DUAL EFFECTS OF CHLOROBUTANOL ON SECRETORY RESPONSE AND INTRACELLULAR CA2+ DYNAMICS IN ISOLATED PANCREATIC ACINI OF THE RAT

1 The effects of chlorobutanol, a widely used drug preservative, on exocrine response and intracellular Ca2+ dynamics were examined in isolated pancreatic acini of the rat. 2 Chlorobutanol (1 mg ml-1) markedly inhibited the secretory response to cholecystokinin octapeptide (CCK-8), carbamylcholine chloride (carbachol), or sodium fluoride, a direct G-protein activator. However, chlorobutanol itself induced a maximal release of amylase when the dose was increased to 4 mg ml-1. 3 An oscillatory fluctuation of cytoplasmic Ca2+ concentration, [Ca2+]c, induced by 5 pm CCK-8 or 0.3 mum carbachol was totally abolished in the presence of 1 mg ml-1 chlorobutanol. 4 A biphasic change in [Ca2+]c induced by 100 pm CCK-8, a rapid rise followed by a gradual decay, was transformed to an oscillatory fluctuation by the preservative. 5 Chlorobutanol inhibited 13 pm [I-125]-CCK-8 or 0.5 nm [H-3]-methylscopolamine chloride binding to the acinar cells in a dose-dependent manner. 6 These results indicate that chlorobutanol produces discernible pharmacological effects on the secretory response in rat pancreatic acinar cells through changes in the Ca2+ dynamics. Possible sites of action could be at a binding process of secretagogues to their receptors, at an activation process of a G-protein located in the plasma membrane, or at the processes following G-protein activation. However, the possibility that the preservative may distort the Ca2+-transport function of the plasma membrane or the membrane of intracellular organella, especially Ca2+-sequestering pools, cannot be excluded.