Smooth Muscle Contraction Flashcards

1
Q

Smooth muscle filament types

A
  • smooth muscle has thick and thin filaments but no sarcomere
  • dense body anchoring points for actin filaments (condensed Z-line)
  • actin filaments bundled to create a spindle
  • myosin filament interspersed between actin filaments
  • since there is no regular organization of the thin and thick filament complexes, smooth muscle lacks A and I bands and is non-striated
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2
Q

Smooth muscle contractions and relaxation speed

A
  • a smooth muscle twitch is characterized by slow contraction velocity and slow relaxation
  • smooth muscle can contract to less than 1/3 of initial resting length
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3
Q

Smooth muscle contraction

A
  • sarcolemma has microdomains called caveolae that are enriched for cell receptors and ion channels, they contain receptors (muscarinic ACh receptors, adrenergic receptors) and ion channels (L type Ca channels, ATP sensitive K channels, Ca sensitive K channels)
  • temporal relationship- Ca2+ and tension and the pCa-tension relationships are similar to those of skeletal and cardiac muscle already described, except that the onset of contraction is slower and the duration of tension is usually longer in smooth muscle, smooth muscle action potential is Ca2+ dependent, inward depolarizing current is carried by calcium ions
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4
Q

Speed and force of contraction of smooth muscle

A
  • smooth muscle usually exhibits prolonged tonic contractions, sometimes lasting hours or even days
  • cross-bridge cycling is much slower in smooth muscle than in skeletal or cardiac muscle, but the proportion of time spent in the tension generating phase of the cross-bridge cycle is longer thus resulting in a greater force of smooth muscle contraction with less energy expenditure (ATP hydrolysis)
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5
Q

Percentage shortening in smooth muscle

A
  • skeletal muscle usually contracts only about 1/4 to 1/3 of its stretched length
  • smooth muscle can often contract to less than 1/3 of its stretched length, enabling the gut, bladder, blood vessels, and other hollow organs to reduce their luminal diameters from very large to almost zero
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6
Q

Unitary Smooth Muscle

A
  • electrically coupled via gap junctions and can be spontaneously active (peristalsis)
  • the term unitary refers to smooth muscle in which millions of smooth muscle cells organized in sheets or bundles contract in a coordinated fashion as a single unit
  • little innervation
  • function in syncytium
  • response to stretch
  • little response to SNS
  • local control of contraction
  • small blood vessels, GI tract, uterus, most arteriolar muscle
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7
Q

Multiunit smooth muscle

A
  • composed of discrete smooth muscle fibers, each of which is innervated by a single nerve ending as in skeletal muscle
  • their contraction is seldom spontaneous
  • examples include the smooth muscle fibers of the ciliary muscle and the iris of the eye, and the piloerector muscles that cause erection of the hairs when stimulated by the sympathetic nervous system
  • function as individual units
  • innervated
  • few gap junctions
  • little response to stretch
  • response to SNS
  • neural factors control contraction
  • airway smooth muscle, piloerector muscle, ciliary muscle of eye, some arteriolar muscle
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8
Q

SM contraction driven by calcium influx

A
  • use two sources for Ca: the extracellular fluid and the SR
  • in most cases an AP depolarizes the sarcolemma, resulting in an influx of Ca2+ primarily through L type
  • Ca2+ can also be released after agonist binding to G-protein coupled receptors- those receptors activate phospholipase C which generates IP3
  • Ca2+ is then released into the sarcoplasm from rudimentary SR by IP3 and possibly some Ca induced Ca
  • contraction is caused by increased concentration of intracellular calcium
  • Ca is removed from sarcoplasm by Ca2+ pumps in the SR membrane and in the sarcolemma and by 3Na/Ca exchange across the sarcolemma
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9
Q

Smooth muscle contraction regulatory proteins

A
  • the key regulatory protein in smooth muscle is myosin light chain kinase (MLCK)
  • Ca2+ binds to a calmodulin moiety on myosin light chain kinase (MLCK) resulting in phosphorylation of the regulatory light chain (RLC) of myosin
  • a conformational change in the regulatory light chain (RLC) then permits the myosin to interact with actin
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10
Q

