W6 - Pharmacology of the uterus Flashcards
What are the structures of the myometrium?
Smooth muscle of the uterus
*Outer longitudinal fibres
*Middle figure-eight fibres
*Inner circular fibres
At the centre there is the uterus, then the endometrium, the myometrium and the outermost perimetrium. The myometrium is a very muscular organ.
What are the mechanical properties of the myometrium?
Rhythmic contractions
Spontaneously active
Vary during menstrual cycle and pregnancy
Force content towards the cervix
These contractions can vary depending on the various parts of the menstrual cycle and during pregnancy, which indicates it might be sensitive to different hormones
Contractions originate in the muscle itself
Doesn’t require neuronal or hormonal input
BUT highly sensitive to e.g. sex hormones
So what initiates the contractions?
Spontaneous depolarisation of ‘pacemaker’ cells like in the heart.
Give rise to action potentials, which can then spread to different cells.
- Electrical communication between cells
- Gap junctions spread depolarisation
Myometrium can function as a syncytium. This is having a whole organ working together as one function unit. This is particularly obvious during the later stages of pregnancy. Mid pregnancy, there are spontaneous contractions at different points. As we get close to delivery, different areas of the uterus all start contracting as one.
What is excitation-contraction coupling?
There is mechanical activity of smooth muscle where there is increase in tension then going back to normal. Membrane potential of pacemaker cells, activated by depolarisation firing off action potentials and the electrical activity can then be conducted by syncytium of uterus, which initiates contraction.
Slow waves of pacemakers and smooth muscle responses are modulated by neurotransmitters and hormones.
How is the basal and elevation of [Ca+] relavent?
Similar to other smooth muscle tissues
[Ca2+]i -> contraction
*Graded response: incremental increases in [Ca2+]i
incremental increases in force of contraction
*Mechanisms for lowering [Ca2+]i: e.g. Ca2+ extrusion
Depending on how much Calcium increases in the cells, will translate to how much of a contraction you will get. There are different mechanisms in place for lowering calcium. It’s the influx of calcium through membrane depolarisation of those opening of voltage gated calcium channels flooding into the cell when we get new membrane depolarisation spreading from those pace maker cells. These are being depolarised in muscle cells - these channels were open and calcium will come in.
How is contraction modulated by hormones and neurotransmiters?
This depends on where they act at. These can be moderated by things like oxytocin, which will cause greater contraction of the uterus.
Eg, Ca2+ /Calmodulin activates Myosin light chain kinase -> Myosin light chain/actin interactions -> Contraction
The depolarisation can then spread from cell to cell through gap junctions for electrical coupling.
How do you measure uterine contraction?
- E.g. Isometric tension recording
Measure tension generated with diameter of the muscle ring remains constant - Y1 practicals: Large organ baths – aortic ring experiments
- Widely used techniques to investigate the functional properties of uterine, vascular, airway and bladder smooth muscle segments.
What are oxytocin-induced contractions?
We get a lot more contractions within the time period where we add oxytocin. There is a greater force being generated.
What are ion channel modulators?
This is relaxation.
Eg. Calcium channel blockers or Potassium channel activators.
These prohibit membrane depolarisation, so the higher the concentration, less likely contractions.
How is everything regulated by neurotransmitters?
Sympathetic (not parasympathetic) innervation
Expression of α- and β- adrenoceptors
α-adrenoceptor agonist – contraction
β2-adrenoceptor agonist – relaxation
How do sex hormones regulate?
Progesteone inhibits contraction
Oestrogen increases contraction
Both act as nuclear and membrane receptors
Non-pregnant uterus:
Weak contractions early in cycle
Strong contractions during menstruation (progesterone low)
Pregnant uterus
Weak and uncoordinated contactions in early pregnancy (high progesterone)
7 month till term – Oestrogen increases, progesterone stays constant Oestrogen / progesterone ratio increases throughout last trimester culminating with strong, coordinated contractions for delivery
How does oxytocin regulate?
Non-peptide hormone synthesised in hypothalamus and released from the posterior pituitary gland
Released in response to suckling and cervical dilatation
Oestrogen (released at later stages of pregnancy) causes:
oxytocin release, increase expression of oxytocin receptors
Oxytocin also increases synthesis of prostaglandins
How do prostaglandins regulate?
Prostaglandins induce myometrial contraction (PGE and PGF)
Role in dysmenorrhoea (severe menstrual pain), menorrhagia (severe menstrual blood loss), pain after parturition
NSAIDs are effective – reduce contraction and pain
Oxytocin stimulates release of prostaglandins
What are contractile agents?
Ergots
Oxytocin
Prostaglandins
The general effect all of these have is that they increase intracellular calcium, which is going to cause contractions of the smooth muscle within our myometrium.
How do Ergots turn to ergometrine?
- Ergot - fungus that grows on some cereals (e.g. rye) and grasses - Contains ergometrine (an active compound). This has a prolonged uterine contraction. This is not used for induction of labout - can be dangerous.
Action
* Powerful and prolonged uterine contraction
Mechanism
* Stimulation of alpha-adrenoceptors, 5-HT receptors?
Uses
* Post-partum bleeding - NOT induction
Used to stop postpartum bleeding or haemorrhage after child birth, which will cause contraction of the blood vessels around the uterus to help stop the bleeding.
