Nitric oxide and aspirin: a new mediator for an old drug.
Aspirin is known to cause a multitude of pharmacologic actions through inhibition of cyclooxygenase(s) and reduced formation of prostaglandins. Recently, however, novel cytoprotective and antioxidant mechanisms of aspirin have been identified that are independent of cyclooxygenase inhibition. It was shown that aspirin directly stimulates the activity of endothelial nitric oxide (NO) synthase without affecting the expression of endothelial NO synthase. Increased NO formation was found to underlie aspirin-induced sustained protection of endothelial cells from oxidant injury. Downstream targets of NO that mediate tissue protection include the stress proteins heme oxygenase-1 (HO-1) and ferritin. Both HO-1 and ferritin have been identified as targets of, and inducible by, aspirin and, in the case of HO-1, aspirin-triggered lipoxins. It is important to note that these effects are specific to aspirin and not induced by other nonsteroidal antiinflammatory drugs such as diclofenac, indomethacin, or salicylates or by selective cyclooxygenase-2 inhibitors. HO-1 and its antioxidant product bilirubin have been reported to be not only involved in vasoprotection, but to have a similar function in gastric tissue. Stimulation of NO formation through aspirin and ensuing HO-1 induction might therefore help to reduce gastric injury or irritation. Moreover, NO functions as a smooth muscle-relaxing agent and is thus thought to counteract the reduction in gastric blood flow caused by inhibitors of prostaglandin synthesis. It is therefore conceivable that activation of these novel antioxidant pathways contributes, at least in part, to gastric tolerability and the favorable cardiovascular safety profile of aspirin.
Schröder
Henning
H
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA. schro601@umn.edu
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology; D000975:Antioxidants / Q000009:adverse effects / Q000494:pharmacology; D001241:Aspirin / Q000009:adverse effects / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D005293:Ferritins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D009569:Nitric Oxide; D005293:Ferritins; D052250:Nitric Oxide Synthase Type III; D051547:Heme Oxygenase-1; D001241:Aspirin