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 microM 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 [125I]-CCK-8 or 0.5 nM [3H]-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 Ca(2+)-transport function of the plasma membrane or the membrane of intracellular organella, especially Ca(2+)-sequestering pools, cannot be excluded.
Habara
Y
Y
Department of Molecular Physiology, National Institute for Physiological Sciences, Okazaki, Japan.
Kanno
T
T
D000681:Amylases / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002724:Chlorobutanol / Q000494:pharmacology*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D019832:N-Methylscopolamine; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010276:Parasympatholytics / Q000493:pharmacokinetics; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000493:pharmacokinetics; D015398:Signal Transduction / Q000187:drug effects; D012844:Sincalide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012969:Sodium Fluoride / Q000494:pharmacology
D010276:Parasympatholytics; D011949:Receptors, Cholecystokinin; D012602:Scopolamine Derivatives; D002217:Carbachol; D012969:Sodium Fluoride; D000681:Amylases; D002724:Chlorobutanol; D012844:Sincalide; D002118:Calcium; D019832:N-Methylscopolamine