Smooth muscle relaxation regulatory proteins

A
  • when MLCP a soluble phosphatase in the sarcoplasm, dephosphorylates the regulatory light chain of myosin, then interaction between actin and myosin is blocked and the muscle relaxes
  • reduction of the concentration of intracellular calcium by calcium ion pumps in the sarcolemma and in the sarcoplasmic reticulum membrane also cause relaxation
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11
Q

Categories of smooth muscle contraction

A
  • electromechanical- action potential or stretch- in this case depolarization opens L type calcium channels leading to an increase in cytosolic calcium, activation of MLCK, phosphoylation of myosin and contraction
  • pharmacomechanical- ligand binding to cell surface receptor- G protein activation (Gq), PLC gamma activation, IP3 generation +Dag, IP3 receptor opening in SR
  • increase in intracellular Ca2+- CICR (Ca2+ induced Ca2+ release), Ca2+ calmodulin activation of MLCK, activation of smooth muscle myosin, contraction
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12
Q

Smooth muscle activation

A
  • contractile activity of smooth muscle may be spontaneous as in the peristaltic waves of the intestine, stomach, colon, and during the uterine contractions of labor
  • uterus at term develops synchronous contractions and pacemakers with diastolic depolarizations
  • vascular smooth muscle usually does not exhibit spontaneous activity, but instead contracts in response to excitation by stretch, adrenergic neurons, endothelial cells or circulating chemical factors in the blood
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13
Q

Membrane potential in smooth muscle

A
  • resting potential of smooth muscle is about -50 to -60mV, some 30 mV less negative than skeletal muscle
  • spike action potentials in unitary smooth muscle are of short duration (10-50 msec) relative to the contraction time. Depolarization is caused mainly by an inward current of Ca2+ followed by repolarization by an outward current of potassium. Most smooth muscle APs have no sodium current
  • some visceral smooth muscle exhibits slow waves (or pacemaker waves) that initiate superimposed spike potentials; uterine smooth muscle APs have plateaus
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14
Q

Basal electric rhythm

A
  • refers to waves of rhythmic depolarization of intestinal smooth muscle cells, which originate at a specific point and then are propagated along the length of the GI tract
  • pacemaker activity of the network of interstitial cells of Cajal are not of suffient magnitude to initiate APs in the smooth muscle
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15
Q

Latch state

A
  • during sustained smooth muscle contraction it is observed that Ca2+ concentrations in the sarcoplasm fall and myosin light chain becomes dephosphoylated
  • caused by MLCP dephosphorylation of the myosin light chain while the myosin head is bound to actin
  • in latch bridge state the crossbridge maintains tension and the subsequent dissociation of the myosin head from the actin filament is very slow
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16
Q

Endothelin

A
  • dual action agonist depending on ET receptor expression
  • 21 amino acid peptide that is produced by the vascular endothelium from a 39 amino acid precursor, big ET-1, through the actions of an endothelin converting enzyme found on the endothelial cell membrane
17
Q

Intracellular Mechanism of Endothelin

A
  • once ET-1 is released by the endothelial cell, it binds to receptors on the target tissue
  • ETA or ETA receptors- both couple with Gq G protein and trigger the formation of IP3
  • increased IP3 causes calcium release by SR which causes smooth muscle contraction
  • in blood vessles, ETA receptor is dominant
  • in addition to ETa and ETb receptors on the smooth muscle, ETb receptors are also found on endothelium
  • when ET-1 binds to endotheial ETB receptors the formation of NO is stimulated (causes vasodilation)
  • ET-1 in the heart causes release of calcium by SR increases contractility and heart rate
18
Q

Cardiovascular Effects of Endothelin

A

-distribution of endothelial and smooth muscle receptors helps to explain the phenomenon that systemic administration of ET-1 causes transient vasodilation (initial endothelial ETb activation) and hypotension, followed by prolong vasocontriction and hypersension (smooth muscle ETa and ETb activation)

19
Q

Diseases and Conditions associated with elevated

A

-powerful vasoconstrictor properties, and its effects on intracellular calcium, ET-1 has been implicated in the pathogenesis of hypertension, coronary vasospasm and heart failure

