REPRO: Pharmacology Of The Uterus

Question 1

Briefly, describe the muscular structure of the uterus.

Answer 1

• outer longitudinal fibres
• middle figure-eight fibres
• inner circular fibres

Question 2

What are some mechanical properties of the myometrium?

Answer 2

• 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 (the action of giving birth)

Question 3

How is synchronous contraction achieved?

Answer 3

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.

Question 4

Briefly, what is the contractility mechanism of smooth muscle in the uterus?

Answer 4

We get:
ICC periodic activation of inward current –> depolarisations –> Ca2+ entry through VGCCs –> an increase in [Ca2+]i –> contraction

This works through the Gα q/11 subunit mechanism:
oxytocin (bind to oxytocin receptor) –> active Gq/11 protein –> phospholipase C (from PIP2) –> activating IP3 and DAG.

IP3 –> activates IP3 receptors on ER –> release of Ca2+ from ER.
DAG –> increase ion channel excitability.

Gap junctions for electrical coupling (other surrounding cells).

Slow waves of the ICCs and smooth muscle responses are modulated by neurotransmitters and hormones.

Question 5

Describe the cellular mechanisms of smooth muscle contraction.

Answer 5

There is the rise in intracellular Ca2+ due to action of ion channels - increase membrane excitability, as well as the activation of VGCCs - induce Ca2+).

Rise of intracellular Ca2+ –> bind to Calmodulin –> Myosin light chain kinase –> myosin light chain/ actin interactions –> contraction

Question 6

What effect does increasing calcium levels have on these SMCs?

Answer 6

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.

• Mechanisms for lower [Ca2+]i - e.g. Ca2+ extrusion.
• can also be taken up by the ER or Mitochondria.

Question 7

Describe the effect of gradually increasing calcium levels on these SMCs.

Answer 7

• at low concentrations of stimulants on ICCs:
• there is an increased slow wave frequency, producing an increased frequency of contractions.

Increasing oxytocin –> increase magnitude of contraction due to increase Ca2+.

• at higher Ca2+ 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
• Ht higher concentrations still:
• there is an increased plateau of slow wave, producing prolonged sustained contractions

Question 8

What will the effects of large concentrations of stimulants on ICCs indicate?

Answer 8

• 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.

Continuous contractions can also cause pain.

Question 9

Describe the innervation of the uterus, and how it is regulated by neurotransmitters.

Answer 9

The myometrium is sympathetically (not parasympathetically) innervated. This means there is the expression of α and β adrenoreceptors.

• α adrenoreceptor agonist –> contraction. (alpha 1) –> same pathway as oxytocin.
• β adrenoreceptor agonist - relaxation. (Beta 2)

Question 10

Describe how the uterus is regulated by sex hormones.

Answer 10

• Progesterone inhibits contractions.

- Oestrogen increases contractions.

Question 11

Describe the contractions in a pregnant and nonpregnant uterus.

Answer 11

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)

Question 12

How do sex hormones (steroids) directly affect ICCs?

Answer 12

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. This will lead to increased contraction.

Question 13

Describe how the uterus is regulated by prostaglandins.

Answer 13

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 frequency/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.

Question 14

List some examples of prostaglandin analogues.

Answer 14

EXAMPLES: dinoprostone (PGE2), carboprost (PGF2α), misoprotol (PGE1) analogues

Question 15

What are the uses and concerns of using prostaglandin analogues?

Answer 15

USES:

• induction of labour before term
• induction of abortion
• postpartum bleeding
• softening the cervix

CONCERNS:

• dinoprostone can cause systemic vasodilation
• they have the potential for cardiovascular collapse (if given as cervical gel /vaginal insert)
• PGs can make the uterus hypertonus and cause the foetus distress

Question 16

Describe the regulation of the uterus by oxytocins.

Answer 16

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. - increase contractions of uterus (positive feeback).

Question 17

Why can we not use oxytocin interchangeably with prostaglandins?

Answer 17

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).

Question 18

List some examples of oxytocin analogues and describe the pharmacological actions.

Answer 18

EXAMPLES: syntocinon and pitocin are synthetic versions of oxytcin
Syntometrine is a combination of oxytocin (causing rapid contractions) and ergot (causing prolonged contractions).

PHARMACOLOGICAL ACTIONS:

• low concentrations of oxytocin analogues can increase the frequency/force of contractions
• high concentrations cause hypertonus (foetal distress)

Question 19

What are the uses of using oxytocin analogues?

