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

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

Production

Release stimuli

·   COX-1: constitutive

·   COX-2: inducible (by inflammatory cytokines)

Effect

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

·   Activates guanylyl cyclase / ↑cAMP / activation of PKA

   -> Vasodilatation, inhibition of platelet aggregation

   -> Antagonist of TXA₂

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 G_q GPCR

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

Production

·   As for PGI₂

·   TXA₂ synthase enzyme

Release stimuli

·   Inflammation

·   Vessel injury

Effect

·   Binds TXA₂ receptor

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

·   Vasoconstriction, platelet aggregation

Production

·   Angiotensin -> angiotensin 2

(catalyst: angiotensin converting enzyme on pulmonary endothelium)

Release stimuli

·   ACE constitutively expressed

Effect

·   Binds AT2 receptor

·   G_q GPCR -> ↑Ca²⁺

·   Peripheral vasoconstriction (arterial > venous)

·   Renal arteriolar vasoconstriction (afferent > efferent)