.
IP3-gated Ca2+ channels: Hormones and neurotransmitters directly release Ca2+ from the SR through inositol triphosphate (IP3)-gated Ca2+ channels.
Mechanisms for increasing intracellular Ca

18. Cross-bridge cycling in smooth muscle
Intracellular [Ca2+] increases.
Ca2+ binds to calmodulin and this binding is in co-operative manner leading to 4 Ca2+ ions binding to calmodulin. The Ca2+–calmodulin complex binds to and activates myosin light-chain kinase.
When activated, myosin light-chain kinase phosphorylates myosin light chain. When myosin is phosphorylated, the confirmation of the myosin head is altered greatly increasing its ATPase activity. (skeletal muscle ATPase activity is always high)
This increase in ATPase activity allows myosin head to be charged and to bind to actin initiating cross-bridge cycling leading to production of tension and muscle contraction.

20. SM in relaxed & contracted state

21. Calponin and Caldesmon are other two thin filamentous proteins which in resting state of muscle bind actin and also inhibit myosin ATPase preventing the interaction of actin and myosin.
Ca2+-calmodulin complex leads to their phosphorylation which in turn releases them from their inhibition.

22. Relaxation in smooth muscles
Occurs when the intracellular Ca2+ concentration falls.
Mechanisms for fall in intracellular Ca:
Repolarisation of sarcolemmal membrane which closes voltage gated Ca2+ channels
Direct inhibition of Ca2+ channels on sarcolemma by ligands such as cGMP
Inhibition of IP3 production and decreased release of Ca2+ from sarcoplasmic reticulum
SERCA pump
Activation of myosin light chain phosphatase which dephosphorylates myosin light chain leading to inhibition of myosin ATPase.

23. Major routes of calcium
entry and exit from the
cytoplasm of smooth muscle. The ATPase
reactions are energy-consuming ion pumps.
The processes on the left side increase cyto-plasmic calcium and promote contraction;
those on the right decrease internal calcium
and cause relaxation. PIP2, phosphatidylinos-itol 4,5-bisphosphate; IP3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol

24. Dephosphorylation of myosin
Relaxation of SM
Contraction ↓
Dephosphorylation of myosin
- Relaxation or
- sustained contraction due to latch bridge mechanism i.e Prolonged tonic contraction for hours with little use of energy
When the myosin kinase and myosin phosphatase enzymes are both strongly activated, the cycling fre- quency 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.

25. Comparison of Smooth Muscle Contraction and Skeletal Muscle Contraction
Slow Cycling of the Myosin Cross-Bridges
Energy Required to Sustain Smooth Muscle Contraction
Slowness of Onset of Contraction and Relaxation of the Total Smooth Muscle Tissue.
Force of Muscle Contraction.
“Latch” Mechanism for Prolonged Holding of Contractions ofSmooth Muscle.

26. Smooth muscle contracts slowly and efficiently.

27. Characteristics of smooth muscle contraction
Slow cycling of myosin cross bridges – less ATPase activity
Less energy required for sustaining muscle contraction
Slowness of onset of contraction and relaxation
Maximum force of contraction is greater
Latch mechanism for prolonged holding of contraction
Latch mechanism 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.

28. Electrical properties of SM
RMP (In the normal resting state, the intracellular potential isusually about -50 to -60 millivolts,). It is Unstable leading to spontaneous excitation.
Depolarisation due to the entry of Ca++ mainly and Na+ to a lesser extent.
Repolarisation due to delayed K+ efflux & closure of Ca++ channels.

29. Action Potentials in Unitary Smooth Muscle
(1) spike potentials or (2) action potentials with plateaus.

30. Membrane potential (mV)
Action potential
Ca2+ influx
K+ efflux
Membrane potential (mV)
-45
Threshold of VOC’s
-60
The smooth muscle
cell membrane has far more voltage-gated calcium
channels than does skeletal muscle but few voltagegated
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 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. This accounts in large measure for the prolonged
plateau action potentials of some smooth
muscle fibers
200 msec

31. A, Typical smooth muscle action potential (spike potential) elicited
by an external stimulus. B, Repetitive spike potentials, elicited by
slow rhythmical electrical waves that occur spontaneously in the
smooth muscle of the intestinal wall. C, Action potential with a
plateau, recorded from a smooth muscle fiber of the uterus.

32. Some smooth
muscle is self-excitatory.That is, action potentials arise
within the smooth muscle cells themselves without
an extrinsic stimulus. This often is associated with a
basic slow wave rhythm of the membrane potential
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,
but 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.Then contraction
does occur

33. Some smooth muscle generates its own
(pacemaker potentials/slow waves), e.g., intestinal peristalsis

34. A, Action potentials may be generated and lead to a twitch or larger summed mechanical responses. Action potentials are characteristic of single-unit smooth muscles (many viscera). Gap junctions permit the spread of action potentials throughout the tissue. B, Rhythmic activity produced by slow waves that trigger action potentials. The contractions are generally associated with a burst of action potentials. Slow oscillations in membrane potential usually reflect the activity of electrogenic pumps in the cell membrane. C, Tonic contractile activity may be related to the value of the membrane potential in the absence of action potentials. Graded changes in Em are common in multiunit smooth muscles (e.g., vascular), where action potentials are not generated and propagated from cell to cell. D, Pharmacomechanical coupling; changes in force produced by the addition or removal (arrows) of drugs or hormones that have no significant effect on membrane potential

35. Excitation of Visceral Smooth Muscle by Muscle Stretch
When visceral (unitary) smooth muscle is stretched sufficiently, spontaneous action potentials usually are generated. They result from a combination of (1)the normal slow wave potentials and (2) decrease in overall negativity of the membrane potential caused by the stretch itself.

