Reproduction: Pharmacology of the uterus Flashcards
What are the 3 layers of smooth muscle within the myometrium and how are the muscle fibres orientated in each layer?
- Inner layer - circular fibres
- Middle layer - spiral (figure of 8) fibres
- Outer layer - longitudinal fibres
What are some of the mechnical properties of the myometrium?
- Spontaneously active (myogenic) - able to contract without neuronal/hormonal input
- Highly sensitive to neurotransmitters and hormones
- Contractions are rhythmic
Apart from smooth muscle cells what other cell type is found in the myometrium?
Interstitial cells of cajal (ICCs)
What role do the interstitial cells of cajal play in the contraction of the myometrium?
- ICCs contain gap junctions and make connections via those gap junctions with adjacent cells
Why are the gap junctions of the interstitial cells of cajal important in the contraction of the myometrium?
- Gap junctions connect all of the different cells within the myometrium so forms a syncytium
- Gap junctions allow for some ions through
- Combination of these 2 things mean that all cells in myometrium are electrically coupled - depolarisation can spread throughout all cells of myometrium
Explain how the electrical activity within the myometrium results in its contraction?
- Within the ICCs of myometrium there’s always some level of base depolarisation
- Eventually depolarisation reaches above threshold potential within ICCs and because the ICCs are connected to the smooth muscle cells of the myometrium it means this wave of depolarisation spreads to smooth muscle cells causing the threshold potential to be reached in them too
- This leads to increased Ca2+ entry into smooth muscle cells via activation of voltage gated calcium channels
- This increase in intracellular Ca2+ leads to contraction of smooth muscle of myometrium
What are the 2 main ways in which intracellular calcium levels can be increased?
- Calcium influx from outside the cell due to activation of voltage gated calcium channels
- Release of calcium from stores such as the sarcoplasmic reticulum into the cytosol
Explain how the increase in intracellular calcium leads to smooth muscle contraction?
- Calcium binds to calmodulin to form calcium-calmodulin complex
- This complex activates myosin light chain kinase
- myosin light chain kinase phosphorylates light chain of myosin causin a chnage in its structure and increasing its affinity for ATP
- This means once myosin binds ATP it will hydrolyse it and then be in position to bind to binding sites on actin thus producing contraction.
What property of the ICCs mean that contraction of the myometrium is spontaneous/myogenic?
- Basic activity of particular ion channels within the ICCs which will lead to depolarisation
- This depolarisation will be spread to other ICCs and smooth muscle cells via gap junctions
Explain how particular hormones just as oxytocin can cause contraction of the myometrium
- Oxytocin will bind to a1 adrenoreceptors on smooth muscle cells
- This causes a subunit of Gq protein to bing GTP and dissociate from rest of G protein
- This results in activation of phospholipase C which will convert PIP2 into IP3 and DAG
- IP3 binds to receptors on sarcoplasmic reticulum resulting in calcium being released into cytosol
- This will eventually lead to smooth muscle contraction via Ca2+ binding to calmodulin and activating myosin light chain kinase
- DAG produced can cause activation of ion channels leading to depolarisation which will activate voltage gated calcium channels
Explain some of the methods of calcium extrusion from smooth muscle cells
- Calcium can be taken back up by sarcoplasmic reticulum via Ca2+ ATPase (SERCA)
- Na+/K+ ATPase can pump out Na+ and pump in K+ to create a gradient for Na+/Ca2+ transporter which will pump out Ca2+ and pump Na+ into cell
Explain how the frequency and force of contractions of the myometrium change as the concentration of contractile stimulants increase
- Low concentration: Increase in frequency of contraction but not force
- Higher concentrations: Increase in frequency and force
- Even higher concentrations: Increase in frequency and force of contractions accompanied by slow fall back to below threshold so contractions sustained for longer
- Extremely high concentrations: Incomplete relaxation (hypertonus) due to Ca2+ extrusion methods being ineffective
What are the different type of receptors expressed in the myometrium and what effect does the activation of these receptors have on it?
- α1-adrenoceptor – linked to Gq G protein which will cause contraction
- β2-adrenoceptor – Linked to Gs G protein which will cause relaxation
How does activation of β2-adrenoceptors lead to relaxation of smooth muscle?
- Activation leads to Gs subunit of β2-adrenoceptor to bind GTP
- Gs subunit then activates adenylate cyclase which causes cAMP to be formed from ATP
- cAMP then activates protein kinase A
- Protein kinase A phosphorylates K+ channels present on smooth muscle cells causing outflow of K+ from smooth muscle cells
- This caues hyperpolarisation meaning depolarisation and by extension contraction can’t occur
- Protein kinase A also inhibits myosin light chain kinase so myosin light chain can’t be phosphorylated so myosin can’t bind to actin and produce contraction
- Potein kinase A also activates SERCA causing increased Ca2+ uptake into sarcoplasmic reticulum leading to lower intracellular Ca2+
What effects do progesterone and oestrogen have on myometrium contraction?
- Progesterone inhibits contraction (causes relaxation)
- Oestrogen increases contraction
