Physiological, metabolic, neuroendocrine and pharmacological regulation of nitric oxide in humans.

Genetically controlled nitric oxide production is currently assessed mainly by the colorimetric determination of the plasma levels of nitrite/nitrates, specific end-products of NO, or by the magnitude of the vasorelaxation obtained with forearm occlusion venous plethysmography after infusion of stimulating (acetylcholine) or inhibiting (N-monomethyl-arginine) substances. NO levels decrease in the elderly compared to young people and more in men than in women. Many shear stresses (physical exercise, cold pressor test, mental test) increase NO production; in these circumstances NO inhibits platelet aggregation and endothelial adhesivity: among endogenous metabolic factors mainly LDL impairs endothelium dependent vasodilation through an altered synthesis of NO, whereas triglycerides seem to have no influence; oxidized LDL may stimulate NO-production to counteract its damaging effects on endothelial cells. The hypothesis whereby an early production of NO is followed by a drop due to a prolonged cell injury is still controversial. Lipid lowering agents (drugs, apheresis) improve endothelial function. Some endogenous vasoactive substances, (acetylcholine, adenosine, bradykinin, and arginine) stimulate NO production, whereas others, such as angiotensin II, histamine, aspirin, indomethacin have inhibitory effects. As regards drugs glyceriltrinitrate and isosorbide dinitrate, acting as NO donors, improve endothelial function; other drugs are current being studied in this sense.