Nitric oxide production pathways in erythrocytes and plasma

Nitric oxide (NO) is a potent regulator of vascular tone and hemorheology. The signaling function of NO was largely unappreciated until approximately 30 years ago, when the endothelium-derived relaxing factor (EDRF) was identified as NO. Since then, NO from the endothelium has been considered the major source of NO in the vasculature and a contributor to the paracrine regulation of blood hemodynamics. Because NO is highly reactive, and its half-life in vivo is only a few seconds (even less in the bloodstream), any NO bioactivity derived from the intraluminal region has traditionally been considered insignificant. However, the availability and significance of NO signaling molecules derived from intraluminal sources, particularly erythrocytes, have gained attention in recent years. Multiple potential sources of NO bioactivity have been identified in the blood, but unresolved questions remain concerning these proposed sources and how the NO released via these pathways actually interacts with intravascular and extravascular targets. Here we review the hypotheses that have been put forward concerning blood-borne NO and its contribution to hemorheological properties and the regulation of vascular tone, with an emphasis on the quantitative aspects of these processes.