Arachidonic Acid Metabolites

(Prostaglandins and Related Compounds)

Prostaglandins and related compounds (collectively referred to as prostanoids or eicosanoids) such as
prostacyclin (PGI2), leukotrienes (LTs) and thromboxanes (TXs) are produced by many different cells in the body.
Although their primary physiological actions are generally related to inflammation and hemostasis, by nature they all
are vasoactive and can modulate cardiovascular function, particularly vascular tone. Their effects are very localized
because they are paracrine hormones; that is, they are released by one cell and act on nearby cells.

Prostanoids

Prostanoids are fatty acid compounds derived from membrane phospholipids. When these phospholipids are acted
upon by phospholipase A2, arachidonic acid is formed. Two important pathways for arachidonic acid metabolism
are the cyclooxygenase (COX) and 5-lipoxygenase (5-LO) pathways. The COX pathway forms intermediate
compounds called cyclo-endoperoxides (PGG 2 and PGH2). Enzymes, many of which are tissue specific, then
convert the cyclo-endoperoxides into the final biologically active prostanoid.

There are different forms of the COX enzyme, two of which are COX-1 and COX-2. Aspirin and other non-steroidal
anti-inflammatory drugs (NSAIDs) such as ibuprofen and acetaminophen (Tylenol®) are non-selective inhibitors of
the COX enzymes. Newer NSAIDs are relatively selective for COX-2, and generally have fewer gastrointestinal-
related side effects. COX-1 is constitutive and therefore produces prostanoids under basal conditions. In contrast,
COX-2 is inducible and is upregulated during inflammation.

Smooth muscle cells in blood vessels produce prostaglandins (PGs). PGE 2 generally acts as a vasodilator by
stimulating the Gs-protein pathway, whereas PGF2α commonly produces vasoconstriction by stimulating the Gq-
protein pathway.

Vascular endothelium produces PGI2 as its primary derivative of arachidonic acid. This prostanoid is a potent
vasodilator and inhibitor of platelet adhesion to the endothelium, and acts through the Gs-protein pathway.
Therefore, it is anti-thrombotic. These actions are similar to those of endothelium-derived nitric oxide. Endothelial
dysfunction or damage, which occurs in atherosclerosis, for example, can cause vasospasm and thrombosis.

Platelets produce TXA2, which is a potent vasoconstrictor acting through the Gq-protein pathway. Its production is
enhanced during inflammation and tissue injury, and following platelet activation. It is important in producing arterial
vasoconstriction when a vessel is cut and bleeding (hemostatic function).

Leukocytes produce leukotrienes such as LTC 4 in response to inflammation and tissue injury. Like TXA 2, it is a
potent vasoconstrictor and acts through the Gq-protein pathway. Leukotrienes (and prostaglandins) can also make
the vascular endothelium more "leaky" thereby promoting edema formation during inflammation.