REPRO: Pharmacology of the Uterus Flashcards
Briefly, describe the muscular structure/smooth muscle of the uterus.
myometrium:
- outer longitudinal fibres
- middle figure-eight fibres
- inner circular fibres
How does the myometrium contract?
It is myogenic, providing rhythmic contractions
- doesn’t need activation of neuronal pathways or hormonal input, but is still highly sensitive to neurotransmitters and hormones
- rhythmic contractions for parturition
- contractions mean an increase in uterine pressure, forcing content towards the cervix and acts as a natural ligature to prevent blood loss
Where are gap junctions located?
- between ICCs
- between ICCs and myometrial smooth muscle cells
- between myometrial smooth muscle cells
How is the myometrium myogenic?/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.
They function as a syncytium.
What do gap junctions allow for?
communication between cells via movement of molecules, ions and electrical impulses (electrical coupling)
the gap junctions, therefore, function as a syncytium to achieve synchronous contraction of the myometrium
Briefly, what is the contractility mechanism of smooth muscle in the uterus?
We get:
1) ICC periodic activation of inward current
2) Causes depolarisation of smooth muscle cells (electrical coupling via gap junctions) which then opens VGCCs
3) Ca2+ influx through VGCCs
4) Increase in [Ca2+]i
5) Contraction of myometrial smooth muscles
This works through the Gα q/11 subunit mechanism.
What effect does increasing calcium levels have on smooth muscle contraction?
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.
What causes more sustained myometrial contractions?
slow waves of ICCs and smooth muscle responses mediated by neurotransmitters & hormones
Methods by which [Ca2+]i increases
- Ca2+ entry via VGCCs
- Ca2+ release from sarcoplasmic reticulum after IP3 binds IP3 receptors on SR
How does an increase in [Ca2+]i cause contraction? 1
1) Calmodulin (calcium sensor) binds Ca2+
2) Calmodulin activates myosin light chain kinase
3) Myosin light chain kinase phosphorylates myosin, allowing for myosin to interact with actin and increasing ATPase activity of myosin, altering myosin structure and increasing its affinity for ATP, allowing it to be primed for contraction
What must happen for rhythmic contractions of the myometrium?
A subsequent decrease in Ca2+ after the initial increase so the myometrial smooth muscle cells don’t stay contracted all the time
Methods by which [Ca2+]i decreases
- Ca2+ pumped out of the cell via Ca2+ ATPase
- Ca2+ taken up by sarcoplasmic reticulum via SERCA pumps to be stored
- Ca2+ extruded via Na+/Ca2+ exchanger
- small amount of Ca2+ stored in mitochondria
Effect of ICC stimulant concentration on contraction
Low concentration of stimulants on ICCs
- increase in slow wave frequency
- increased frequency of contractions
High concentration of stimulants on ICCs
- increase in action potential frequency on top of slow waves
- increase in frequency & force of contraction
Higher concentrations
-increase in plateau of slow-wave producing sustained contractions
Large concentrations
- hypertonus (incomplete relaxation) and Ca2+ extrusion processes not effective
- interferes with foetal blood flow and causes foetal distress
Describe the innervation of the uterus, and how it is regulated by neurotransmitters.
Mostly sympathetic innervation
- alpha-adrenoceptor (aGq) causes contraction
- beta 2 adrenoceptor (aGs) causes relaxation
Describe how the uterus is regulated by sex hormones.
Progesterone inhibits contractions.
Oestrogen increases contractions.
Contractions in non-pregnant vs pregnant uterus
Non-pregnant
- weak contractions in early cycle
- strong contractions during menstruation (high prostaglandins, low progesterone)
Pregnant
- weak and uncoordinated in early pregnancy (high progesterone)
- strong and coordinated and parturition (high oestrogen)
Effect of oestrogen and progesterone on gap junctions
Oestrogen increases the expression of gap junctions
Progesterone decreases the expression of gap junctions
*causes contraction/relaxation of myometrium at parturition
Effect of prostaglandins on uterus contraction
Prostaglandins (PGE2 & PGF2a) induce myometrial contraction
- coordinate increased frequency & force of contractions
- increase gap junctions
- soften cervix
What promotes the synthesis of uterine prostaglandins and where are they produced?
Oestrogen promotes the synthesis of PGE2 & PGF2a either in the:
- myometrium (autocrine)
- endometrium (paracrine)
*oxytocin also increases the synthesis of PGs to induce contraction
Side effects of uterine prostaglandins after parturition
dysmenorrhoea (painful menstruation)
menorrhagia (prolonged bleeding)
pain
*treat using NSAIDs which reduce contractions and pain by inhibiting cyclo-oxygenase enzyme (which normally produces PGs)
List some examples of prostaglandin analogues.
Dinoprostone (PGE2)
Carboprost (PGF2a)
Mistoprotol (PGE1)
What are the uses of prostaglandin analogues?
USES:
- induction of labour before term
- induction of abortion
- pospartum bleeding
- softening the cervix
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.
What are the concerns of using prostaglandin analogues?
CONCERNS:
- dinoprostone can cause systemic vasodilation
- they have the potential for cardiovascular collapse (if given as cervical. vaginal insert)
- PGs can make the uterus hypertonus and cause the foetus distress
