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