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.

Evidence for two different types of P2 receptors stimulating insulin secretion from pancreatic B cell.

Adenine nucleotides have been shown to stimulate insulin secretion by acting on P2 receptors of the P2Y type. Since there have been some discrepancies in the insulin response of different analogues of ATP and ADP, we investigated whether two different types of P2 receptors exist on pancreatic B cells. The effects of alpha,beta-methylene ATP, which is more specific for the P2X subtype, were studied in vitro in pancreatic islets and isolated perfused pancreas from rats, in comparison with the potent P2Y receptor agonist ADPbetaS.

Involvement of K+ channel permeability changes in the L-NAME and indomethacin resistant part of adenosine-5'-O-(2-thiodiphosphate)-induced relaxation of pancreatic vascular bed.

1. We have previously demonstrated that adenosine-5'-O-(2-thiodiphosphate) (ADPbetaS), a potent P2Y-purinoceptor agonist, relaxed pancreatic vasculature not only through prostacyclin (PGI2) and nitric oxide (NO) release from the endothelium but also through other mechanism(s). In this study, we investigated the effects of an inhibitor of the Na+/K+ pump, of ATP-sensitive K+ (K(ATP)) channels and of small (SK(Ca)) or large (BK(Ca)) conductance Ca2+-activated K+ channels.

Effects of homocysteine on acetylcholine- and adenosine-induced vasodilatation of pancreatic vascular bed in rats.

1. Epidemiological and experimental data have shown that homocysteine may provoke vascular lesions and that moderate homocysteinaemia may constitute an independent risk factor for vascular disease. It is now documented that homocysteine damages human endothelial cells in culture, possibly by producing hydrogen peroxide in an oxygen-dependent reaction.

Comparative effects of adenosine-5'-triphosphate and related analogues on insulin secretion from the rat pancreas.

Adenosine tri- and diphosphate (ATP and ADP) and their structural analogues stimulate insulin secretion from the isolated perfused rat pancreas, an effect mediated by P2Y-purinoceptor activation. Concerning the base moiety of the nucleotide, it was previously shown that purine but not pyrimidine nucleoside triphosphates were active and that substitution on purine C2 with the 2-methylthio group greatly enhanced the potency. In this study, we further analyze the consequences of ribose and polyphosphate chain modifications.

Study of the mechanisms involved in adenosine-5'-O-(2-thiodiphosphate) induced relaxation of rat thoracic aorta and pancreatic vascular bed.

1. The endothelium-dependent relaxation of blood vessels induced by P2Y-purinoceptor activation has often been shown to involve prostacyclin and/or nitric oxide (NO) release. In this work, we have investigated the mechanisms involved in the relaxant effect of the P2Y agonist, adenosine -5'-O-(2-thiodiphosphate) (ADP beta S) using two complementary preparations: rat pancreatic vascular bed and aortic ring.

Effect of n-hexacosanol on insulin secretion in the rat.

n-Hexacosanol, a long-chain saturated fatty alcohol extracted from Hygrophyla erecta Hochr., has been recently shown to exert neurotrophic properties on central neurons and to stimulate phagocytosis in macrophages. The present work was designed to investigate the effects of hexacosanol on stimulated insulin secretion in vivo and in vitro.

[Vasoconstrictor effect of uridine triphosphate on pancreatic vascular bed].

Purinoceptors have been classified according to their sensitivity to structural analogues of purines. In addition to the well established and widely distributed P2 purinoceptor subtypes (P2X and P2Y), the existence of "pyrimidine" or "nucleotide" receptors was proposed, which are sensitive to the pyrimidine nucleotide, uridine triphosphate (UTP). Recently, this class of receptor has been included in the P2 purinoceptor classification as a P2U subtype.

Purinergic receptors on insulin-secreting cells.

The insulin secreting B cell is fitted with the two types of purinergic receptors: P2 (for ATP and/or ADP) and P1 (for adenosine). The activation of P2 purinoceptors by ATP or ADP evokes a biphasic stimulation of insulin secretion from isolated perfused rat pancreas; this stimulation is dose-dependent between 10(-6) and 10(-4) M. Non hydrolysable structural analogues are also effective, and the relative potency of various agonists (2-methylthio ATP >> ATP = ADP = alpha, beta-methylene ATP >> AMP) gave evidence for a P2y purinoceptor subtype.

