Biological actions and properties of endothelium-derived nitric oxide formed and released from artery and vein.

About 10 years ago we discovered that bubbling nitric oxide (NO) gas into KrebsRinger bicarbonate solution containing isolated precontracted strips of bovine coronary artery caused a rapid and pronounced, but transient, relaxant response that was antagonized by oxidized hemoproteins, such as methemoglobin, and by methylene blue. NO activated soluble guanylate cyclase prepared from coronary artery; this response was inhibited by methemoglobin, methylene blue, and ferricyanide. The observation that lipophilic methylene blue, but not the charged ferricyanide, antagonized vascular relaxant responses to NO suggested that NO interacts with intracellular smooth muscle receptors to cause relaxation. Moreover, the findings that nitroprusside and nitrosoguanidine, known to release NO in biological fluids," caused arterial relaxation that was antagonized by methylene blue but not by ferricyanide or methemoglobin were consistent with the view that intracellular NO is the reactive intermediate. Although the pharmacological implications of these original findings were clear, the physiological relevance of such observations for NO and cyclic GMP remained elusive for several years.