Parturition Flashcards
Hormonal mechanisms maintaining myometrial quiescence in pregnancy
- progesterone is a myometrial inhibitor that prevents contractions during pregnancy
- induces muscle relaxation in myometrium
- causes production of NO
- inactivates prostaglandins
- in humans, levels of progesterone do NOT fall at onset of labor, however there is likely a functional withdrawal of progesterone due to changes in expression of receptors
Contraction associated proteins (contraction activated proteins)
- those that enhance the interaction between actin and myosin
- those that increase excitability of myometrial cells
- those that promote intracellular connectivity
Proteins which promote myocyte contractility– actin and myosin effects
a. Actin must be converted from a globular form to a filamentous form and attach to the cytoskeleton to allow the development of tension
b. Myosin is activated when it is phosphorylated by myosin light chain kinase (i.Myosin light chain kinase is activated by increased intracellular calcium and calmodulin)
c. Calcium from intracellular stores must be released in order for actin and myosin to interact and cause contraction i.Calcium channels are ligand activated and respond to prostaglandins E and F via the prostaglandin receptor
Proteins which promote myocyte excitability
a. Myocytes maintain an electrochemical potential gradient across the plasma membrane (i.In the cell is negative relative to outside the cell)
b. Gradient is maintained by the Na-K exchange pump
c. Additionally, a calcium and voltage gated K efflux pump increases the potential difference across the membrane and makes it less likely to depolarize
d. During labor, the function and distribution of these K efflux pumps change i.This lowers the required stimulus to depolarize
Proteins which increase intracellular connectivity
a. Labor must develop synchronous contraction to be effective
b. Possible pacemaker cells of the uterus are thus far elusive
c. Synchrony is achieved by 2 mechanisms
i. Molecular: Myometrial cells are connected via gap junctions comprised of connexin 43
ii. Cellular: Electrical conduction through connecting myofibrils transmits the electrical signal to an adjacent cell that becomes activated. Activated myocytes secrete prostaglandins, which act in a paracrine fashion to depolarize neighboring myocytes. This causes a wave of activity as more fibers are recruited and a refractory period follows.
List the phases of myometrial activation
Phase 0: quiescence Phase 1: activation Phase2: stimulation/contraction Phase 3: involution/contraction
Phase 0: quiescence
- Progesterone causes production of NO
- NO is a smooth muscle relaxant
- Low levels of CRH interact with a GPCR to activate the protein Kinase A pathway
- PKA inhibits myometrium contraction
Phase 1: activation
- increase in contraction activated proteins
- Increased oxytocin receptors on myometrial cells
- Increased gap junctions
- Increased number of Calcium channels
- Increased prostaglandin receptors
- Loss of prostaglandin dehydrogenase allows prostaglandins to become functional from placenta
- The myometrium begins synthesizing prostaglandins
Phase 2: stimulation/contraction
Oxytocin stimulates myometrial production of prostaglandins
- Prostaglandins from placental membranes and the myometrium bind to receptors which increase calcium influx through channels
- The GPCR Gq pathway becomes the dominant pathway for CRH which stimulates PKC and induces contraction
- Increased calcium influx results in increased calmodulin and thus increased active myosin light chain kinase
Phase 3: involution/contraction
corresponds to 6 hours post-partum of clinical stages of labor
Describe the mechanisms by which myometrial calcium is increased near term
- before labor: myocyte has high interior electronegativity (hyperpolarized cell)
- due to Na-K ATPase and open K+ channels.
- during myocyte contraction: intracellular calcium levels rise via Ca influx through voltage gate Ca channels and thru release of intracellular Ca
- Near parturition, prostaglandins E and F bind to their receptors, promoting the opening of ligand regulated Ca channels
- receptors also cause release of intracellular Ca
- Ca rushes in, electronegativity drops and promotes opening of many VGCCs and depolarization.
- Oxytocin will also bind to receptors and activate Gaq, which activates PLC. PLC activates protein kinase C which activates myosin light chain kinase and causes release of IP3 which contributes to release of Ca from intracellular stores.
Roles of progesterone in parturition
Near term, the levels of progesterone fall causing loss of inhibition of myometrial contraction and cessation of growth accommodating behavior by the uterus (i.e. the uterus stops growing like it did the 9 months before).
Role of CRH in parturition
- corticotropin releasing hormone
- early in pregnancy: maintains quiescence by blocking myosin light chain kinase
- later it induces contraction via PKC pathway
- Difference to to different receptor isoforms:
early: CRH binding to CRH receptor 1 alpha leads to releaxation in myometrium
late: receptors change to Gaq pathway linked to PKC activation and contraction
CRH increases throughout pregnancy, and CRH binding protein begins to fall at end of pregnancy causing an increase in free/active CRH.
- causes release of cortisol in mother and baby
- glucocorticoids promote expression of CRH gene in placental tissue (feedforward)
- increased cortisol stimulates maturation of fetal lungs
Cortisol and parturition
-in developing fetus stimulates final lung maturation
Estrogens and parturition
- inhibits CRH production in placenta
- favors parturition by inducing contraction
- synthesized in response to increases in CRH which stimulates fetal steroidogenesis and production of DHEA-S, followed by estrogen
- COX2 and IL8 cause changes in estrogen receptors, which then causes a change in expression of connexin 43 and oxytocin receptor.
