AbstractThe possible relevance of changes in extracellular and/or intracellular pH to the insulinotropic action ofL‐arginine andL‐homoarginine was investigated in rat pancreatic islets. A rise in extracellular pH from 7·0 to 7·4 and 7·8 augmented the secretory response to these cationic amino acids whilst failing to affect the uptake ofL‐arginine by islet cells and whilst decreasing the release of insulin evoked byD‐glucose. Under these conditions, a qualified dissociation was also observed between secretory data and45Ca net uptake. Moreover, at high extracellular pH, the homoarginine‐induced increase in86Rb outflow from prelabelled islets rapidly faded out, despite sustained stimulation of insulin release. The cationic amino acids failed to affect the intracellular pH of islet cells, whether in the absence or presence ofD‐glucose and whether at normal or abnormal extracellular pH. These findings argue against the view that the secretory response toL‐arginine would be related to either a change in cytosolic pH or the accumulation of this positively charged amino acid in the β‐cell. Nevertheless, they suggest that the yet unidentified target forL‐arginine and its non‐metabolized analogue in islet cells displays pH‐dependency with optimal resp