  • for heart failure- ET-1 is released by the failing myocardium where it can contribute to calcium overload and hypertrophy.
  • endothelin receptor antagonists have been shown to decrease mortality and improve hemodynamics in experimental models of heart failure
  • a number of studies suggest a role for ET-1 in pulmonary hypertension as well as in systemic hypertension
  • a nonselective ET-1 receptor antagonst Bosentan is currently used in the treatment of pulmonary hypertension
20
Q

Epinephrine can cause two different responses

A
  • alpha 1- Gq, PLC, IP3= then calmondulin activated MLCK, and active myosin-phosphate and then there are contraction- skin arteriolar SM, gut arteriolar SM
  • beta 2 receptor- act via Gs to stimulate adenylate cyclase which produces cAMP and activates protein kinase A, PKA then phosphorylates MLCK and inactivates it- relaxes skeletal arterior SM, heart muscle arterioral SM, bronchiolar smooth muscle (lung)
21
Q

Acute control of local blood flow

A

-achieved by rapid changes in local vasodilation or vasoconstriction of the arterioles, metarterioles, and precapillary sphincters, occuring within seconds to minutes to provide very rapid maintenance of appropriate local tissue blood flow

22
Q

Active hyperemia

A
  • when any tissue becomes highly active, such as an exercising muscle, GI gland during a hypersecetory period, or even the brain during rapid mental activity, the rate of blood flow through the tissue increases
  • the increase causes cells to devour tissue fluid nutrients rapidly and also to release large quantities of vasodilator substance
  • oxygen lack theory- low O2 causes smooth muscle relaxation of the sphincher
  • vasodilator theory-substances including adenosine are released by active muscle causes relaxation of sphincter
23
Q

Adenosine Receptors

A
  • adenosine is a nucleotide (with ribose sugar) related to ATP, but without the phosphate groups
  • binds A1, A2A, and A2B adenosine G protein coupled receptors in human vascular smooth muscle
  • relaxation - A2 adenosince receptors can couple to Gs leading to Adenylate cyclase stimulation and an increase cAMP and PKA activity
  • elevated PKA activity is associated with vascular smooth muscle relaxation
  • another mechanism- A1 adenosine receptor can couple to ATP sensitive K+ channels causing smooth muscle hyperpolarization and a decrease of calcium influx
24
Q

Stress Relaxation of Smooth Muscle

A
  • stress relaxation is a property of biological tissues that is related to their viscoelastic properties
  • if a blood vessel is isolated, tied off at one end and cannulated at the other end so that it can be filled with a known volume of fluid and have its pressure measured at the same time then a sudden increase in volume increases pressure, the pressure decreases over time
  • bladder has even greater degree of stress relaxation
25
Q

Active Smooth Muscle Relaxation

A
  • stretch signals in the stomach and duodenal lumen result in relaxation of the gastric fundus. ACh, NO, VIP (vasoactive intestinal polypeptide), CCK (cholecystokinin, DVC (dorsal vagal complex)
  • receptive relaxation- results in a drop in gastric pressure immediately after eating that persists until all solid have been emptied from the stomach
  • vaso vagal and intrinsic reflexes are triggered by the activation of mechanosensitive nerve endings within the stomach wall
  • ACh released by vagal pathways acts presynatically to release additionall neurotransmitters that actively relax the gastric smooth muscle layers
26
Q

Active Smooth Muscle Relaxation by Agonists

A
  • smooth muscle relaxes when cytosolic calcium declines or when PKA is activated
  • NO- released by autonomic neuron and the endothelial cell the lines the blood vessel
  • first phase mediated by both NO and ACh the neuron releases NO, which diffuses to smooth muscle cell,
  • ACh binds to M3 muscarinic receptor leading to production of NO
  • both sources of NO activate guanylyl cyclase and raise cGMP in the smooth muscle cell in the smooth muscle cell and contribute to the first phase of relaxation
  • cGMP activates CGMP dependent protein kinase I which through several steps elevates MLCP myosin light chain phosphatase activity
  • tends to occur more with prolonged or intense stimulation, the neuropeptide VIP binds to receptors on the smooth muscle cell adn causes a delayed relaxation through an increase in cAMP or a decrease in Ca2+
27
Q

Many mechanisms to relax smooth muscle

A
  • vascular smooth is a downstream effector of many system wide physiological response
  • signals produced during these physiological responses can rapidly and simultaneously coordinate the vascular response by directly controlling vascular smooth muscle relaxation