In 1980, Robert Furchgott discovered that vascular endothelium produced an "endothelium-derived relaxing factor" (EDRF) that dilated blood vessels. In 1988, Louis Ignarro and Salvador Moncada independently identified EDRF as nitric oxide (NO). Furchgott, Ignarro, and Ferid Murad shared the 1998 Nobel Prize in Medicine.
Structure: diatomic radical simplicity
NO is a diatomic molecule with one unpaired electron — a free radical. Its unpaired electron makes it highly reactive with other radicals, O₂ (forming NO₂ → nitrites/nitrates), and Fe²⁺ of hemoproteins — which is precisely its physiological action mechanism. Small and non-polar, NO diffuses freely through lipid membranes without transporters, acting as a local short-range messenger (half-life 1–10 seconds in tissues).
Three NOS isoforms, three functions
eNOS (endothelial): produces NO in response to blood flow shear stress and chemical signals (acetylcholine, bradykinin). Generates vasodilatory NO signal. nNOS (neuronal): produces NO as a retrograde neurotransmitter in glutamatergic synapses; also regulates GI smooth muscle relaxation. iNOS (inducible): expressed in macrophages and neutrophils in response to inflammatory cytokines — produces 100–1000× higher NO concentrations as a cytotoxic weapon against intracellular pathogens.
The Viagra connection
Endothelial NO diffuses to penile vascular smooth muscle → activates soluble guanylate cyclase (sGC) → produces cGMP → activates PKG → relaxation → erection. Sildenafil (Viagra) inhibits PDE5 (the enzyme that degrades cGMP), prolonging and amplifying the endogenous NO-cGMP signal. It doesn't create an erection — it potentiates the normal physiological response to sexual stimulation. (Sildenafil was originally developed for angina — the erection side effect was discovered in clinical trials.)