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I Angel

Publications and source records attributed to I Angel.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1989

Coupling between hypothalamic alpha 2-adrenoceptors and [3H]mazindol binding site in response to several hyperglycaemic stimuli in mice.

The hypothalamic response to circulating glucose and insulin levels was studied in the mouse by differentially attenuating glucose-homeostasis. The administration of glucose, 2-deoxyglucose or the alpha 2-adrenoceptor agonist UK 14.304 was accompanied by a persistent hyperglycaemia; however, an increase in insulin levels was obtained with glucose and a decrease with the other two manipulations. Both alpha 2-adrenoceptors (labeled with [3H]idazoxan) and the anorectic recognition site (labeled with [3H]mazindol) were upregulated by the three treatments. A good correlation was obtained between circulating glucose levels and either hypothalamic [3H]mazindol binding (r = 0.70, P less than 0.001) or [3H]idazoxan binding (r = 0.63, P less than 0.001), as well as between the two binding sites (r = 0.88, P less than 0.001). No correlation was obtained between circulating insulin levels and these binding sites (r = 0.18, r = 0.26, P = n.s. for [3H]mazindol and [3H]idazoxan binding, respectively). It is suggested the alpha 2-adrenoceptors and the anorectic binding sites are associated in their response to glucose as part of a hypothalamic center involved in the regulation of feeding mechanisms.

Animals↗
PubMed1988

The use of microtiter plates for the simple and sensitive determination of insulin by an ELISA method.

A method of insulin determination using a commercially available ELISA kit was modified for use in microtiter plates. The adapted assay, based on the binding of porcine anti-guinea pig insulin antibodies to microtiter plates and insulin-peroxidase conjugate as displacer, is sensitive between 0.5 and 30 ng/ml. Since it uses only 10-40 microliter of sample material it enables the determination of 5-100 pg of insulin. The rapid (5-6 h), automatable, reproducible and reliable assay makes it possible to determine many samples in a short time.

Animals↗
PubMed1988

Adrenergic-induced hyperglycemia in anaesthetized rats: involvement of peripheral alpha 2-adrenoceptors.

The selective alpha 2-adrenoceptor agonist, UK 14.304, induces a time- and dose-dependent hyperglycemic response in the anaesthetized rat. This hyperglycemia seems to be mediated through the pancreas because lesions of the pancreatic beta-cells induced with streptozotocin completely abolished this hyperglycemic response to UK 14.304 while ganglionic blockade by chlorisondamine did not affect the response. The non-selective agonist, adrenaline, induces a similar hyperglycemic response which is antagonized selectivity by the alpha 2-adrenoceptor antagonist, idazoxan. Combined alpha 1- and beta-adrenoceptor blockade resulted in an increase in the alpha 2-adrenoceptor-mediated hyperglycemic response to adrenaline. Since adrenaline is known not to cross the blood-brain barrier it is concluded that alpha 2-adrenoceptor stimulation induces hyperglycemic responses through a peripheral effect that involves postsynaptic alpha 2-adrenoceptors in the pancreatic beta-cell which are linked to the inhibition of insulin release.

Anesthesia↗
PubMed1988

Anorectic activities of serotonin uptake inhibitors: correlation with their potencies at inhibiting serotonin uptake in vivo and 3H-mazindol binding in vitro.

