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I Angel

Publications and source records attributed to I Angel.

At least 37 records · Page 2Linked to original sources
PubMed1995

Alpha 2-adrenoceptors and the regulation of glucose, insulin and amylin levels in diabetic rats.

The effects of the selective alpha 2-adrenoceptor agonist UK 14.304 on glucose, insulin and amylin levels were examined in neonatal streptozotocin-induced diabetic rats. UK 14.304 (0.03 to 0.3 mg/kg i.p.) induced a dose-dependent reduction of both insulin and amylin levels in normal rats while UK 14.304 at 0.03 mg/kg had already a maximal effect in diabetic rats. Amylin/insulin molar ratios rose after UK 14.304 administration in diabetic rats but remainded constant in normal rats. The alpha 2-adrenoceptor antagonist deriglidole (3 mg/kg i.p.) slightly increased insulin and amylin levels in the two groups of rats but glucose levels were more markedly decreased in diabetic rats. Deriglidole completely antagonized UK 14.304 (0.1 mg/kg i.p.)-induced changes thereby normalizing amylin/insulin molar ratios in diabetic rats. These results suggest that insulin and amylin are both under inhibitory control via alpha 2-adrenoceptor though the responses may be differentially regulated. It is further suggested that diabetes in the neonatal streptozotocin-induced rat model is associated with a hypersensitivity of the pancreas to alpha 2-adrenoceptor stimulation.

Amyloid↗
PubMed1995

Effects of alfuzosin on urethral and blood pressures in conscious male rats.

This study was undertaken to determine simultaneously the effects of alfuzosin on urethral and blood pressures in the same conscious male rat. Alfuzosin (i.v., 3, 10 and 30 micrograms/kg) dose-dependently decreased urethral pressure without affecting mean arterial blood pressure. At the higher dose, blood pressure was only slightly and transiently decreased while a marked decrease (-40%) in urethral pressure was observed. Therefore, this experimental model is suitable to assess uroselectivity.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1995

Involvement of alpha 2-adrenoceptors in metabolic and hormonal responses to a mixed meal in beagle dogs.

The effects of alpha 2-adrenoceptor blockade or activation on glucose, insulin, free fatty acids (FFA), and glycerol responses to a mixed meal were studied in the beagle dog. The alpha 2-adrenoceptor antagonist deriglidole (1 mg/kg po), administered 45 min before feeding, significantly reduced glycemia and increased insulin, FFA, and glycerol levels. Although the alpha 2-adrenoceptor agonist UK-14.304 (3 micrograms/kg sc), administered 15 min before feeding, had no effect per se, it completely blocked meal-induced insulin release, thus promoting a mild increase in glycemia, and prolonged the meal-induced FFA decrease. Deriglidole antagonized the reduction of insulin secretion and the hyperglycemia induced by UK-14.304. The meal-induced fall in FFA levels was still observed after deriglidole treatment and was markedly amplified when UK-14.304 was administered with deriglidole. These results suggest that, in the dog, insulin release and lipolysis are very sensitive to alpha 2-adrenoceptor stimulation. It is also suggested that the meal-evoked decrease in lipid mobilization results from an increase in alpha 2-adrenoceptor stimulation rather than from an increase in insulin secretion.

Adrenergic alpha-Agonists↗
PubMed1994

The imidazoline SL 84.0418 shows stereoselectivity in blocking alpha 2-adrenoceptors but not ATP-sensitive K+ channels in pancreatic B-cells.

The novel alpha 2-adrenoceptor antagonist SL 84.0418 (2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydro-2-propyl-pyrrolo[3, 2,1- hi]-indole hydrochloride) is a racemic mixture of a (-) enantiomer (SL 86.0714) and a (+) enantiomer (SL 86.0715 or deriglidole). It was recently reported to inhibit alpha 2-adrenoceptors and ATP-sensitive K+ channels in mouse pancreatic B-cells, and to increase insulin release. We have now studied the stereospecificity of these responses with isolated mouse islets. Both enantiomers were equipotent in potentiating insulin release induced by 15 mM glucose alone. SL 86.0714 and deriglidole were also equally effective in inhibiting 86Rb efflux from islets perifused with a low-glucose medium, and in reversing the inhibition of glucose-induced insulin release caused by the opening of ATP-sensitive K+ channels with diazoxide. In contrast, deriglidole was approximately 100-fold more potent than SL 86.0714 in reversing the inhibition of insulin release caused by the activation of alpha 2-adrenoceptors with clonidine. The effects of SL 84.0418 are thus stereoselective on alpha 2-adrenoceptors, but not on ATP-sensitive K+ channels of pancreatic B-cells.

