Chronic Exposure to Exogenous Nitric Oxide May Suppress Its Endogenous Release and Efficacy

Summary: The aim of the study was to investigate the effects of semichronic treatment with molsidomine, an exogenous nitric oxide (NO) donor, on the biosynthesis of and the responses to this gas in large arteries. For this purpose, groups of 10 rabbits were fed either a control diet or a diet containing 200 ppm of molsidomine. Sixteen weeks later, rings of the isolated aorta of the latter rabbits appeared to be less sensitive to the dilating effects of acetylcholine, SIN-1, and NO. As complete relaxation was still attained with SIN-1, and as the shift for NO was of a similar magnitude, part of the attenuation is explained by a diminished sensitivity of the smooth muscle cells to NO, rather than a suppression of the release of NO from SIN-1. In addition, the biosynthesis of NO in segments treated with exogenous NO was depressed, as indicated by bioassay of the NO released upon stimulation of the endothelial cells with acetylcholine. These results indicate that exposure to large quantities of NO may lead to downregulation of the endogenous biosynthesis in the generator cells and a diminished responsiveness of the effector cells.