Table 2-1 ▪ FUNCTIONS OF THE VASCULAR ENDOTHELIUM RELATED TO VASOMOTOR FUNCTION | ||||||||
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which activates phospholipase A2 and subsequently releases arachidonic acid. Under basal conditions the arachidonic acid is then metabolized by COX-1, which results in the production of prostaglandin H2 (PGH2) and subsequently PGI2.59 Prostacylin binds to receptors on vascular smooth muscle and platelets and through G-protein mediated activation of adenylate cyclase increases cyclic adenosine monophosphate (cAMP) (Fig. 2-7). Increased cAMP stimulates potassium-induced cellular hyperpolarization and the phosphorylation of protein kinase A (PKA), which increases calcium extrusion from the cell and causes vasodilation and also inhibits platelet activation.59 Prostacylin also act through peroxisome proliferator-activated receptor (PPAR)β/δ, which causes a decrease in intracellular calcium and subsequent vasodilation and platelet inhibition through mechanisms that are still being studied. There is cross talk between PGI2 and NO and they have synergistic vasodilatory and antithrombotic actions. Prostacyclin increases NO release and, concomitantly, NO prolongs the effect of prostacyclin by inhibiting its breakdown.59,60
Table 2-2 ▪ ENDOTHELIUM-DERIVED VASODILATING AND VASOCONSTRICTING FACTORS | |||||||||||||||||||||
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causes endothelium-dependent hyperpolarization, which in turn decreases cytosolic calcium and causes vasorelaxation through the various mediator-specific pathways (Fig. 2-8).61
serious cardiovascular events, including myocardial infarction and stroke.84,85 This increased risk resulted in the Food and Drug Administration requiring labeling of all selective and nonselective NSAIDs to reflect the possibility of an increased risk for myocardial infarction and stroke with their use.86 It is important to note that the increased risk varies depending on the medication87, 88, 89 and a prospective clinical trial is ongoing to determine the cardiovascular risk of selective and nonselective NSAIDS. The probable mechanism of these adverse effects is that while COX-2 inhibitors do not inhibit thromboxane they do inhibit vascular prostacyclin causing increased systolic blood pressure and platelet activation, which increases the likelihood of thrombus formation.90, 91, 92