Adenosine Triphosphate↗
PubMed1994

In vitro stimulation of insulin release by SL 84.0418, a new alpha 2-adrenoceptor antagonist.

SL 84.0418 (2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydro-2-propyl-pyrrolo[3, 2,1- hi]-indole hydrocholoride) is a novel alpha 2-adrenoceptor antagonist which possesses anti-hyperglycaemic properties in vitro study, we tested its effects on insulin release from isolated mouse islets. In the presence of 15 mM glucose, SL 84.0418 produced a concentration-dependent (0.1-100 microM) increase of insulin release with a slightly higher potency than tolbutamide. SL 84.0418 antagonized the inhibition of glucose-induced insulin release caused either by the alpha 2-adrenoceptor agonist clonidine or by diazoxide, a selective opener of ATP-sensitive K+ channels in the beta-cell membrane. Its potency was greater on the inhibition by clonidine than on that by diazoxide, complete antagonism of the inhibition being achieved by 0.9 microM and 6 microM SL 84.0418 respectively. When alpha 2-adrenoceptors were blocked by the antagonist idazoxan, the low concentrations of SL 84.0418 (0.1-0.3 microM) no longer increased insulin release, whereas the effect of higher concentrations (> or = 1 microM) was not affected. SL 84.0418 (> or = 1 microM) inhibited 86Rb efflux from islets perifused with a medium containing 3 mM glucose, i.e. under conditions where many ATP-sensitive K+ channels are open. It also reduced the acceleration of 86Rb efflux that diazoxide caused in the presence of 6 mM glucose. Moreover, SL 84.0418 directly inhibited ATP-sensitive K+ currents measured in single beta-cells by the whole-cell mode of the patch-clamp technique.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1993

In vivo pharmacological profile of SL 84.0418, a new selective, peripherally active alpha 2-adrenoceptor antagonist.

SL 84.0418 is a novel pyrrolo-indole derivative with potent and selective alpha 2-adrenoceptor antagonist activity in vitro and anti-hyperglycemic properties in vivo. In the present study we demonstrated that SL 84.0418 and its active (+) enantiomer, SL 86.0715, show a high degree of selectivity for alpha 2-adrenoceptors in vivo, preferentially blocking alpha 2-adrenoceptors in the periphery. While having no effects on basal blood pressure and heart rate, p.o. (3 and 10 mg/kg) or i.v. (0.3 mg/kg) administered SL 84.0418 or SL 86.0715 antagonized the hypertensive responses mediated by postsynaptic vascular alpha 2-adrenoceptors after the administration of UK 14304 or norepinephrine to pithed rats. The (-) enantiomer of SL 84.0418, SL 86.0714, was devoid of alpha 2-adrenoceptor antagonist properties in vivo, while the (+) enantiomer of SL 84.0418, SL 86.0715, showed alpha 2-adrenoceptor antagonist activity similar to that of the racemate. SL 84.0418 (3 mg/kg p.o.) did not modify the centrally mediated hypotensive and bradycardic effects of i.c.v. administered clonidine. Furthermore, in the mouse, SL 84.0418 potently antagonized the hyperglycemic responses to epinephrine or UK 14304, which are mediated by peripheral alpha 2-adrenoceptors, but failed (in doses up to 30 mg/kg i.p.) to antagonize the clonidine-induced hypolocomotion, which is mediated by central alpha 2-adrenoceptors. These results suggest that SL 84.0418 preferentially antagonizes peripheral alpha 2-adrenoceptors. SL 84.0418 administered to pithed rats (3 mg/kg p.o. or 0.3 mg/kg i.v.) did not modify the vasoconstriction induced by cirazoline (effect mediated by alpha 1-adrenoceptors) nor the tachycardia induced by norepinephrine (effect mediated by beta-adrenoceptors).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1993

Litoxetine: a selective 5-HT uptake inhibitor with concomitant 5-HT3 receptor antagonist and antiemetic properties.

