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S Z Langer

Publications and source records attributed to S Z Langer.

At least 73 records · Page 4Linked to original sources
PubMed1989

Alpha-adrenoceptor subtypes in blood vessels: physiology and pharmacology.

The existence of alpha 1- and alpha 2-adrenoceptors subtypes is now well established. Presynaptically, alpha 2-adrenergic autoreceptors modulate norepinephrine release. In vascular smooth muscle both alpha 1- and alpha 2-adrenoceptors exist postjunctionally, the alpha 1 subtype being innervated preferentially in most vascular beds. alpha 2-Adrenoceptors may be present on the smooth muscle cell as well as the endothelial cell where they may participate in the release of endothelium derived relaxing and constricting factors. Developing insights into the role of alpha-adrenoceptor subtypes in the cardiovascular system, and into the classification of subtypes of alpha 1- and alpha 2-adrenoceptors may be expected to have, if confirmed, significant therapeutic implications for drug discovery in the cardiovascular system.

Animals↗
PubMed1989

Effects of Ca++ on [3H]diltiazem binding and its allosteric interaction with dihydropyridine calcium channel binding sites in the rat cortex.

In membranes from the rat cerebral cortex, the benzothiazepine [3H]diltiazem and the dihydropyridine [3H]nitrendipine label distinct but allosterically interacting calcium channel antagonist recognition sites. In the present study we evaluated the relationship between Ca++ and calcium channel antagonists binding sites within the voltage-dependent Ca++ channel. [3H]Nitrendipine binding to the rat cerebral cortex at 37 degrees C is not inhibited by Ca++, studied as CaCl2, in concentrations up to 10 mM. In contrast, [3H]diltiazem binding under these conditions is inhibited by Ca++ with an IC50 of 0.31 mM. The inhibition of diltiazem binding by Ca++ is reflected in an increase in the EC50 of diltiazem for enhancement of [3H]nitrendipine binding at 37 degrees C but not in the magnitude of its maximal heterotropic positive cooperative effect. Similarly, Ca++ increases the IC50 of verapamil for inhibition of [3H]nitrendipine binding at 37 degrees C without affecting the magnitude of its heterotropic negative cooperative effect. Schild analyses of these data indicate that Ca++ is an essentially competitive antagonist of the allosteric effects of diltiazem (KB = 0.32 mM) and verapamil (KB = 0.33 mM). At 0 degrees C, Ca++ is a negative allosteric inhibitor of the [3H]nitrendipine binding site (IC50 = 0.1 mM) and selectively increases the IC50 of diltiazem and verapamil for the inhibition of [3H]nitrendipine binding to membranes from the rat cerebral cortex. It may thus be suggested that the diltiazem and verapamil recognition sites are closely linked or identical with Ca++ binding site within the slow voltage-dependent Ca++ channel.

Allosteric Regulation↗
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

Studies on the serotonin transporter in platelets.

[3H]-Imipramine and [3H]-paroxetine label with high affinity a recognition site which is associated with the serotonergic transporter in blood platelets. The pharmacological profile of [3H]-imipramine and [3H]-paroxetine binding is highly correlated with the potency of drugs to inhibit the uptake of serotonin. Dissociation kinetic experiments suggest that the substrate recognition site for serotonin may be different from the modulatory site which is labeled with [3H]-imipramine or [3H]-paroxetine. The existence of an endocoid acting on the imipramine receptor to modulate the serotonin transporter has been proposed by several laboratories. In clinical studies most laboratories have reported a decrease in Bmax of [3H]-imipramine binding in platelets from depressed untreated patients when compared with matched healthy volunteers. The Bmax of [3H]-imipramine binding in platelets appears to be a state-dependent biological marker in depression.

Animals↗
PubMed1988

Short-term lithium administration to healthy volunteers produces long-lasting pronounced changes in platelet serotonin uptake but not imipramine binding.

