Both increase of the glucose concentration and activation of purinoceptors are known to affect pancreatic alpha-cells. Effects obtained with various purino derivatives at 2.8 and 8.3 mmol/liter glucose have been taken to indicate that external ATP is less potent than adenosine as a stimulator of glucagon release. However, when making a corresponding comparison at 20 mmol/liter glucose, we observed marked stimulation of glucagon release from isolated rat islets with 100 micromol/liter adenosine-5-O-2-thiodiphosphate but inhibition with 10 micromol/liter adenosine. Analyses of 30-sec samples of perfusate from rat pancreas indicated that a rise of the glucose concentration from 3 to 20 mmol/liter rapidly induces a glucagon peak followed by regular 4- to 5-min pulses. The glucagon pulses preceded those of insulin with a phase shift (1.8 +/- 0.1 min) near half the interpeak interval. Because of the antisynchrony, the maximal glucagon effect on liver cells will be manifested during periods with low concentrations of insulin. In support for the idea that neural P2Y(1) receptors are important for coordinating the secretory activity of the islets, both the insulin and glucagon pulses disappeared in the presence of the purinoceptor inhibitor MRS 2179 (10 micromol/liter). However, in contrast to what was observed for insulin, MRS 2179 lowered average glucagon release to the level of the oscillatory nadirs.