The selective 5HT uptake inhibitor, litoxetine (SL 81.0385), currently under development as an antidepressant was shown to have antiemetic properties in the ferret. Litoxetine (at 1 and 10 mg/kg i.v.) dose dependently reduced the number of retches and vomiting as well as the number of emetic episodes induced by cisplatin (10 mg/kg i.v.) and delayed the onset of emesis. Fluoxetine (at 1 or 10 mg/kg i.v.) failed to inhibit cisplatin-induced emetic responses and, in contrast, significantly increased the number of retches and vomiting and accelerated the onset of emesis. The possibility that the antiemetic effects of litoxetine may be mediated through an interaction with 5HT3 receptors was studied using [3H]quipazine or [3H]BRL 43694 to label the 5HT3 receptor. Litoxetine has moderate affinity for cerebral 5HT3 receptors (Ki = 85 nM), while fluoxetine, similar to other 5HT uptake inhibitors, has only negligible affinity for this receptor (Ki = 6.5 microM). It is proposed that litoxetine inhibits cisplatin-induced emetic responses due to its moderate 5HT3 antagonist properties. The clinical use of the majority of serotonergic antidepressants (e.g. fluoxetine, fluvoxamine etc.) is associated with gastrointestinal discomfort (particularly nausea and vomiting) as a major side-effect. If nausea and vomiting associated with the use of 5 HT uptake inhibitors are due to stimulation of 5HT3 receptors, the concomitant 5HT3 antagonism of litoxetine may limit the gastrointestinal side-effects of this novel antidepressant and thus offer an important advantage.

Animals↗
PubMed1993

Inhibition of insulin release induced by galanin in the dog is not exclusively mediated by activation of ATP-sensitive K+ channels.

Exogenous galanin (9 pmol/min during 20 min i.a.) decreased insulin levels in the plasma sampled from the pancreatic vein of the blood-perfused pancreas of dogs in which ganglionic transmission and beta-adrenoceptors had been blocked. This effect was not modified by idazoxan (1 mg/kg followed by 0.02 mg/kg/min i.v.) but was partially reduced (50%) by glibenclamide (1 mg/kg followed by 0.02 mg/kg/min i.v.). This dose of glibenclamide blocked entirely the hypoinsulinemic activity of diazoxide, an activator of pancreatic ATP-modulated K+ channels, whereas the dose of idazoxan prevented the effect of the alpha 2-adrenoceptor agonist UK-14,304. Therefore, in dogs, the decrease in insulin secretion produced by exogenous galanin is only partially mediated by activation of glibenclamide-sensitive ATP-gated K+ channels and is independent of alpha 2-adrenoceptor stimulation.

Adenosine Triphosphate↗
PubMed1992

Regulation of the anorectic drug recognition site during glucoprivic feeding.