Platelet [3H]-5HT uptake, [3H]-imipramine binding and endogenous 5HT levels were measured in healthy volunteers during short-term (20 days) administration of lithium, and following its withdrawal. The Vmax of [3H]-5HT uptake was significantly decreased during lithium treatment. Following lithium withdrawal, platelet [3H]-5HT uptake (Vmax) remained decreased and was followed by a pronounced rebound effect in some of the subjects for up to 3 months. The affinity constant (Km) of [3H]-5HT uptake was not modified. Binding of tritiated imipramine during the same period and platelet 5HT levels measured till 14 days after withdrawal was not affected by lithium treatment. As lithium is devoid of in vitro effects on both 5HT uptake and imipramine binding, it is concluded that the effects of lithium on the 5HT transporter do not reflect a direct effect on the transporter complex. Our results indicate that lithium-induced changes at the level of 5HT uptake in platelets are not correlated with concomitant variations in platelet 5HT content and can be dissociated from modifications at the level of imipramine binding sites within the macromolecular complex of the 5HT transporter. Moreover, platelet 5HT uptake is apparently modulated by lithium, with a similar pattern in healthy volunteers and in manic-depressive patients.

Adult↗
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

Imidazopyridines as a tool for the characterization of benzodiazepine receptors: a proposal for a pharmacological classification as omega receptor subtypes.

At present, the nomenclature of benzodiazepine (BZ) receptors is based on its historical association with the BZ structure. However, it is mainly through the new compounds chemically unrelated to BZs that the central and peripheral subtypes of BZ receptors have been characterized. We therefore propose the nomenclature of a greek letter omega, as omega 1, omega 2 and omega 3 to designate respectively the central BZ1, BZ2 and the peripheral BZ receptor. Among the several classes of non-BZ drugs with affinity for different receptors, the imidazopyridines provide a valuable tool for the characterization of omega receptor subtypes. Most BZs are non selective ligands for the central omega 1 and omega 2 receptors while the selectivity for omega 1 receptor subtypes is present in several non BZ chemical series: imidazopyridines (zolpidem), triazolopyridazines (CL 218872), betacarbolines (beta-CCE) and pyrazoloquinolines (CGS 8216). Selective ligands for the omega 2 subtype are not available so far. The so called peripheral BZ receptor is also present in the central nervous system, therefore the proposed nomenclature of omega 3 receptors resolves this paradox because it does not designate location and it is defined in terms of pharmacological specificity. Selective ligands for omega 3 receptors include the BZ Ro 5-4864, and the isoquinolinecarboxamide PK 11195, while the imidazopyridine alpidem is the ligand with the highest affinity for this receptor subtype.

Animals↗
PubMed1988

Effects of antidepressants on monoamine transporters.

1. Using [3H]antidepressants, high affinity binding sites associated with the neuronal transporter for serotonin, noradrenaline, dopamine and adrenaline have been identified. 2. The association of high affinity [3H]imipramine binding with the serotonin transporter in brain and platelets is well established. Although the exact relationship between the [3H]imipramine recognition site and the serotonin transporter remains to be elucidated, it appears that the [3H]imipramine labelled component of the serotonin transporter represents a novel receptor that functions to modulate serotonin uptake. 3. Most data available to date support the hypothesis that [3H]imipramine binding to platelet represents a biological marker in depression. The majority of studies indicate that the Bmax of platelet [3H]imipramine binding is lower in depressed, untreated patients than in the control population and that this finding is relatively specific to depression. 4. Among the [3H]antidepressant binding sites associated with the other monoaminergic transporters, the recent identification of [3H]desipramine binding to the neuronal transporter for adrenaline offers novel perspectives. Thus, given the high affinity for [3H]desipramine binding to the adrenaline transporter in the frog heart for not only desipramine but also imipramine and the atypical antidepressants mianserin and iprindol, it is possible that an interaction with the adrenaline transporter is of significance to the clinical effects of antidepressant drugs.

Anti-Anxiety Agents↗
PubMed1988

Modulation of the electrically evoked release of 5-[3H]hydroxytryptamine from rat cerebral cortex: effects of alpidem, CL 218872, and diazepam.

