2004A10 Describe the vasoactive substances released by the endothelium.
Explain the role they play in regulating blood flow through the peripheral circulation.

 

List:

·       Intro: endothelium

·       Vasodilators

·       Vasoconstrictors

 

Intro:

·       Endothelium is a single cell layer on inner lining of blood vessels

·       Produces vasoactive hormones: mostly autocrine and paracrine

o   Coupling of local blood flow to local metabolic rate

o   Prevent damage from excessive blood flow

o   Primary haemostasis

 

Vasodilators:

 

Nitric oxide:

Production

·  L-arginine -> NO + citrulline

·  eNOS: small amounts

·  iNOS: large amounts

Release stimuli

·  Shear stress

·  Neurotransmitters: bradykinin, substance P, histamine

·  Metabolic activity:

·  ↑H+, K+, PaCO2, adenosine, temp, lactate, ↓PaO2

·  Propofol, volatiles

Effect

·  Diffuse into vascular smooth muscle

·  Activates guanylyl cyclase / ↑cGMP / activate MLCP, ↑Ca2+ reuptake, ↑K+ efflux

   -> Vasodilatation

   -> Inhibition of platelet aggregation

   -> Mediates ↑skeletal muscle blood flow in exercise

 

Prostacyclin:

Production

Release stimuli

·  COX-1: constitutive

·  COX-2: inducible (by inflammatory cytokines)

Effect

·  Binds to Gs G protein-coupled receptor (GPCR)

·  Activates guanylyl cyclase / ↑cAMP / activation of PKA

   -> Vasodilatation, inhibition of platelet aggregation

   -> Antagonist of TXA2

 

Vasoconstrictors:

 

Endothelin:

Production

·  ECE on endothelial cell membrane

Release stimuli

·  Stimuli: shear stress, SNS, AT2, ADH, thrombin

·  Inhibitors: NO, PGE2, PGI2, ANP

Effect

·  ETA receptor: constriction

·  ETB1: dilatation

·  ETB2: constriction

·  Via Gq GPCR

·  Drug targets in pulmonary hypertension (e.g. bosentan)

 

Thromboxane A2:

Production

·  As for PGI2

·  TXA2 synthase enzyme

Release stimuli

·  Inflammation

·  Vessel injury

Effect

·  Binds TXA2 receptor

·  Gq GPCR / PLC / PIP2 / IP3 -> ↑Ca2+

·  Vasoconstriction, platelet aggregation

 

Angiotensin 2:

Production

·  Angiotensin -> angiotensin 2

(catalyst: angiotensin converting enzyme on pulmonary endothelium)

Release stimuli

·  ACE constitutively expressed

Effect

·  Binds AT2 receptor

·  Gq GPCR -> ↑Ca2+

·  Peripheral vasoconstriction (arterial > venous)

·  Renal arteriolar vasoconstriction (afferent > efferent)