Smooth Muscle Physiology

Describe the Smooth muscle contractile properties

Characteristics:

• Slow cycling of myosin cross-bridges

  • ↑ time of cross-bridge attachment.

• Low energy requirement

  • Due to fewer cross bridge cycles, less ATP is split

• Slow onset and relaxation of contraction

  • slow cross bridge cycling coupled with delayed
    response to Ca2+ ions

• Force of contraction could be higher then skeletal muscles

• Stress relaxation

  • Allows hollow organs to expand and contract as needed

  • Muscle contracts or relaxes at an appropriate level to maintain pressure within the organ

    • ie. Filling and emptying of bladde

  • “latch” mechanism (a tonic contraction)

    • Large and sustained contraction with low energy expenditure

1. Describe the innervation of smooth muscles

2. Mechanism?

Smooth muscle innervation: unitary

• Unitary: Aggregates (bundles or sheets) of hundreds or
  thousands of fibers act as a single unit

Mechanism of unitary:

• Membrane adherent to one another → force generated in one fiber can be transmitted to the next

• Fibers are connected by gap junctions → ion flow from one fiber to another → electrical activity propagation throughout the entire tissue

Describe the difference in action potential between smooth/skeletal muscles

Difference in action potential:

• Ca2+ plays a role in the generation of the AP

  • SM = more voltage-gated L-type Ca2+

  • Less participation of Na+ in action potential

  • Ca 2+ channels open slower and stay open longer

    • allowing some cells to have plateaus in their AP’s

Describe how Some smooth muscles contract without an AP

Contraction w/o AP:

• Oscillations in Vm may be sufficient for tonic contraction even without an AP.

• Hormones and neurotransmitters may cause contraction with no change in Vm via release of Ca2+ from SR

***MAIN POINT: ITS ALL ABOUT Ca2+ availability***

1. Describe the difference source of Ca2+ in SM vs skeletal muscles

2. Describe the difference in Calcium release from SR

Difference in Sources of Calcium in Smooth muscle

• SR is poorly devloped; no T-tubules or terminal cisternae

• Instead, SM uses caveolae

• Both extracellular and intracellular Ca2+ initiate contraction.

  • intracellular levels are the one regulated (ANS/hormones)

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Difference Ca2+ release mechanism:

• Skeletal Muscles: Voltage propogation → DHPR physically unlatching RyRs → Ca2+ release

• SM; Ca2+ travels through L-type Ca2+ channel → Ca2+ BINDS to RyRs → Ca2+ release

Describe the mechanism of SM contraction:

• Role of Caldesmon, tropomyosin, calponin

• Role of Ca2+ to activate thick filaments

• Termination of contraction

• Ca2+ regulation of smooth muscle

Role of Caldesmon, tropomyosin, calponin:

• Caldesmon + tropomyosin → regulate the access of myosin to actin

  • Relaxed SM = caldesmon-tropomyosin complex blocks binding site on myosin

• Calponin = smooth muscle-specific, actin-, tropomyosin- and calmodulin- binding protein involved in regulation or modulation of contraction.

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Role of Ca2+ to activate thick filaments:

• Four Ca2+ binds calmodulin (CM) → CaCM complex activates myosin light chain kinase (MLCK) → phosphorylates regulatory light chain (on myosin head) → increases ATPase activity of myosin

***OVERALL MESSAGE: Contraction requires the phosphorylation of the myosin regulatory chain***

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Termination of contraction

• Even with the removal of calcium, MLCK may become inactive, but as long as the MLC is phosphorylated, contraction can continue.

• Relaxation requires de-phosphorylation of the MLC by MLC phosphatase.

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Ca2+ regulation of smooth muscle:

• cyclic AMP-dependent(PKA)

  • NE acting on β receptors

  • Phosphorylates MLCK → inactivates it

    • reduces the sensitivity to Ca2+ and can
      decrease force production and relax tonic
      smooth muscle

    • ***Note that this does not affect Ca2+ levels***

• Rho-associated protein kinase (ROK)

  • NE, 5-HT, histamine

  • phosphorylates MLCP → inactivates it

    • prolonging the effect of MLCK and contributing to tonic contraction

    • ***Note, this does not alter [Ca2+ ]***

Describe the cross-bridge cycle of SM (similar to skeletal muscles so review)

How does dephosphorylation affect myosin atpase?

De-phosphorylation slows activity of myosin ATPase

• dephosphorylated myosin dissociates from actin very slowly, producing slow cross-bridge cycline

  • This maintains tension via tonic contraction

Describe these two images

Describe the Latch Mechanism

Dephosphorylation of the myosin light chain by MLCP
helps maintains tonic contraction with reduced cross bridge cycling and therefore extremely low energy expenditure

[REVIEW] NT release from para/sympathetic pre/post ganglioninc neurons

Describe how hormones can excite or inhibit Smooth Muscles

Excitation:

• hormone binds ligand gated Na+ or Ca2+ channels → depolarize the membrane.