The effect of omega (benzodiazepine)-receptor agonists, antagonists, and inverse agonists on the electrically evoked release of 5-[3H]hydroxytryptamine ([3H]5-HT) was studied in superfused slices of the rat frontal cerebral cortex. The electrically evoked release of [3H]5-HT was enhanced by nanomolar concentrations of diazepam and the selective omega 1-receptor agonists alpidem and CL 218872. The omega 1/omega 2- and omega 1-receptor antagonists flumazenil and CGS 8216, respectively, did not modify the electrically evoked release of [3H]5-HT. The omega 3-receptor agonist Ro 5-4864 and the omega 1-receptor inverse agonist ethyl-beta-carboline-3-carboxylate on their own did not affect the electrically evoked release of [3H]5-HT. On the other hand, the inverse agonist 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid methyl ester (DMCM), at micromolar concentrations, inhibited both the spontaneous and the evoked release of [3H]5-HT. The facilitation of the electrically evoked release of [3H]5-HT by diazepam, alpidem, or CL 218872 was potentiated by gamma-aminobutyric acid (GABA). Exposure to flumazenil and CGS 8216 antagonized the facilitation by diazepam, alpidem, or CL 218872 of [3H]5-HT release. The inhibition of the release of [3H]5-HT by DMCM was not modified by exposure to either flumazenil, CGS 8216, or GABA. The inhibitory effect of DMCM was not observed when monoamine oxidase activity was inhibited by pargyline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Limitations of the benzodiazepine receptor nomenclature: a proposal for a pharmacological classification as omega receptor subtypes.

At present, the nomenclature of benzodiazepine (BZ) receptors is based on historical association with the BZ structure. However, it is mainly through the new compounds chemically unrelated to BZ that the central and peripheral subtypes of BZ receptors have been characterized. We therefore propose the nomenclature of a Greek letter omega, as omega 1, omega 2, and omega 3 to designate the central BZ1, BZ2, and peripheral BZ receptors, respectively. Among the several classes of non-BZD drugs with affinity for different receptors, the imidazopyridines provide a valuable tool for the characterization of omega receptor subtypes. Most BZ are nonselective ligands for the central omega 1 and omega 2 receptors, while selectivity for omega 1 receptor subtypes is present in several non BZ chemical series: imidazopyridines (zolpidem), triazolopyridazines (CL 218872), betacarbolines (beta-CCE), and pyrazoloquinolines (CGS 8216). Selective ligands for the omega 2 subtype are not available so far. The so-called peripheral BZ receptor is also present in the central nervous system; therefore, the proposed nomenclature of omega 3 receptors resolves this paradox because it does not designate location and is defined in terms of pharmacological specificity. Selective ligands for omega 3 receptors include the BZ Ro 5-4864, and the isoquinolinecarboxamide PK 11195, while the imidazopyridine alpidem is the ligand with the highest affinity for this receptor subtype.

Animals↗
PubMed1988

The beta 1-adrenoceptor antagonist, betaxolol, is not released from the heart of the anaesthetized dog during sympathetic nerve stimulation.

1. We investigated the hypothesis that the beta 1-adrenoceptor antagonist, betaxolol, can be accumulated by cardiac sympathetic nerve endings and then released together with noradrenaline during accelerans nerve stimulation. 2. Dogs were chronically treated with betaxolol (1 mg kg-1 daily, s.c.) for 7 days. Twenty four hours after the last dose, there was a significant retention of betaxolol in the heart of these dogs treated chronically with the beta 1-adrenoceptor antagonist. However, during in vivo accelerans nerve stimulation, the concentration of betaxolol in the coronary sinus was not modified, whereas the noradrenaline concentration increased significantly. 3. Chronic betaxolol treatment antagonized the tachycardia induced by electrical stimulation of the cardiac accelerator nerves or by intravenous isoprenaline. However, the tachycardia induced by nerve stimulation was not antagonized to a greater extent than that induced by isoprenaline. 4. These findings are discussed in relation to a similar in vivo study in dogs treated with propranolol, in which the drug was found to be released into the coronary circulation during stimulation of the accelerans nerve.

Adrenergic beta-Antagonists↗
PubMed1988

Day-night rhythm of 5-methoxytryptamine biosynthesis in the pineal gland of the golden hamster (Mesocricetus auratus).

5-Methoxytryptamine is a potent agonist of presynaptic 5-hydroxytryptamine autoreceptors modulating serotonin release in the central nervous system. This methoxyindole can be synthesized in the pineal gland, but its presence in vivo is still controversial, probably because of rapid catabolism by monoamine oxidase. An improved high-pressure liquid chromatography method, with coulometric detection, has been developed for the simultaneous measurement of melatonin, 5-methoxytryptamine, 5-methoxytryptophol and 5-methoxyindolacetic acid. We have demonstrated a day-night rhythmicity in the amount of 5-methoxytryptamine in the pineal gland of golden hamsters (Mesocricetus auratus) maintained under a long photoperiod (14 h light: 10 h darkness) and pretreated with the monoamine oxidase inhibitor pargyline. Levels of 5-methoxytryptamine were highest at 16.30 h and lowest at 00.30 h. The rhythm for 5-methoxytryptamine appears to be the same as for serotonin (opposite in phase to that of melatonin). The identification of 5-methoxytryptamine has been confirmed by analysis with gas chromatography-mass spectrometry.