Answer 19

USES:

• induction of labour at term (doesn’t soften cervix)
• treat/prevent post-partum haemorrhage

Question 20

What is ergot?

Answer 20

Ergot is a fungus that grows on some cereals (eg. rye) and grasses.
It contains an array of potent agents, including ergot alkalois (eg. ergometrine, ergotamine; both based on LSD moiety), histamine, tyramine and acetylcholine.

When ingested, it causes ergotism, gangrene, convulsions and induces abortions.

Question 21

Describe the mechanism of actions, the actions and the uses of ergot.

Answer 21

ACTION:
- powerful and prolonged uterine contractions, but only when the myometrium is relaxed

MECHANISM:
- stimulation of α adrenoreceptors, 5HT receptors?

USES:
- post-partum bleeding (not induction)

Question 22

When would myometrial relaxants be used?

Answer 22

Relaxants may be used in premature labour.
It would be to delay the delivery by up to 48 hours, so that the mother can be transferred to a specialist unit, and given antenatal corticosteroids to aid foetal lung maturation and increase the chances of survival.

Question 23

List some examples of myometrial relaxants and explain the implications.

Answer 23

β2 adrenoreceptor stimulants (eg. salbutamol):

• relax uterine contractions by a direct action on the myometrium
• used to reduce the strengths of contractions in premature labour
• may occur as a side effect of the drug used in asthma

Ca2+ channel antagonists (eg. nifedipine):
- used in hypertension

Oxytocin receptor antagonists (eg. retosiban)

COX inhibitors (eg. NSAIDs):

• decrease prostaglandins
• useful to treat dysmenorrhoea and menorrhagia
• may cause foetal renal dysfunction

Question 24

How do β2 adrenoreceptors produce relaxation of smooth muscle?

Answer 24

Stimulation of β2-adrenoceptors on smooth muscle (vascular, airway, myometrial) produces relaxation.

β2 -adrenoceptor stimulation –> PKA activity.

• increase Ca2+ ATPase (SERCA) – increase uptake into SR/exclusion from cell
• increase K+ channel activity –> hyperpolarisation –> decrease Ca2+ entry via VGCCs
• decrease MLCK.

Question 25

Summary of Pharmacology on Uterus.

Answer 25

Induction of labour at term
- Oxytocin

Induction of labour/termination in early term
- Prostaglandins (not oxytocin – no oxytocin receptors)

Post-partum bleeding
- Prostaglandins, oxytocin, ergots

Prevent premature birth

• β2-adrenoreceptor agonists
• Ca2+ channel blockers, Mg Sulfate
• Oxytocin inhibitors
• Slow waves electrical activity of ICC drive myogenic contractions of myometrium
• Ca2+ signalling mechanisms in myometrium are similar to other smooth muscle
• Myometrial contractility is sensitive to sex hormones, oxytocin and prostaglandins
• Contractile and relaxant agents of myometrium have therapeutic values but need to be used with caution

Question 26

How can we measure uterine contractions?

Answer 26

We can use isometric tension recording.
This is when you measure the tension generated with the diameter of the muscle ring remaining constant.

You can use large organ baths, examples being the aortic ring experiments we did in Year 1.

These are widely used techniques to investigate the functional properties of uterine, vascular, airway and bladder smooth muscle segments.

Question 27

How can we measure uterine relaxations?

Answer 27

• Ca2+ channel blockers can be used to measure the uterine relaxations. It shows that the VGCC are vital for contraction. Most of the Ca2+ that is required for contraction comes from the extracellular space.
• K+ channel activator can also be used to measure the uterine relaxations. Activation of K+ channels lead to efflux of K+ out of the cell. This causes less depolarised membrane of the cell and thus reducing Ca2+ entry.

Question 28

Glossary

Answer 28

• Myometrium – smooth muscle layer(s) of the uterus
• Myogenic – spontaneously active
• Interstitial cells of Cajal – pacemaker cells found in the interstitial area
• Gap junctions – connections between cells that allow transfer of (electrical) signal
• Slow waves – electrical activity of interstitial cells of Cajal
• VGCC – voltage-gated calcium channels
• Parturition – childbirth
• Ergometrine – a potent contractor of the uterus found in ergot
• Carboprost – an example of contractile prostaglandin analogues that can be used to induce labour
• Functional syncytium – a mass of cells that function as one