Inhibition of glucose-induced insulin secretion by a peripheral-type benzodiazepine receptor ligand (PK11195).

We have recently shown that benzodiazepines with high affinity for peripheral-type receptors such as 4'-chlordiazepam inhibit insulin secretion in vitro. PK 11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxami de], a potent and selective ligand for peripheral benzodiazepine binding sites, was also shown to inhibit insulin release from rat pancreatic islets. Both substances have been reported to interact with mitochondrial binding sites.

2-Thioether-5'-O-(1-thiotriphosphate)-adenosine derivatives: new insulin secretagogues acting through P2Y-receptors.

P2-receptors (P2-Rs) represent significant targets for novel drug development. P2-Rs were identified also on pancreatic B cells and are involved in insulin secretion. The aim of our study was to synthesize and evaluate pharmacologically the novel P2Y-R ligands, 2-thioether-5'-O-phosphorothioate adenosine derivatives, as potential insulin secretagogues.

[Involvement of P2X and P2U receptors in the constrictor effect of ATP on the pancreatic vascular bed].

The effects of ATP on the pancreatic vascular bed were studied on the isolated rat pancreas perfused at a constant pressure so as any change in the vascular tone induces a modification in the flow rate. This study was performed in two different experimental conditions: 1) In the presence of indomethacin, inhibiting the cyclo-oxygenase and prostacyclin (PGI2) synthesis, ATP (which acts on vasodilatator P2Y receptors and vasoconstrictor P2X and P2U receptors) was used at a concentration (165 microM) which did not modify per se the vascular flow rate. With indomethacin, ATP induced a slight but significant and long lasting decrease in the flow rate.

Contrasting effects of streptozotocin-induced diabetes on the in vitro relaxant properties of adenosine in rat pancreatic vascular bed and thoracic aorta.

In the present work, we have studied adenosine-induced vasodilation in streptozotocin-induced diabetic rats and compared it to that observed in normal age-matched or weight-matched animals. Experiments were performed on a vascular bed, the isolated perfused pancreas, and a large vessel, the thoracic aorta, provided from the same animal. Vasodilator activity was assessed, for isolated pancreas, as the increase in flow induced by the infusion of 2 microM adenosine for 30 min, or for noradrenaline-contracted aortae, as the relaxant response to adenosine (1 microM-1 mM).

2-thioether 5'-O-(1-thiotriphosphate)adenosine derivatives as new insulin secretagogues acting through P2Y-Receptors.

P2-Receptors (P2-Rs) represent significant targets for novel drug development. P2-Rs were identified also on pancreatic B cells and are involved in insulin secretion. Therefore, novel P2Y-R ligands, 2-thioether 5'-O-phosphorothioate adenosine derivatives (2-RS-ATP-alpha-S), were synthesized as potential insulin secretagogues.