The mechanism of anorectic action of several serotonin uptake inhibitors was investigated by comparing their anorectic potencies with several biochemical and pharmacological properties and in reference to the novel compound SL 81.0385. The anorectic effect of the potent serotonin uptake inhibitor SL 81.0385 (ED50 = 4 mg/kg, i.p.) was potentiated by pretreatment with 5-hydroxytryptophan and blocked by the serotonin receptor antagonist metergoline. A good correlation (r = 0.98, p less than 0.01) was obtained between the ED50 values of anorectic action and the ED50 values of serotonin uptake inhibition in vivo (but not in vitro) for several specific serotonin uptake inhibitors. Most of the drugs tested displaced [3H]-mazindol from its binding to the anorectic recognition site in the hypothalamus, except the pro-drug zimelidine which was inactive (IC50 greater than 100 microM). Excluding zimelidine, a good correlation (r = 0.835, p less than 0.01) was obtained between the affinities of these drugs for [3H]-mazindol binding and their anorectic action indicating that their anorectic activity may be associated with an effect mediated through this site. Taken together these results suggest that the anorectic action of serotonin uptake inhibitors is directly associated to their ability to inhibit serotonin uptake and thus increasing the synaptic levels of serotonin. The interactions of these drugs with the anorectic recognition site labelled with [3H]-mazindol is discussed in connection with the serotonergic regulation of carbohydrate intake.

Animals↗
PubMed1988

Pharmacological characterization of the hyperglycemia induced by alpha-2 adrenoceptor agonists.

The selective alpha-2 adrenoceptor agonist UK 14.304 induced in the mouse a dose-dependent hyperglycemic response which was accompanied by a concomitant inhibition of insulin secretion. Similar effects were observed with the preferential alpha-2 receptor agonists clonidine and guanabenz whereas less pronounced effects were found with (-)-epinephrine. No significant effects on blood glucose levels were observed with the alpha-1 adrenoceptor agonist methoxamine. Adrenalectomy or depletion of catecholamine stores by reserpine, alpha-methylparatyrosine or DSP4 failed to modify the hyperglycemic response to UK 14.304. However, streptozotocin diabetic mice did not respond to UK 14.304. The hyperglycemia induced by submaximal doses of UK 14.304 was antagonized by the centrally and peripherally acting alpha-2 adrenoceptor antagonists rauwolscine, yohimbine, idazoxan and phentolamine, by the peripheral antagonist benextramine but not by prazosin (alpha-1 selective) or propranolol (beta adrenergic). Thus, it may be suggested that the alpha agonist-induced hyperglycemia is mediated via postsynaptic alpha-2 adrenoceptors located on pancreatic beta cells and that it is mediated through the inhibition of insulin secretion.

Adrenalectomy↗
PubMed1987

Site of action of anorectic drugs: glucoprivic- versus food deprivation-induced feeding.

Feeding induced by 2-deoxyglucose was compared with feeding induced by food deprivation in terms of antagonism by anorectic drugs and of anatomical site of action. Glucoprivic feeding was completely blocked by microinjection of amphetamine, fenfluramine, and mazindol into the paraventricular nucleus of the hypothalamus (PVN). Deprivation-induced feeding was not blocked by amphetamine, fenfluramine, or mazindol microinjected into the PVN. Neither the feeding induced by 2-deoxyglucose nor its reversal by amphetamine were blocked by pretreatment with the beta-adrenergic antagonist, propranolol. Amphetamine and fenfluramine blocked both glucoprivic- and deprivation-induced feeding when microinjected into the perifornical region of the lateral hypothalamus. These data suggest that food consumption induced by 2-deoxyglucose treatment can be antagonized by anorectic drugs acting at recognition sites present in several hypothalamic nuclei, while deprivation-induced feeding acts through different receptor mechanisms which may be specific to the perifornical region of the lateral hypothalamus.

Amphetamine↗
PubMed1987

[3H]GBR-12935 binding to the dopamine transporter is decreased in the caudate nucleus in Parkinson's disease.

The specific binding of [3H]GBR-12935 to membranes prepared from human caudate nucleus is saturable (Bmax 1.36 +/- 0.18 pmol/mg protein), sodium dependent and of high affinity (KD 2.34 +/- 0.18 nM). Freezing of tissue from rat brain, or refrigeration followed by freezing, results in a small but significant (less than or equal to 20%) decrease in specific [3H]GBR-12935 binding when compared to the binding observed in fresh (nonfrozen) tissue, and this decrease may account, in part, for the differences in specific binding between rat and human brain membranes. Despite small differences in binding site density between fresh and frozen tissue there is a good correlation (r = 0.98; p less than 0.01) between the potencies of a series of drugs in displacing specific [3H]GBR-12935 binding to human caudate membranes and rat striatum as well as in inhibiting dopamine uptake in rat striatal synaptosomes (r = 0.96; p less than 0.01). The specific binding of [3H]GBR-12935 to membranes prepared from the caudate nuclei of patients with Parkinson's disease is decreased compared to membranes prepared from age- and sex-matched controls. These data suggest that [3H]GBR-12935 binds in a sodium-dependent fashion to the dopamine transport complex in human brain and that specific binding is decreased by a pathological degeneration of dopaminergic neurons to the caudate nucleus.

