To study the regulation of islet hormone secretion in exercise-stress, we developed a swimming mouse model. Mice swam for 2, 6, or 10 minutes whereafter blood was sampled for analysis of plasma levels of insulin, glucagon, and glucose. Plasma insulin levels, which were not different from resting controls after 2 or 6 minutes of swimming, were slightly lower after 10 minutes of swimming (P < .05). Plasma glucagon levels were increased after 2, 6, and 10 minutes of swimming (P < .001), and plasma glucose levels were lower after 6 and 10 minutes of swimming (P < .05). Glucose (5.6 mmol/kg)-stimulated insulin secretion was inhibited by 52% ± 9% by the swimming (P < .001). The mechanisms behind this inhibition of glucose-stimulated insulin secretion and the increase in basal plasma glucagon levels induced during 2 minutes of swimming were investigated by the use of autonomic receptor antagonists, administered intraperitoneally 20 minutes before the swimming period. The ganglionic antagonist hexamethonium (56 μmol/kg) prevented the swimming-induced inhibition of glucose-stimulated insulin secretion, indicating involvement of nerves in the inhibition. Also the nonselective α-adrenoceptor antagonist phentolamine (6.0 μmol/kg) and the α₂-adrenoceptor antagonist yohimbine (3.6 μmol/kg) prevented the inhibition of glucose-stimulated insulin secretion induced by swimming, whereas the β-adrenoceptor antagonist l-propranolol (9.6 μmol/kg) had no effect. The swimming-induced increase in plasma glucagon levels was partially inhibited by hexamethonium (by 58% ± 24%, P < .05). Phentolamine and yohimbine totally prevented the increase in plasma glucagon levels, whereas l-propranolol had no effect. In one experimental series, mice were pretreated with both yohimbine and l-propranolol. This combination of antagonists caused the plasma insulin levels to be higher in swimming mice than in resting controls (P < .05). However, the swimming-induced increase in plasma glucagon levels was not affected. We conclude that a short swimming period in the mouse inhibits glucose-stimulated insulin secretion and elevates basal plasma glucagon levels, and that these responses seem to involve mediation by nerves and are reversed by the α₂-adrenoceptor antagonist yohimbine.