Two chemically unrelated inhibitors of lipolysis were used in order to differentiate between the effect of FFA depression and a possible FFA-unrelated drug effect, respectively, on the plasma concentrations of GH, cortisol, and glucagon. Saline infusion served as a control experiment. In eight healthy male volunteers, a similar FFA depression by either iv infusion of nicotinic acid (3-pyridine-carboxylic acid, NA) or oral intake of an adenosine derivative, N(6)-allyl-N(6)-cyclohexyl-adenosine (AD-D), was followed by a significant GH increase (to 22.1 +/- 6.2 and 9.6 +/- 2.9 ng/ml at 240 and 270 min, respectively). Due to the large scatter of the GH concentrations during NA infusion, these responses were not significantly different. No GH increase occurred when the FFA depression was prevented by addition of a lipid infusion. In contrast, plasma cortisol and glucagon both increased significantly (by 107.4 micrograms/liter at 270 min and by 48.4 pg/ml at 60 min, respectively) during NA- but not during AD-D-induced FFA depression. Addition of the lipid infusion abolished the cortisol increase during NA infusion but had no influence on basal cortisol concentrations during AD-D intake. It lowered glucagon to values slightly below basal concentrations when added to the NA infusion and more markedly during AD-D administration. The results provide evidence that 1) depression of plasma FFA per se stimulates the secretion of GH, and 2) the increase of cortisol and glucagon during NA infusion is probably unrelated to the FFA depression. Hence, the stimulatory effect of FFA lack on glucagon secretion needs to be reconsidered.