Endothelium-related vasoactive substances

Endothelium-related vasodilators

Prostacyclin

[BL8:p159, WG21:p600]

Relax vascular smooth muscles via increased cAMP

• Primary function: inhibit platelet adherence to the endothelium
• Primary function: inhibit platelet aggregation
  --> Prevent clot formation
• Vasodilation

Formed in endothelium from arachidonic acid

Released by shear stress caused by pulsatile blood flow

Note:

• Thromboxane A2 produced by platelets
  --> opposite effect (i.e. platelet aggregation and vasoconstriction)
• Aspirin irreversibly inhibits cyclooxygenase
  --> Reduction in both prostacyclin and thromboxane A2
  --> Endothelial cells produce new cyclooxygenase and thus prostacyclin in hours, but platelets cannot

Endothelium-derived relaxing factor (EDRF)

• Found to be nitric oxide (NO)
• Far more important in causing vascular dilation

NO release from endothelium
--> Diffused into vascular smooth muscle
--> NO activates guanylyl cyclase
--> Increase cGMP
--> Decrease cytosolic free Ca2+
--> Relaxation

Production of NO

• Synthesized from L-arginine
• Catalyzed by nitric oxide synthase (NOS)

NB:

• Vasodilation independent of endothelium:
  * Adenosine
  * ANP
  * Histamine via H2 receptors
• Vasodilation by stimulating release of NO from endothelium:
  * Acetylcholine
  * Histamine via H2 receptors
  * Bradykinin
  * VIP, substance P
• Increased shear stress due to increased flow velocity also cause vasodilation via NO, if endothelium remains intact
• Nitroprusside causes dilation via increases in cGMP but doesn't act through endothelium (and NO).
• NO is also important for cytotoxic activity of macrophages
• ANF and NO are the two hormones that act via cGMP

Endothelium-related vasoconstrictors

Endothelin

• Very potent vasoconstrictor peptide
• 3 types: ET-1, ET-2, and ET-3
• Primarily a local paracrine regulator of vascular tone
• Plays a role in closure of ductus arteriosus and regulating transport across blood-brain barrier