The acute effects of 2-deoxy-D-glucose (2-DG)-induced glucoprivic feeding on the anorectic drug recognition site and Na+K(+)-ATPase in the brain were examined in adult rats and in lean and genetically obese mice. The marked hyperglycemia and the induction of feeding caused by the administration of 2-DG to satiated rats and lean mice were associated with significant increases in Na+K(+)-ATPase activity, and in [3H]ouabain binding and [3H]mazindol binding to the anorectic drug recognition site in hypothalamic membranes. Basal and 2-DG-stimulated levels of blood glucose were significantly correlated to the levels of hypothalamic [3H]ouabain (r = + .91, p less than 0.01) and [3H]mazindol (r = + .87, p less than 0.01) binding. A significant correlation (r = .74, p less than 0.05) was also observed between [3H]mazindol binding and [3H]ouabain binding supporting the hypothesis that these hypothalamic binding sites are functionally coupled in their response to circulating glucose. Following the intracerebroventricular (ICV) administration of the diabetogenic drug alloxan, 2-DG did not stimulate feeding or increase [3H]mazindol and [3H]ouabain binding sites in the hypothalamic paraventricular area. Since 2-DG still caused hyperglycemia in alloxan-treated rats, alloxan-induced inactivation of glucoreceptor mechanisms led to an uncoupling of the anorectic drug recognition site from a hypothalamic glucostat. In genetically obese mice (ob/ob), 2-DG also could not induce feeding or increase hypothalamic [3H]ouabain or [3H]mazindol binding, despite a significant hyperglycemic response. In contrast, 2-DG did increase feeding and the binding of [3H]ouabain and [3H]mazindol to the hypothalamus of lean littermates.(ABSTRACT TRUNCATED AT 250 WORDS)

Alloxan↗
PubMed1992

Adrenergic and nonadrenergic cotransmitters inhibit insulin secretion during sympathetic stimulation in dogs.

Vascular and biochemical responses to pancreatic sympathetic nerve stimulation were investigated in the blood-perfused pancreas of anesthetized dogs. During sympathetic nerve stimulation, pancreatic perfusion pressure and norepinephrine release increased, whereas insulin secretion decreased. The latter effect did not occur after pretreatment with the alpha 2-adrenoceptor antagonist idazoxan. However, after beta-adrenoceptor blockade with propranolol, neither single administration of idazoxan nor the alpha 1-adrenoceptor antagonist prazosin or glibenclamide, a blocker of ATP-modulated K+ channels, affected the decrease in insulin secretion induced by sympathetic nerve stimulation. In contrast, the combination of glibenclamide with idazoxan markedly antagonised the decrease in insulin release evoked by the latter procedure. After depletion of catecholamines with syrosingopine, the stimulation-induced inhibition of insulin secretion remained unchanged even though no increases in pancreas perfusion pressure or norepinephrine release were observed. In this preparation, glibenclamide inhibited the decrease in insulin release by 50%. In animals pretreated with the neuronal blocking agent bretylium, all of the responses to sympathetic nerve stimulation were abolished. These results indicate that the inhibitory effects exerted by the sympathetic nervous system on insulin secretion are mediated not only by the classical neurotransmitter norepinephrine acting on alpha 2-adrenoceptors but also by a nonadrenergic cotransmitter that can maintain transmission under conditions of catecholamine deficiency. The postulated nonadrenergic cotransmitter(s) acts, at least partly, via the opening of ATP-modulated K+ channels blockable by glibenclamide, and its release can be prevented by the neuronal blocking agent bretylium.

Animals↗
PubMed1992

SL 84.0418: a novel, potent and selective alpha-2 adrenoceptor antagonist: in vitro pharmacological profile.

One novel, potent and selective alpha-2 adrenoceptor antagonist is 2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydro-2- propylpyrrolo[3,2,1-hi]-indole hydrochloride (SL 84.0418). It inhibits with high affinity the radioligand binding to rat cortical alpha-2 adrenoceptors, as well as to human platelet alpha-2 adrenoceptors labeled with [3H]idazoxan (Ki = 7 nM). SL 84.0418 has low affinity for alpha-1 adrenoceptors labeled with [3H]prazosin (Ki = 3.3 microM). In vitro, SL 84.0418 has no alpha agonist properties, whereas it is a potent alpha-2 adrenoceptor antagonist at both pre- and postsynaptic alpha-2 adrenoceptors. In contrast, it possesses low potency as an antagonist at postsynaptic alpha-1 adrenoceptors demonstrating a more than 1000-fold selectivity toward alpha-2 compared with alpha-1 adrenoceptors. In the same tests, the alpha-2 adrenoceptor antagonist idazoxan had a selectivity ratio of 200. SL 84.0418 is the racemic mixture of two enantiomers, SL 86.0715 [(+) enantiomer] and SL 86.0714 [(-) enantiomer]. The alpha-2 adrenoceptor blocking activities reside with SL 86.0715. Similar to idazoxan, SL 84.0418 increases in a concentration-dependent manner the electrically evoked release of [3H]norepinephrine from rat hypothalamic slices through the blockade of the presynaptic inhibitory alpha-2 adrenoceptors. In isolated hamster adipocytes, SL 84.0418 potently antagonizes the inhibition of lipolysis induced by UK 14,304. In addition, SL 84.0418 inhibits epinephrine-induced aggregation of rabbit platelets, effects mediated by postsynaptic alpha-2 adrenoceptors. SL 84.0418 does not inhibit (IC50 > 1,000 nM) radioligand binding to other receptors or recognition sites, nor does it inhibit calcium, sodium or potassium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1991