Inhibition:

• ligand gated Na+ or Ca2+ channel is closed

• the normally closed K+ channel is opened (Ca2+ activated K+channels).

• In both cases → membrane potential → more negative→ more difficult to initiate contraction

• Hormone may bind to membrane and indirectly inhibit via
  cAMP and cGMP second messenger systems.

  • Indirectly activates Ca2+ pump in cell membrane and SR

  • Net effect is decreased Ca2+ in sarcoplasm

1. Describe how stretch can excite SM

2. What does this allow

Excitation of unitary muscle due to stretch

• Stretching → spontaneous action potentials via

  • Stretch-activated cation-permeable channels

  • Decrease in overall negativity of the membrane caused by the stretch itself

• Allows:

  • gut wall to contract automatically and rhythmically when stretched excessively (ie peristaltic waves).

Describe the transport systems that participate in the regulation of [Ca 2+ ] i in smooth muscle cells:

• What brings Ca2+ into the cell?

• What extrudes Ca2+

• What pumps Ca2+ into the SR?

• How is Ca2+ released from SR

Ca2+ transport systems in SM:

• Brings Ca2+ inside:

  • ROCs: receptor operated calcium channels (

  • SOCs: stretch activated calcium channels (

  • NCX: odium-calcium exchanger

• Extrudes Ca2+

  • PMCA: plasma membrane calcium ATPase

  • NCX: 

• Pumps Ca2+ into SR:

  • SERCA: sarcoplasmic reticulum calcium ATPase

• Ca2+ released from SR:

  • IP 3 Rs: channels gated by IP 3

  • RyRs

In general, how is vasoconstriction/vasodilation mediated?

Vasoconstriction: Increase in Ca2+ concentration (intracellularly)

Vasodilation: Decrease in Ca2+ concentration or decrease phosphorylation of MLC

Describe the force-velocity relationship in smooth muscles

SM’s force-velocity relationship

• Force-Velocity relationship is dependent on level of phosphorylation

  • still, Force is inverse of Velocity

• Maximal shortening velocities are dependent on phosphorylation (proportional)

• Force generation is dependent on Phosphorylation

What does flow-induced vasodilation require?

Flow induced vasodilation requires an intact epithelial lining

What do endothelial cells of vasculature synthesize and secrete?

Endothelial cells synthesize and secrete local factors (endothelium-derived vasoactive substances):

• Local vasodilators: ↓vascular tone (under normal conditions)

• Local vasoconstrictors: ↑ vascular tone

  • ***Usually endothelium-derived vasoconstrictors are released under pathological conditions***

List out some endothelial factors that result in vasodilation/contraction

Vasodilators:

• Nitric oxide (NO)

• Prostacyclin (PGI2)

• Endothelium-derived hyperpolarizing factor (EDHF)

Vasoconstrictions:

• Endothelin (ET)

• Endothelin derived constricting factor-1 and 2 (EDCF1, EDCF2)

1. describe the syntehsis of NO

2. What are its two forms?

NO synthesis:

• produced from the L-arginine via nitric oxide synthase (NOS).

two forms:

• constitutive NOS (cNOS; type III):

  • Ca++ -dependent

  • always produced

• inducible NOS (iNOS; type II):

  • Ca++ independent

  • present during times of inflammation

    • induced by bacterial endotoxins and cytokines

Describe the mechanism in which NO leads to vasodilation

Mechanism:

• NO → SM → activages cGMP → SM relaxation

Effects of cGMP:

• inhibits calcium entry into the cell, and decreases intracellular calcium concentrations

• activates K+ channels, which leads to hyperpolarization and relaxation

• stimulates a cGMP-dependent protein kinase activating myosin light chain phosphatase

Describe the vascular actions of NO

Vascular actions of NO:

• Direct vasodilation (flow dependent and receptor
  mediated)

• Indirect vasodilation by inhibiting vasoconstrictor influences (e.g., inhibits angiotensin II and sympathetic vasoconstriction)

• Anti-thrombotic effect - inhibits platelet adhesion to the vascular endothelium

• Anti-inflammatory effect - inhibits leukocyte adhesion to vascular endothelium; scavenges superoxide anion

• Anti-proliferative effect - inhibits smooth muscle hyperplasia

What are some stimuli for NO release

Stimuli for NO release:

• Acetylcholine,

• bradykinin,

• substance-P,

• ↑K+,

• histamine,

• adenosine,

• ↑H+(acidosis)

Differentiate between the effects of AcH and No

NO: vasodialtion

AcH: vasoconstriction

• on normal endothelial: can make NO release

Describe the possible effects of NO impairment

impairment or reduction in the bioavailability of NO:

• Vasoconstriction (e.g., coronary vasospasm, elevated
  systemic vascular resistance, hypertension)

• Thrombosis due to platelet aggregation and adhesion
  to vascular endothelium

• Inflammation due to up-regulation of leukocyte and
  endothelial adhesion molecules

• Vascular hypertrophy and stenosis