REPRO: Pharmacology of the Uterus Flashcards
Briefly, describe the muscular structure of the uterus.
- outer longitudinal fibres
- middle figure-eight fibres
- inner circular fibres
What are some mechanical properties of the myometrium?
- contractions mean an increase in uterine pressure, forcing content towards the cervix and acts as a natural ligature to prevent blood loss
- it’s spontaneously active (myogenic): it produces regular contractions without neural or hormonal input
- highly sensitive to neurotransmitter and hormones
- rhythmic contractions for parturition
How is synchronous contraction achieved?
There are pacemaker cells in the myometrium called the interstitial cells of Cajal (ICCs), which initiate and coordinate contractions.
There is electrical communication via gap junctions made of connection proteins. These gap junctions are found:
- between ICCs
- between ICCs and smooth muscle cells
- between smooth muscle cells
They function as a syncytium.
Briefly, what is the contractility mechanism of smooth muscle in the uterus?
We get:
- ICC periodic activation of inward currents
- depolarisations
- Ca2+ entry through VGCCs
- an increase in [Ca2+]i
- contraction
This works through the Gα q/11 subunit mechanism.
What effect does increasing calcium levels have on these SMCs?
An increase in [Ca2+]i will lead to contraction. This is a graded response; incremental increases in [Ca2+]i will lead to incremental increases in the force of contraction.
Describe the effect of gradually increasing calcium levels on these SMCs.
- at low concentrations of stimulants on ICCs:
- there is an increased slow wave frequency, producing an increased frequency of contractions
- at higher concentrations:
- there is an increased frequency of action potentials on top of those slow waves
- ie. increased peak of [Ca2+]i, producing both increased frequency and increased force of contractions
- at higher concentrations still:
- there is an increased plateau of slow wave, producing prolonged sustained contractions
What will the effects of large concentrations of stimulants on ICCs indicate?
- the cells will be hypertonus (there is incomplete relaxation)
- the Ca2+ extrusion processes are not effective
- important: it interferes with blood flow, which can cause foetal distress
Describe the innervation of the uterus, and how it is regulated by neurotransmitters.
The myometrium is sympathetically (not parasympathetically) innervated. This means that there is the expression of α and β adrenoreceptors.
An α adrenoreceptor agonist will cause contraction.
A β adrenoreceptor agonist will cause relaxation.
Describe how the uterus is regulated by sex hormones.
Progesterone inhibits contractions.
Oestrogen increases contractions.
Describe the contractions in a pregnant and nonpregnant uterus.
NON-PREGNANT UTERUS:
- weak contractions early on in the cycle
- strong contractions during menstruation (decreased progesterone, increased prostaglandins)
PREGNANT UTERUS:
- weak and uncoordinated contractions in early pregnancy (high progesterone)
- strong and coordinated contractions at parturition (increased oestrogen)
How do sex steroids directly affect ICCs?
Oestrogen/progesterone receptors are found on ICCs.
During parturition, the oestrogen:progesterone ratio increases. Oestrogen increases, while progesterone decreases the expression of gap junctions in the myometrium.
Describe how the uterus is regulated by prostaglandins.
The myometrium and endometrium synthesise PGE2 and PGF2α - this is promoted by oestrogens. Both these prostaglandins induce myometrial contraction.
The prostaglandins act together to:
- coordinate an increased frequecy/force of contractions
- increase the gap junctions
- soften the cervix
They play a role in dysmenorrhoea (severe menstrual pain), menorrhagia (severe menstrual blood loss) and pain after parturition. Thus, NSAIDS are effective, as they can reduce contractions and pain.
Prostaglandins are effective in early and mid-pregnancy.
Compare and contrast these Oxytocin and Prostaglandins
Oxytocin:
- Used to induce/augment labour at term (get labour going or help labour that has started but isn’t going quickly enough
- Dose dependent increases to increase contraction - but too much can cause sustained contraction and fetal distress (which can be very damaging to the baby)
- Also used in postpartum haemorrhage (to stop bleeding)
Prostaglandins:
- Induction of labour - before term
- Induce abortion
- Postpartum bleeding
You cant use oxytocin before term because oxytocin levels and receptors increase as the pregnancy increases due to the effect of the oestrogen. So if oxytocin is given too early it wont have any affect.
Describe the regulation of the uterus by oxytocins.
Oxytocin is a non-peptide hormone synthesised in the hypothalamus and released from the posterior pituitary gland. It is released in response to suckling and cervical dilation.
Oestrogen (released at later stages of parturition) produces:
- increased oxytocin release
- increased oxytocin receptors
- increased gap junctions
Oxytocin also increases the synthesis of prostaglandins.
Why can we not use oxytocin interchangeably with prostaglandins?
Oxytocin receptors are not expressed much (if at all) pre-term; they’re particularly expressed at term, so there wouldn’t be that big of an effect.
Effects of oxytocin require oestrogen-induced oxytocin receptor expression).