Pre- and postsynaptic alpha-2 adrenoceptors as target for drug discovery.

The presynaptic terminal autoreceptors which modulate the release of noradrenaline through a negative feed-back mechanism correspond to the alpha 2-subtype of adrenoceptors. These receptors are also present post-synaptically in the pancreatic islets were they mediate inhibition of the glucose-induced release of insulin. The sympathetic innervation of the pancreatic islets involves alpha 2-adrenoceptors both presynaptically as well as postsynaptically. SL 84.0418 is a novel alpha 2-adrenoceptor antagonist with preferential effects in the periphery and with at least a 10-fold higher selectivity ratio between alpha 2 and alpha 1-adrenoceptors when compared with idazoxan. SL 84.0418 antagonizes the hyperglycemia and the inhibition of insulin release induced by the alpha 2-adrenoceptor agonist UK 14304. The administration of SL 84.0418 significantly reduces the glucose evoked hyperglycemia in several species including man. It is proposed that SL 84.0418 may represent a useful and novel hypoglycemic drug in the treatment of type II diabetes.

Adrenergic alpha-Agonists↗
PubMed1991

The binding site for [3H]glibenclamide in the rat cerebral cortex does not recognize K-channel agonists or antagonists other than sulphonylureas.

The binding of the potent oral antidiabetic sulphonylurea [3H]glibenclamide was studied in rat cerebral cortex membranes. A single population of high affinity and saturable binding sites with equilibrium constants, Kd = 0.2 +/- 0.06 nM and Bmax = 58.6 +/- 6.2 fmol/mg protein was found. Specific [3H]glibenclamide binding to rat cerebral cortex membranes was inhibited by glibenclamide and other sulphonylureas, glibenclamide being the most potent drug and the sulphonylurea of the second generation chlorpropamide the least potent. This observation suggests that this site may be related to the hypoglycaemic properties of sulphonylureas and possibly to their interaction with ATP-sensitive K(+)-channel. Nevertheless, other non-selective K(+)-channel antagonists such as TEA, 4-aminopyridine, quinine, quinidine or apamin failed to interact with this site (IC50 greater than 100 microM). Similarly, both non-selective K(+)-channel agonists such as cromakalim, pinacidil or minoxidil as well as the pancreatic ATP-sensitive K(+)-channel agonist diazoxide failed to interact with this site. It may thus be concluded that this site, under the present experimental conditions, represents a drug specific recognition site which may be coupled to the hypoglycaemic activity of sulphonylureas, possibly on a particulate ATP-dependent K(+)-channel.

Animals↗
PubMed1990

Involvement of alpha-2 adrenergic receptor subtypes in hyperglycemia.

