MECHANISM BY WHICH CYPROHEPTADINE INHIBITS INSULIN SECRETION

Abstract

1 Isolated islets of Langerhans from the rat have been used in studies designed to elucidate the mechanism by which cyproheptadine inhibits insulin secretion. 2 d-Glucose and tolbutamide, both of which require extracellular Ca²⁺ to produce insulin release, failed to evoke a secretory response from islets pretreated with cyproheptadine. Conversely veratridine, the calcium ionophore A23187 and theophylline, all of which are capable of mobilizing sufficient intracellular Ca²⁺ to evoke insulin secretion in the absence of extracellular Ca²⁺, produced similar responses from cyproheptadine pretreated and control islets. 3 Cyproheptadine completely inhibited Ca²⁺ uptake induced by d-glucose and high K⁺_o, two agents which depolarize the islet β-cell membrane, whilst Ca²⁺ uptake elicited by removal of extracellular Na⁺ (i.e. Na⁺-Ca²⁺ counter transport) was only slightly reduced. 4 A significant increase in Na⁺ uptake produced by veratridine was sensitive to tetrodoxin but only partially reduced by cyproheptadine. 5 These results suggest that cyproheptadine inhibits depolarization-dependent calcium entry into pancreatic β-cells.