Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: relevance and clinical implications

Am J Physiol Regul Integr Comp Physiol. 2013 Apr 1;304(7):R473-87. doi: 10.1152/ajpregu.00355.2012. Epub 2013 Feb 6.


The nitric oxide (NO) and cyclooxygenase (COX) pathways share a number of similarities. Nitric oxide is the mediator generated from the NO synthase (NOS) pathway, and COX converts arachidonic acid to prostaglandins, prostacyclin, and thromboxane A(2). Two major forms of NOS and COX have been identified to date. The constitutive isoforms critically regulate several physiological states. The inducible isoforms are overexpressed during inflammation in a variety of cells, producing large amounts of NO and prostaglandins, which may underlie pathological processes. The cross-talk between the COX and NOS pathways was initially reported by Salvemini and colleagues in 1993, when they demonstrated in a series of in vitro and in vivo studies that NO activates the COX enzymes to produce increased amounts of prostaglandins. Those studies led to the concept that COX enzymes represent important endogenous "receptor" targets for amplifying or modulating the multifaceted roles of NO in physiology and pathology. Since then, numerous studies have furthered our mechanistic understanding of these interactions in pathophysiological settings and delineated potential clinical outcomes. In addition, emerging evidence suggests that the canonical nitroxidative species (NO, superoxide, and/or peroxynitrite) modulate biosynthesis of prostaglandins through non-COX-related pathways. This article provides a comprehensive state-of-the art overview in this area.

Publication types

  • Review

MeSH terms

  • Gene Expression Regulation, Enzymologic / physiology*
  • Humans
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Prostaglandins / metabolism


  • Prostaglandins
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Prostaglandin-Endoperoxide Synthases