Nitric oxide (NO) affects two key aspects of O2 supply and demand: It regulates vascular tone and blood flow by activating soluble guanylate cyclase (sGC) in the vascular smooth muscle, and it controls mitochondrial O2 consumption by inhibiting cytochrome c oxidase. However, significant gaps exist in our quantitative understanding of the regulation of NO production in the vascular region. Large apparent discrepancies exist among the published reports that have analyzed the various pathways in terms of the perivascular NO concentration, the efficacy of NO in causing vasodilation (EC50), its efficacy in tissue respiration (IC50), and the paracrine and endocrine NO release. In this study, we review the NO literature, analyzing NO levels on various scales, identifying and analyzing the discrepancies in the reported data, and proposing hypotheses that can potentially reconcile these discrepancies. Resolving these issues is highly relevant to improving our understanding of vascular biology and to developing pharmaceutical agents that target NO pathways, such as vasodilating drugs.Antioxid. Redox Signal. 10, 1185–1198.
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