Potentiating synergism between adenosine diphosphate or triphosphate and acetylcholine on insulin secretion

The interaction between adenosine di- or triphosphate (ADP or ATP) and acetylcholine (ACh) was studied on insulin secretion. The experiments were performed on the isolated perfused rat pancreas, in the presence of a physiological nonstimulating glucose concentration (5.5 mM). ADP or ATP (1.65 microM) and ACh (0.05 microM) elicited a comparable peak of insulin secretion. When either ATP or ADP was simultaneously infused with ACh, insulin secretory response was significantly higher than the sum of the responses of each agonist applied separately. Similar effects were obtained with stable structural analogues of ATP and ADP (adenylimidodiphosphate, AMP-PNP, and alpha, beta-methyleneadenosine 5'-diphosphate, alpha, beta-methylene ADP) whether they acted alone or in combination with ACh. In contrast, adenosine was ineffective. Furthermore, the study of combined half doses of ATP (or ADP) and ACh allowed us to establish a potentiating synergism between both agonists. These data indicate a potentiating synergism on the beta-cell between ACh and ATP or ADP, the substances acting, respectively, via muscarinic cholinergic receptors and purinergic P2 receptors. So, ATP and ADP by activating P2 receptors could be involved in the parasympathetic control of insulin secretion.