5-Methoxytryptamine↗
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

Behavioural and electrocortical power spectrum effects of 5-methoxytryptoline and other analogs after intraventricular administration in rats.

The behavioural and electrocortical power spectrum effects of tryptoline and the 5-hydroxy and 5-methoxy derivatives were studied after microinjection of the drugs into the third cerebral ventricle in freely moving rats. The three compounds produced a dose-dependent desynchronication in electrocortical activity with a concomitant syndrome of behavioural stimulation. The most potent compound was 5-methoxytryptoline, already active at 4 nmol. When given into the third cerebral ventricle, 5-methoxytryptoline antagonized the sedation and hypothermia induced by reserpine. The relative order of potencies was 5-methoxytryptoline greater than 5-hydroxytryptoline greater than tryptoline. Melatonin, the 5-methoxy-N-acetyl derivative of serotonin, when injected into the third cerebral ventricle, did not produce desynchronization and elicited only mild sedation. The high potency of 5-methoxytryptoline following injection into the third cerebral ventricle and the relative order of potencies with 5-hydroxytryptoline and tryptoline is compared to the affinity of these compounds for the modulatory site of the serotonin transporter which was labelled with [3H]imipramine or [3H]paroxetine.

Animals↗
PubMed1987

[3H]desipramine labels with high affinity the neuronal transporter for adrenaline in the frog heart.

Desipramine, a tricyclic antidepressant, inhibits the neuronal uptake of adrenaline and noradrenaline and, as a radioligand, labels the noradrenaline transporter in central and peripheral tissues of the rat. To study whether [3H]desipramine also labels the neuronal adrenaline transporter in vitro, its binding was evaluated in the frog heart, a tissue with a rich adrenergic innervation but virtually devoid of noradrenergic innervation. [3H]Desipramine binding to membranes from the frog heart was of high affinity (Kd = 1.94 nM) and was potently inhibited by nisoxetine and (+)oxaprotiline. Unexpectedly, [3H]desipramine binding to the transporter for adrenaline in the frog heart was also sensitive to inhibition by imipramine and the atypical antidepressants mianserin and iprindol. This is the first study to demonstrate radioligand binding to the neuronal transporter for adrenaline. The results indicate that the pharmacological profile of the transporter for adrenaline may be different from that of the noradrenergic transporter, if species differences can be excluded. It remains to be established if the affinity of imipramine, mianserin and iprindol for the adrenaline transporter contributes to their therapeutic efficacy in depression.

Animals↗
PubMed1987

Effect of acidosis on alpha 1- and alpha 2-adrenoceptor-mediated vasoconstrictor responses in isolated arteries.

We have investigated the effect of reducing the pH (from 7.5 to 7.0 by addition of HCl) on vasoconstrictor responses to noradrenaline in cat middle cerebral artery (in which responses are mediated almost entirely by alpha 2-adrenoceptors) and in rabbit pulmonary artery (in which responses are mediated by alpha 1-adrenoceptors). In the cerebral artery, a reduction in pH caused a pronounced inhibition of the responses to noradrenaline, and the antagonistic effect of idazoxan (100 nM) was increased 10-fold. In contrast, in the pulmonary artery, a reduction in pH had no effect on the responses to noradrenaline and the antagonistic effect of prazosin (100 nM) was not altered. We conclude that acidosis selectively reduces the vasoconstriction mediated by alpha 2-adrenoceptors in vitro.

Acidosis↗
PubMed1987

Pitfalls in demonstrating an endogenous ligand of imipramine recognition sites.

The recognition sites for the 5-hydroxytryptamine (5-HT) uptake inhibitors imipramine and paroxetine may represent receptors for a presently unknown endogenous ligand, whose function would be to modulate 5-HT uptake. Attempts to isolate such a factor from rat brain tissue are described, following a published procedure. It is shown that chromatographic fractions found to inhibit the binding of [3H]imipramine and [3H]paroxetine to rat brain membranes consisted of material essentially unretained by the reverse-phase HPLC column, and they were of high osmolarity. Thus, the activity was probably unspecific in nature, and the presence in rat brain of the factor has not been unequivocally demonstrated.

Animals↗