The ability of a new hypoglycaemic agent, A-4166, compared to sulphonylureas, to increase cytosolic Ca2+ in pancreatic beta-cells under metabolic inhibition

Br J Pharmacol. 1997 Apr;120(7):1191-8. doi: 10.1038/sj.bjp.0701017.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Cyclohexanes / pharmacology*
  • Cytosol / drug effects*
  • Cytosol / metabolism
  • Electron Transport / drug effects
  • Enzyme Inhibitors / pharmacology
  • Gliclazide / pharmacology
  • Glucokinase / antagonists & inhibitors
  • Glucose / pharmacology
  • Hypoglycemic Agents / pharmacology*
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Nateglinide
  • Oxidative Phosphorylation
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / pharmacology
  • Rats
  • Rats, Wistar
  • Sulfonylurea Compounds / pharmacology*
  • Tolbutamide / pharmacology

Substances

  • Cyclohexanes
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Sulfonylurea Compounds
  • Nateglinide
  • Phenylalanine
  • Tolbutamide
  • Glucokinase
  • Gliclazide
  • Glucose
  • Calcium