Alpha-2 adrenoceptor stimulation induces in the mouse a hyperglycemic response which is accompanied by a concomitant inhibition of insulin secretion. To test the possibility that one of the postulated subtypes of alpha-2 adrenoceptors is preferentially implicated in this response, we compared the interaction of several drugs with known selectivity toward alpha-2A or alpha-2B adrenoceptor subtypes in our model. The alpha-2A preferential agonist oxymetazoline induced in the mouse a hyperglycemic response similar to that of the nonselective alpha-2 adrenoceptor agonist UK 14.304. This hyperglycemic response to oxymetazoline was accompanied by a concomitant inhibition of insulin release. Both the effect on glycemic level and the inhibition of insulin release by oxymetazoline were antagonized by the alpha-2 adrenoceptor antagonist idazoxan. The alpha-2B preferential antagonists ARC-239, prazosin or chlorpromazine failed to block the modifications in both glycemic and insulin levels induced by alpha-2 adrenoceptor stimulation. The nonselective antagonists rauwolscine, yohimbine, WY 26703, phentolamine and corynanthine, as well as the receptor antagonists with alpha-2A selectivity like WB 4101, idazoxan and tolazoline, dose-dependently antagonized both the glycemic and the insulin responses to UK 14.304. A positive correlation was obtained between the potencies of these drugs in antagonizing the hyperglycemic response to UK 14.304 and their affinities for alpha-2A adrenergic receptors (r = 0.918, P less than .001) but no correlation was obtained with their affinities for alpha-2B adrenergic receptors (r = 0.048, P = N.S.)(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1990

Pharmacological characterization of alpha-2 adrenergic receptor subtype involved in the release of insulin from isolated rat pancreatic islets.

Alpha-2 adrenoceptors are involved in the inhibition of insulin release induced by sympathetic nerve stimulation. To test the possibility that one of the postulated subtypes of alpha-2 adrenoceptors is differentially implicated in the inhibition of insulin release, we compared the effects of several agonists and antagonists with preferential selectivity for the alpha-2 adrenoceptor subtypes on the release of insulin induced by glucose in rat isolated islets. Similar to the inhibition of glucose-evoked release of insulin by the alpha-2 agonist (nonsubtype selective) UK 14.304, the alpha-2A preferential agonist oxymetazoline, concentration-dependently inhibited the release of insulin. Glucose-evoked insulin release was similarly inhibited by other alpha-2 adrenoceptor agonists such as clonidine, p-aminoclonidine, epinephrine and norepinephrine. However, neither the alpha-1 selective agonist cirazoline, nor the beta adrenoceptor agonist isoproterenol affected glucose-evoked insulin release, thus suggesting that this inhibitory effect is mediated by alpha-2 adrenoceptors, possibly of the alpha-2A subtype. The inhibition of glucose-evoked insulin release induced by the alpha-2 adrenoceptor agonists was concentration-dependently inhibited by the alpha-2 antagonists yohimbine, phentolamine, rauwolscine and idazoxan. However, neither the alpha-1 selective antagonist prazosin, nor the beta selective antagonist propranolol attenuated the inhibition of insulin release induced by alpha-2 adrenoceptor agonists. Furthermore, the inhibition of insulin release induced by UK 14.304 was concentration-dependently antagonized by the alpha-2A preferential antagonist WB-4101.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1989

The effects of serotonergic and dopaminergic lesions on sodium-sensitive [3H]mazindol binding in rat hypothalamus and corpus striatum.

The effects of intracerebroventricular administration of 6-hydroxydopamine (6-OHDA) and 5,7-dihydroxytryptamine (5,7-DHT) on sodium-sensitive [3H]mazindol binding were investigated in the rat hypothalamus and corpus striatum. In the hypothalamus, specific [3H]mazindol binding was inhibited by low concentrations of sodium and stimulated by high-sodium concentrations, whereas in the corpus striatum, only a sodium-dependent stimulation of [3H]mazindol binding was observed. Lesions with 6-OHDA significantly reduced sodium-dependent [3H]mazindol binding in the corpus striatum, but had no effect on the binding of [3H]mazindol in the absence of sodium. Lesions of serotonergic neurons with 5,7-DHT, however, had no effect on [3H]mazindol binding in the striatum, but resulted in a significant increase in the number of [3H]mazindol binding sites in the hypothalamus. These data suggest that [3H]mazindol may bind to two anatomically distinct binding sites, one that is stimulated and the other inhibited by sodium. The sodium-stimulated binding sites appear to be located on dopaminergic terminals in the striatum, and in the hypothalamus, the sodium-inhibited sites appear to be regulated by serotonergic neuronal activity.

5,7-Dihydroxytryptamine↗