Calcitonin gene-related peptide (CGRP) is an intrapancreatic neuropeptide with potential effects on islet hormone secretion. To investigate its pancreatic actions, we examined the effects of a 10 min perfusion of synthetic human CGRP on islet hormone release from the isolated dog pancreas (n = 6) at 5.5 mM glucose. At 0.1 nM, CGRP inhibited insulin secretion (P less than 0.01), which was already observed at 2 min after its introduction. After CGRP perfusion was stopped, a stimulatory off-response occurred. In contrast, at higher dose levels, CGRP stimulated insulin secretion. At 1.0 nM, the stimulation was weak and transient (P less than 0.01), occurring only during the first 3 min of CGRP perfusion. At 10 nM, the stimulation continued for 6 min (P less than 0.05), and at 50 nM, the stimulation was marked and sustained throughout the 10 min perfusion period (P less than 0.01). After the CGRP perfusion at 1.0 and 10 nM, but not at 50 nM, a marked stimulatory off-response in insulin secretion was seen. Glucagon and somatostatin secretion were not significantly affected by CGRP at any of the examined concentrations. We conclude that CGRP exerts dual effects on insulin secretion from the perfused dog pancreas: inhibition at low concentrations and stimulation at high concentrations. This pattern of effect might represent a new regulatory concept for neural influences on islet function: the qualitative response being determined by the amount of neurotransmitter released.