Tricyclic antidepressant imipramine reduces the insulin secretory rate in islet cells of Wistar albino rats through a calcium antagonistic action

Aims/hypothesis. Treatments with antidepressants have been associated with modifications in glucose homeostasis. The aim of this study was to assess the effect of imipramine, a tricyclic antidepressant, on insulin-secreting cells. Methods. Insulin radioimmunoassay, radioisotopic, fluorimetric and patch-clamp methods were used to characterise the effects of imipramine on ionic and secretory events in pancreatic islet cells from Wistar albino rats. Results. Imipramine induced a dose-dependent decrease in glucose-stimulated insulin output (IC50=5.2 mumol/l). It also provoked a concentration-dependent reduction in Ca-45 outflow from islets perifused in the presence of 16.7 mmol/l glucose. Moreover, imipramine inhibited the increase in Ca-45 outflow mediated by K+ depolarisation. Patch-clamp recordings further revealed that imipramine provoked a marked and reversible decrease of the inward Ca2+ current. In single islet cells, imipramine counteracted the rise in [Ca2+](i) evoked by glucose or high K+ concentrations. Conclusions/interpretation. These data indicate that imipramine dose-dependently reduces the insulin secretory rate from rat pancreatic beta cells. Such an effect appears to be mediated by the inhibition of voltage-sensitive Ca2+ channels with subsequent reduction in Ca2+ entry. Thus, it is possible that some adverse effects of imipramine are related, at least in part, to its capacity to behave as a Ca2+ entry blocker.