Caudate Nucleus↗
PubMed1987

Characterization of [3H]mazindol binding in rat brain: sodium-sensitive binding correlates with the anorectic potencies of phenylethylamines.

Saturable low-affinity binding sites for [3H]mazindol have been demonstrated in crude synaptosomal membranes from rat brain using both a centrifugation and a filtion assay. Studies on the regional distribution of these binding sites revealed that the hypothalamus and brainstem had the highest density of sites. Kinetic analysis of the binding of [3H]mazindol to hypothalamic membranes demonstrated a single class of noninteracting binding sites with an apparent affinity constant (KD) of 10.2 +/- 0.7 microM and maximal number of binding sites (Bmax) of 786 +/- 94 pmol/mg of protein. Specific [3H]mazindol binding was rapidly reversible, temperature sensitive, labile to pretreatment with proteolytic enzymes, and inhibited by physiological concentrations of sodium. In most peripheral tissues, such as the liver and kidney, very low levels of binding were observed; however, the adrenal gland had a relatively high density of sites. The potency of a series of anorectic drugs in inhibiting specific [3H]mazindol binding to hypothalamic membranes was highly correlated with their anorectic potencies in rats, but not with their motor stimulatory effects. These results suggest the presence of a specific drug recognition site in the hypothalamus that may mediate the anorectic activity of mazindol and related phenylethylamines.

Animals↗
PubMed1986

Glucose regulates [3H](+)-amphetamine binding and Na+K+ ATPase activity in the hypothalamus: a proposed mechanism for the glucostatic control of feeding and satiety.

Binding sites for [3H](+)-amphetamine in the hypothalamus may mediate the anorectic actions of amphetamine and related phenylethylamines. To investigate further the role of these sites in the central control of appetite, the binding of [3H](+)-amphetamine to the hypothalamus and brainstem was measured following food deprivation and refeeding, the onset of genetic obesity, or the administration of 2-deoxy-D-glucose. Food deprivation for 24 to 72 hours reduced the Bmax for [3H](+)-amphetamine binding in the hypothalamus and brainstem but not in other brain areas or peripheral tissues. The decrease in hypothalamic and brainstem [3H](+)-amphetamine binding observed following food deprivation was time-dependent and rapidly reversed by brief refeeding with either rat chow or a 10% glucose solution. Moreover the changes in [3H](+)-amphetamine binding were highly correlated to corresponding alterations in blood glucose concentration. Furthermore, D-glucose, but not L-glucose increases the number of hypothalamic [3H](+)-amphetamine binding sites when administered in vivo or when added to hypothalamic slices in vitro. These data suggest that the [3H](+)-amphetamine binding site in the hypothalamus and (or) brainstem may be coupled to a central "glucostat."

Animals↗
PubMed1986

Regulation of [3H]mazindol binding to subhypothalamic areas: involvement in glucoprivic feeding.

