2011B09 Outline the physiological roles of prostaglandins in the body.

· Intro

· Pathway

· The big 3

· Body systems

Definition

· Lipid mediators derived from arachidonic acid

· Production induced by cyclo-oxygenase

o COX-1: constitutive, for homeostasis

o COX-2: inducible, for inflammation etc

Actions

· Autocrine and/or paracrine

· Inhibitory or excitatory

· Two PGs may have opposing effects at the same tissue

o e.g. TXA₂ vasoconstrict, PGI₂ vasodilate

· One PG may have different effects on different tissues

o e.g. PGI₂ vascular smooth muscle dilation, GIT smooth muscle constriction

Cellular mechanism

· Bind to G protein coupled receptors

o G_s : ↑cAMP

o G_i : ↓cAMP

o G_q : ↑IP₃/DAG -> ↑Ca²⁺

Inflammation

· WBC -> cytokines (TNFα, IL1, IFN) -> ↑activity iNOs -> ↑NO -> ↑activity of COX-2

· ↑production of PGD₂, PGE₂

· Vasodilation, cap leak, chemotaxis, mast cell degranulation, promotion of T cell differentiation

Pain

· Causes nociception, hyperalgaesia, allodynia

· Inflamed tissue, WBC -> prostaglandin -> nociceptor activation and sensitization

· Sensitised nociceptor -> substance P, NKA -> inflammation

· Note vicious cycle

Pyrexia

· PGE₂ in hypothalamus -> ↑temp set point ->fever

· Production induced by cytokines (TNFα, IL-1), other

Cardiovascular	· PGI₂: local vasodilatation · TXA₂: local vasoconstriction · Role in HPV unclear
Respiratory	· Bronchial smooth muscle: PGD₂ and PGF_2α constriction, PGE₂ dilation · Pulmonary vasculature: role in HPV unclear
Renal	· Renin-angiotensin: ↓NaCl load to DT -> ↑PGE₂, PGI₂ release -> ↑renin release · i.e. hormonal autoregulation of GFR
Gastrointestinal	· Activity of mucus neck cells: mucus, HCO₃^- (note COX-1 only)
Haematological	· PGI₂: ↓platelet aggregation · TXA₂: ↑platelet aggregation
Genitourinary	· PGE₂, PGF_2α: myometrial contraction · Important in menstruation and in labour · Receptors always present cf. oxytocin