We studied the effects of the l-arginine analogue NG-nitro-l-arginine (l-NNA), in comparison with its d-isomer (d-NNA), on endothelium-dependent dilations of rabbit femoral arteries (RFA) and on the release of endothelium-derived relaxant factor (EDRF) from native and cultured endothelial cells. In addition, we examined the effects of l- and d-NNA on the l-arginine- and NADPH-dependent synthesis of nitric oxide (NO) in the cytosol of porcine aortic endothelial cells. l-NNA enhanced the noradrenaline-induced contraction of endothelium-intact, but not of endothelium-denuded segments of RFA, indicating an inhibition of basal EDRF release. l-NNA also inhibited significantly the endothelium-dependent dilations to acetylcholine (ACh). Both effects of l-NNA were attenuated by l-arginine. l-NNA rapidly inhibited the release of EDRF from cultured and native endothelial cells stimulated with thimerosal or ACh. l-NNA concentration-dependently and reversibly antagonized the l-arginine- and NADPH-dependent activation of a purified soluble guanylate cyclase (GC) by cytosol from.Sreshly harvested porcine aortic endothelial cells, suggesting a direct competition between l-NNA a l-arginine at the level of endothelial NO-synthesis. d-NNA was ineffective in all instances. These results prove l-NNA to be a stereospecific inhibitor of the cytosolic NO formation from l-arginine in endothelial cells. Therefore, l-NNA will be a useful tool to elucidate the molecular mechanism of mammalian NO synthesis.
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Miilsch, A., Busse, R. NG-nitro-L-arginine (N5-[imino(nitroamino)methyl]-L-ornithine) impairs endothelium-dependent dilations by inhibiting cytosolic nitric oxide synthesis from l-arginine. Naunyn-Schmiedeberg's Arch Pharmacol 341, 143–147 (1990). https://doi.org/10.1007/BF00195071
- Nitric oxide
- Endothelial cytosol
- Soluble guanylate cyclase