Prior glucose deprivation increases the first phase of glucose-induced insulin response: possible involvement of endogenous ATP and (or) ADP.

A possible implication of endogenously released ATP and (or) ADP in insulin response to glucose stimulation was investigated in the isolated rat pancreas. The first phase of insulin response to the same glucose concentration (8.3 mM) was much higher in pancreas previously perfused in the absence of glucose than in pancreas previously perfused with 4.

Stimulation of insulin secretion and improvement of glucose tolerance in rat and dog by the P2y-purinoceptor agonist, adenosine-5'-O-(2-thiodiphosphate).

1. In vivo effect of a P2y-purinoceptor agonist, adenosine-5'-O-(2-thiodiphosphate) (ADP beta S), on insulin secretion and glycaemia were studied both in rats and dogs. 2.

[Research of the mechanism of the inhibition of insulin secretion induced by a peripheral benzodiazepine: 4'-chlordiazepam].

We have previously shown that the selective peripheral-type benzodiazepine agonist 4'-chlordiazepam inhibited glucose-induced insulin secretion from rat pancreatic islets. The present work was designed to further investigate the mechanism of this effect. Since interactions have been described between benzodiazepines and purinergic modulators such as adenosine, we studied the effect of the adenosine receptor antagonist 8-phenyltheophylline.

P2y purinoceptor responses of beta cells and vascular bed are preserved in diabetic rat pancreas.

1. To investigate the effect of experimental diabetes on the P2y purinoceptor responses of pancreatic beta-cells and vascular bed, we used adenosine-5'-O-(2-thiodiphosphate) (ADP beta S), a potent and stable P2y agonist. This work was performed in the isolated perfused pancreas of the rat.

Dual regulation of pancreatic vascular tone by P2X and P2Y purinoceptor subtypes.

The effects of ATP on the pancreatic vascular bed of the rat were studied under resting tone. ATP exerted two different effects depending on the concentration used: a slight vasodilatation in the 1.65-49.

Adenosine-5'-O-(2-thiodiphosphate) is a potent agonist at P2 purinoceptors mediating insulin secretion from perfused rat pancreas.

1. The effects of a P2 purinoceptor agonist, adenosine 5'-O-(2-thiodiphosphate) (ADP-beta-S) have been studied on insulin secretion and flow rate of the isolated perfused pancreas of the rat. 2.

Inhibition by chlordiazepoxide of adenosine-stimulated glucagon secretion.

The action of a water soluble benzodiazepine, chlordiazepoxide (CDZ) on the stimulatory effect of adenosine on glucagon secretion from the isolated pancreas of the rat perfused in presence of 2.8 mM glucose was studied. CDZ 10(-7) and 10(-6) M had no effect per se on glucagon secretion under our experimental conditions.

Difference in the potentiating effect of adenosine triphosphate and alpha, beta-methylene ATP on the biphasic insulin response to glucose.

1. The effects of exogenous adenine nucleotides and structural analogues on the biphasic insulin response to an increase of glucose concentration in the physiological range (from 4.2 to 8.

Purinergic receptors involved in the stimulation of insulin and glucagon secretion.

The study of purinergic receptors in the endocrine pancreas is a recent field of investigations. Until recently, ATP has been considered only as an intracellular fuel by most authors. Nevertheless for some years evidence has been obtained that extracellular ATP and/or ADP could act on the B cell membrane to increase insulin secretion.

Evidence for two different P2-purinoceptors on beta cell and pancreatic vascular bed.

1 The effects of a 2-substituted analogue of adenosine 5'-triphosphate (ATP), 2-methylthioadenosine triphosphate (2-methylthio ATP) have been studied on insulin secretion and flow rate of the isolated pancreas of the rat, perfused in the presence of glucose (8.3 mM). 2 2-Methylthio ATP (16.