To determine whether the islet-acinar relationship is mediated microvascularly or by diffusion from islets, isolated dog pancreata were perfused anterogradely (n = 4) or retrogradely (n = 5). Interstitial fluid (ISF) was sampled utilizing a microdialysis technique. Three to five microdialysis probes were placed in the dorsal lobe of each pancreas. Insulin and somatostatin were measured in dialysate, as well as in perfusate, under both resting (5.6 mM glucose) and stimulated (12.2 mM glucose plus 20 mM arginine) conditions. During the stimulative period, retrograde ISF responses were markedly less than anterograde responses, whereas perfusate (intravascular) anterograde and retrograde responses were not different; ratios of the sum of increments above basal levels of ISF concentrations to the sum of increments of perfusate concentrations (sigma delta ISF/sigma delta perfusate) of insulin and somatostatin during anterograde vs. retrograde perfusion were 35.1 +/- 8.8 (SE; n = 9) vs. 13.8 +/- 2.8% (n = 10) and 37.1 +/- 14.2 (n = 7) vs. 8.5 +/- 4.2% (n = 9), respectively (both, P < 0.05). These data strongly suggest that these islet hormones may be delivered to the exocrine interstitial space via a directed microcirculation from the islet to the acinar tissue.