36. Depolarization of Multi-Unit Smooth Muscle Without Action Potentials
Normally contract mainly in response to nerve stimuli.
The nerve endings secrete acetylcholine in the case of some multi-unit smooth muscles and norepinephrine in the case of others.
In both instances, the transmitter substances cause depolarization of the smooth muscle membrane, and this in turn elicits contraction.
Action potentials usually do not develop; the reason is that the fibers are too small to generate an action potential.
Yet, in small smooth muscle cells, even without an action potential, the local depolarization (called the junctional potential) caused by the nerve transmitter substance itself spreads “electrotonically” over the entire fiber and is all that is needed to cause muscle contraction.
(When
action potentials are elicited in visceral unitary smooth
muscle, 30 to 40 smooth muscle fibers must depolarize
simultaneously before a self-propagating action potential
ensues.)

37. Effects of Hormones on Smooth Muscle Contraction.
Effect of Local Tissue Factors and Hormones to Cause Smooth Muscle Contraction Without Action Potentials
Smooth Muscle Contraction in Response to Local Tissue Chemical Factors.
Effects of Hormones on Smooth Muscle Contraction.

38. 1. Lack of oxygen in the local tissues causes smooth muscle relaxation and, therefore, vasodilatation. 2. Excess carbon dioxide causes vasodilatation. 3. Increased hydrogen ion concentration causes vasodilatation. Adenosine, lactic acid, increased potassium ions, diminished calcium ion concentration, and increasedbody temperature can all cause local vasodilatation

39. Modulation of Smooth Muscle Activity by Neurotransmitters, Hormones, and Local Factors

40. 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,
Sometimes action potentials result,
Action potentials that are already occurring may be enhanced.
Depolarization occurs without action potentials, and this depolarization allows calcium ion entry into the cell,
closes the sodium and calcium channels to prevent entry of these positive ions;
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;

41. Smooth muscle that exhibits rhythmical contraction in the absence of external stimuli also necessarily exhibits which of the following? A) “Slow” voltage-sensitive Ca11 channels B) Intrinsic pacemaker wave activity C) Higher resting cytosolic Ca11 concentration D) Hyperpolarized membrane potential E) Action potentials with “plateaus

42. Mechanical properties of SM
1. Spontaneous activity seen.
2. Maintained state of partial contraction is
Tonus or Tone.
3. No correlation between electrical & mechanical events
Muscle starts contracting 200msec after the spike – peak contraction is after 500msec

43. Some contractile activity patterns exhibited by smooth muscles
Some contractile activity patterns exhibited by smooth muscles. Tonic smooth muscles are normally contracted and generate a variable steady-state force. Examples are sphincters, blood vessels, and airways. Phasic smooth muscles commonly exhibit rhythmic contractions (e.g., peristalsis in the gastrointestinal tract) but may contract intermittently during physiological activities under voluntary control (e.g., voiding of urine and swallowing).

44. Mechanical properties of SM– contd.
4. Plasticity
Relationship between initial length of muscle fiber and tension
Tension is variable at any given length
Studied in Human urinary bladder
Useful in accomodating more blood by vessels, more food by stomach & more urine by bladder without a rise in pressure.

46. Smooth and skeletal muscle mechanical characteristics compared.
Typical
length-tension curves from skeletal and smooth muscle. Note
the greater range of operating lengths for smooth muscle and
the leftward shift of the passive (resting) tension curve.

50. Modulation of Smooth Muscle Activity by Neurotransmitters, Hormones, and Local Factors

51. Other factors that influence SM:
Hormones & drugs:
Adrenaline & Noradrenaline : Similar to SNS
ACh : Similar to PNS
Atropine : Cause relaxation by blocking parasympathetics.
Pilocarpine : Similar to Ach
Estrogen and Progesterone on uterus
Oxytocin at the time of labour
Cold, Stretch & barium ions stimulate contraction.
Hypoxia, hypercapnia, acidosis, K+ cause relaxation

52. Q Which statement below most closely describes the role of calcium ions in the control of smooth muscle contraction? (A) Binding of calcium ions to regulatory proteins on thin filaments removes the inhibition of actin-myosin interaction (B) Binding of calcium ions to regulatory proteins associated with thick filaments, specifically calmodulin, activates the enzymatic activity of myosin molecules (C) Calcium ions serve as a direct inhibitor of the interaction of thick and thin filaments (D) A high concentration of calcium ions in the myofilament space is required to maintain muscle in a relaxed state

53. Q. Compared with skeletal muscle,smooth muscle (A) Contracts more slowly, but exerts considerably more force (B) Contracts more rapidly, but exerts considerably less force (C) Maintains long-duration contractions economically (D) Exerts considerable force but can do little shortening

54. Differences between skeletal,smooth and cardiac muscle
Morpological properties—
Distribution
Structure
Size and shape
Sarcoplasmic reticulum
Sarcotubular system
Nerve supply
Control and rhythmicity
Blood supply

55. Electrical properties
RMP AP
Absolute refractory period

56. Mechanical properties
Mechanical events
Duration of muscle twitch
Excitation contraction coupling
All or none law
Length tension relationship
Fatigue
Energy utilization