The distribution of low-affinity sodium-sensitive binding sites of [3H]mazindol were studied in rat hypothalamic nuclei. Using microdissection methods, it was demonstrated that the highest level of [3H]mazindol binding is localized to the paraventricular nucleus (PVN) and the lowest binding is observed in the lateral hypothalamus. Following food deprivation, a significant decrease in [3H]mazindol binding in the PVN and ventromedial hypothalamus (VHM) were observed. Refeeding food-deprived rats resulted in restoration of the level of binding in the PVN, and this was correlated with changes in blood glucose levels. Thus, changes in the binding of [3H]mazindol in the PVN may reflect local changes in glucose levels. In related studies, the involvement of the PVN in the regulation of food deprivation or 2-deoxyglucose (2-DG)-induced food intake was studied. Application of amphetamine (20 micrograms) into the PVN had no effect on food deprivation induced feeding, but significantly inhibited 2-DG induced (glucoprivic) feeding. The PVN may play an important role in the glucostatic regulation of feeding and in mediating the anorectic action of amphetamine and related anorectic drugs on glucoprivic feeding.

Amphetamine↗
PubMed1985

Glucostatic regulation of (+)-[3H]amphetamine binding in the hypothalamus: correlation with Na+,K+-ATPase activity.

Preincubation of rat hypothalamic slices in glucose-free Krebs-Ringer buffer (37 degrees C) resulted in a time-dependent decrease in specific (+)-[3H]amphetamine binding in the crude synaptosomal fraction prepared from these slices. The addition of D-glucose resulted in a dose- and time-dependent stimulation of (+)-[3H]amphetamine binding, whereas incubation with L-glucose, 2-deoxy-D-glucose, or 3-O-methyl-D-glucose failed to increase the number of (+)-[3H]amphetamine binding sites. Ouabain potently inhibited the glucose-induced stimulation of (+)-[3H]amphetamine binding, suggesting the involvement of Na+,K+-ATPase. Preincubation of hypothalamic slices with glucose also resulted in an increase in Na+,K+-ATPase activity and the number of specific "high-affinity" binding sites for [3H]ouabain, and a good correlation was observed (r = 0.89; P less than 0.02) between the glucose-stimulated increase in (+)-[3H]amphetamine and [3H]ouabain binding. Similar increases in (+)-[3H]amphetamine binding, [3H]ouabain binding, and Na+,K+-ATPase activity were observed in the hypothalamus after parenteral administration of glucose to rats. The administration of anorectic doses of amphetamine (0.1-5.0 mg/kg of body weight) also increased Na+,K+-ATPase activity in the hypothalamus. These data suggest that the (+)-[3H]amphetamine binding site in hypothalamus, previously linked to the anorectic actions of various phenylethylamines, is regulated both in vitro and in vivo by physiological concentrations of glucose. Glucose and amphetamine appear to interact at common sites in the hypothalamus to stimulate Na+,K+-ATPase activity, and the latter may be involved in the "glucostatic" regulation of appetite.

Animals↗
PubMed1985

Characterization of endogenous inhibitors of [3H]-imipramine binding and [3H]-serotonin uptake from rat serum.

The effects of rat serum extracts on the uptake of [3H]-serotonin and the displacement of [3H]-imipramine binding in rat forebrain synaptosomes and human platelets was studied. Deproteinated rat serum markedly inhibited synaptosomal [3H]-serotonin uptake in a dose-dependent and reversible manner. The crude extract was fractionated by C18-reverse phase HPLC. Three major peaks of inhibitory activity were found. One of the peaks was identified as serotonin and was significantly reduced after chronic reserpinization. The second major peak inhibited both [3H]-serotonin uptake and [3H]-imipramine binding in synaptosomes and platelets. This fraction had a minimal effect on the uptake of [3H]-norepinephrine, [3H]-dopamine or [3H]-GABA and was less effective in inhibiting [3H]-desipramine binding than [3H]-imipramine binding.

Animals↗
PubMed1984

Inhibition of synaptosomal 5-[3H]hydroxytryptamine uptake by endogenous factor(s) in human blood.

The inhibition of 5-[3H]hydroxytryptamine uptake into rat forebrain synaptosomes by human plasma extracts was studied. Highly potent, small (Mr less than 10 000), and heat stable factor(s) were found to inhibit 5-[3H]hydroxytryptamine uptake specifically, reversibly and in a non-competitive manner. The possible role of these factor(s) as endogenous modulators of serotonergic activity is discussed.

Animals↗