The ability of a new hypoglycaemic agent, A-4166, compared to sulphonylureas, to increase cytosolic Ca2+ in pancreatic beta-cells under metabolic inhibition.
1. N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166) is a new non-sulphonylurea oral hypoglycaemic agent which stimulates insulin release by increasing cytosolic Ca2+ concentration ([Ca2+]i) in beta-cells. 2. We studied comparative effects of A-4166 and sulphonylureas on [Ca2+]i, measured by dual-wavelength fura-2 microfluorometry, in single rat pancreatic beta-cells under normal conditions and conditions where glucose metabolism was inhibited. 3. A glucokinase inhibitor, mannoheptulose (10 mM), a mitochondrial respiratory inhibitor, KCN (100 microM), and uncouplers, dinitrophenol (DNP, 50 microM) and carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP, 0.3 microM), were used to abolish glucose-induced increases in [Ca2+]i in a reversible manner. 4. Under control conditions, A-4166 was one order more potent than tolbutamide in increasing [Ca2+]i, and maximal responses were evoked by 30 microM A-4166 and 300 microM tolbutamide. These equipotent concentrations were employed for the comparative study where glucose metabolism was inhibited. 5. In the presence of mannoheptulose, [Ca2+]i responses to tolbutamide, but not those to A-4166, were attenuated in a reversible manner. 6. KCN, DNP and FCCP inhibited [Ca2+]i responses to tolbutamide to a much greater extent than those to A-4166. Responses to tolbutamide even at 3.3 times the equipotent concentration (1000 microM) were also markedly attenuated by these inhibitors. Responses evoked by another sulphonylurea, gliclazide, were inhibited by DNP to a larger extent than A-4166-induced responses. 7. The results indicate that A-4166 acts more effectively than sulphonylureas to increase [Ca2+]i in beta-cells during metabolic inhibition.
Fujitani
S
S
Department of Physiology, Kagoshima University School of Medicine, Japan.
Okazaki
K
K
Yada
T
T
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003510:Cyclohexanes / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects* / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005907:Gliclazide / Q000494:pharmacology; D005941:Glucokinase / Q000037:antagonists & inhibitors; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000077715:Nateglinide; D010085:Oxidative Phosphorylation; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014044:Tolbutamide / Q000494:pharmacology
D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D000077715:Nateglinide; D010649:Phenylalanine; D014044:Tolbutamide; D005941:Glucokinase; D005907:Gliclazide; D005947:Glucose; D002118:Calcium