The nature of endothelium-derived vascular relaxant factor

This 1984 Nature paper, published three years before nitric oxide was identified as the answer, was an important early step in the scientific detective story of "endothelium-derived relaxing factor" (EDRF), a then-mysterious substance released by the cells lining blood vessels that causes surrounding muscle to relax and vessels to widen.

Using isolated rabbit blood vessel preparations, the researchers proved that EDRF is a true "humoral" substance, meaning it is a diffusible chemical messenger that can travel from where it's made to have effects elsewhere, rather than requiring direct nerve contact or physical touch between cells. They also proposed a specific chemical identity for EDRF: an unstable compound containing a carbonyl group (a type of chemical structure found in aldehydes and ketones).

This specific chemical proposal turned out to be incorrect: three years later, in 1987, two independent research teams (Ignarro's and Moncada's) showed conclusively that EDRF is actually nitric oxide, a simple gas. This paper remains historically valuable for its rigorous proof that EDRF is a genuine diffusible messenger molecule, even though its guess about EDRF's precise chemical structure did not hold up.