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A series of substituted benzylnitrates (1) and the formally but not chemically similar cyclohexylmethylnitrate (CHMN) have been synthesised. Vasodilating activities were measured on endothelium-intact and N(G)-nitro-L-arginine (L-NNA)-blocked porcine right coronary arteries, precontracted with prostaglandin F(2alpha) (PGF(2alpha)). Glyceroltrinitrate (GTN) was used as reference. In intact coronary arteries the vasodilating activities of all benzylnitrates are lower compared with GTN, but higher compared with CHMN. However, blocking the function of the endothelium by L-NNA, the activity of all benzylnitrates increased, whereas that of CHMN and GTN remained nearly unaffected. Under these conditions, the mononitrates 4-nitro-benzylnitrate (1c) and 4-nitrooxymethyl-benzonitrile (1h) even showed higher vasodilator activities than the trinitrate GTN and in general, vasorelaxation by the benzylnitrates as defined by the concentrations for half maximal effects (EC(50) values) was found to be 2-3 orders of magnitude higher than that induced by CHMN. The study demonstrates that the in vitro activities of organic nitrates do not correlate with the number of nitrate groups within the molecule nor to the lipophilicity of the molecules. Instead, vasodilator activity is highly sensitive to the structure and the type of the substituents in the molecular carrier of the nitrate group.