The importance of peptidergic nerve fibres for the regulation of whole pancreatic and islet blood flow was studied by administration of the neurotoxin capsaicin. Administration of capsaicin induces an acute release and depletion of mainly substance P and calcitonin gene-related peptide from sensory nerve fibres. When given repeatedly to adult rats for several days, the neuropeptides are irreversibly depleted from the nerve endings. Depletion of substance P was confirmed by immunohistochemical stainings in the present study. A bolus dose of capsaicin (4 micrograms/kg body weight) reduced both whole pancreatic and islet blood flow in anesthetized rats, whereas repeated treatment with capsaicin led to an increase in both pancreatic and islet blood flow. In vitro experiments on isolated islets exposed to capsaicin (0.25 and 2.5 microM) for 4 days showed no effect on beta-cell function. We conclude that peptidergic nerves have an important role for the maintenance of basal vascular tone in both the endocrine and exocrine parts of the pancreas, and may thereby influence the regulation of insulin secretion in rats.