COX1 and COX2 are two isoforms of cyclooxygenase. COX1 facilitates the production of prostacyclins in endothelial cells, which inhibit blood clots. In vascular smooth muscle cells and platelets, COX1 facilitates the production of thromboxane A2, which promotes blood clot formation. Maintaining cardiovascular health relies on the balance between prostacyclins and thromboxane A2 generated by distinct cell types. Low doses of aspirin, a nonsteroidal anti-inflammatory drug (NSAID), reduce the production of thromboxane A2 by platelets without significantly affecting endothelial prostacyclin production, thus having an antithrombotic effect. COX2 is activated by inflammatory stimuli, and NSAIDs suppress the inflammatory response by inhibiting COX2. Both COX1 and COX2 play a role in protecting the stomach by producing prostanoids. Inhibiting both COX1 and COX2 is necessary to cause damage to the gastrointestinal tract. The negative effects of NSAIDs on the gastric mucosa, such as an increased risk of gastrointestinal bleeding, are likely due to the inhibition of both COX1 and COX2 by these nonselective COX inhibitors.

Selective COX2 inhibitors, such as celecoxib and rofecoxib, effectively inhibit COX2 and are extensively used to reduce inflammation. These drugs were initially believed to have fewer negative effects on the gastrointestinal tract compared to nonselective NSAIDs. However, in 2005, the U.S. Food and Drug Administration (FDA) announced that both selective COX2 inhibitors and nonselective NSAIDs increase the risk of heart attacks and strokes. As a result, the FDA required warning labels on the packaging of COX2-selective and nonselective NSAIDs to highlight the potential for these adverse cardiovascular events. Additionally, although COX2-selective inhibitors were thought to not cause gastrointestinal bleeding, the FDA added a caution about the potential for increased risk of gastrointestinal bleeding to the warning labels of these drugs. In 2015, the FDA further strengthened the warnings, stating that both COX2-selective and COX2-nonselective NSAIDs increase the risk of heart attacks and strokes.

ANP binds to the extracellular domain of the plasma membrane receptor guanylyl cyclase, leading to a conformational change in the receptor that triggers receptor dimerization and activation of guanylyl cyclase. Guanylyl cyclase metabolizes GTP to cGMP. cGMP then activates cGMP-dependent protein kinase, which phosphorylates proteins on specific serine and threonine residues. In the kidney, ANP inhibits the reabsorption of sodium and water by the collecting duct.

Nitric oxide activates a soluble receptor guanylyl cyclase, which converts GTP to cGMP. Increased levels of cGMP relax smooth muscle. Nitroglycerin is known to elevate blood concentrations of nitric oxide.
There are two isoforms of cyclooxygenase: COX1 and COX2. When activated in endothelial cells, COX1 facilitates the production of prostacyclins, which inhibit blood clots (thrombin). In vascular smooth muscle cells and platelets, COX1 facilitates the production of thromboxane A2, which is prothrombotic. Thus cardiovascular health depends in part on the balance between prostacyclins and thromboxane A2, generated by distinct cell types. Low doses of aspirin, a nonsteroidal antiinflammatory drug (NSAID), reduce thromboxane A2 production by platelets with little effect on endothelial prostacyclin production. Thus low-dose aspirin is antithrombotic (i.e., reduces blood clots). COX2 is activated by inflammatory stimuli. Thus the ability of NSAIDs (e.g., aspirin, ibuprofen, naproxen, acetaminophen, indomethacin) to suppress the inflammatory response is due to inhibition of COX2. Both COX1 and COX2 facilitate the production of prostanoids that protect the stomach. Several lines of evidence suggest that both COX1 and COX2 must be inhibited to elicit damage to the gastrointestinal tract. Consequently, the negative effects of NSAIDs on the gastric mucosa (e.g., increased incidence of gastrointestinal bleeding) are most likely due to inhibition of COX1 and COX2 by these nonselective COX inhibitors.
Selective COX2 inhibitors (e.g., celecoxib, rofecoxib) are very effective in selectively inhibiting COX2 and are used extensively to reduce the inflammatory response. Because COX2 inhibitors are thought to lack the negative effects elicited by NSAIDs on the gastrointestinal tract, their use has increased dramatically. However, in 2005, the U.S. Food and Drug Administration (FDA) announced that selective COX2 inhibitors, as well as nonselective NSAIDs, increase the risk for heart attacks and strokes and required that COX2selective and nonselective NSAIDs carry a warning label on product packaging that highlighted the potential for the increased risk for adverse cardiovascular events and stroke. In addition, although much evidence suggests that COX2selective inhibitors do not cause gastrointestinal bleeding, in 2005 the FDA also required the pharmaceutical industry to add to the warning label on COX2-selective drugs a caution about the potential for increased risk for gastrointestinal bleeding. In 2015, the FDA strengthened warnings that both COX2-selective and COX2-nonselective NSAIDs increase the risk of heart attacks and strokes.
bSee U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA Strengthens Warning That Non-aspirin Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Can Cause Heart Attacks or Strokes. < http://www.fda.gov/
Drugs/DrugSafety/ucm451800.htm >; 2015 Accessed 25.07.16.
ANP binds to the extracellular domain of the plasma membrane receptor guanylyl cyclase and induces a conformational change in the receptor that causes receptor dimerization and activation of guanylyl cyclase, which metabolizes GTP to cGMP. cGMP activates cGMP-dependent protein kinase, which phosphorylates proteins on specific serine and threonine residues. In the kidney, ANP inhibits reabsorption of sodium and water by the collecting duct (see
Nitric oxide activates a soluble receptor guanylyl cyclase that converts GTP to cGMP, which relaxes smooth muscle. Because nitroglycerin increases blood concentrations of