In vitro and in vivo profiling of fadolmidine, a novel potent α2-adrenoceptor agonist with local mode of action

Chronic stress exerts vagally dependent effects to disrupt gastric motility; previous studies have shown that, among other nuclei, A2 neurons are involved in mediating these effects. Several studies have also shown robust in vitro and in vivo effects of α2-adrenoceptor agonists on vagal motoneurons. We have demonstrated previously that brainstem vagal neurocircuits undergo remodeling following acute stress; however, the effects following brief periods of chronic stress have not been investigated. Our aim, therefore, was to test the hypothesis that different types of chronic stress influence gastric tone and motility by inducing plasticity in the response of vagal neurocircuits to α2-adrenoreceptor agonists. In rats that underwent 5 days of either homotypic or heterotypic stress loading, we applied the α2-adrenoceptor agonist, UK14304, either by in vitro brainstem perfusion to examine its ability to modulate GABAergic synaptic inputs to vagal motoneurons or in vivo brainstem microinjection to observe actions to modulate antral tone and motility. In neurons from naïve rats, GABAergic currents were unresponsive to exogenous application of UK14304. In contrast, GABAergic currents were inhibited by UK14304 in all neurons from homotypic and, in a subpopulation of neurons, heterotypic stressed rats. In control rats, UK14304 microinjection inhibited gastric tone and motility via withdrawal of vagal cholinergic tone; in heterotypic stressed rats, the larger inhibition of antrum tone was due to a concomitant activation of peripheral nonadrenergic, noncholinergic pathways. These data suggest that stress induces plasticity in brainstem vagal neurocircuits, leading to an upregulation of α2-mediated responses. NEW & NOTEWORTHY Catecholaminergic neurons of the A2 area play a relevant role in stress-related dysfunction of the gastric antrum. Brief periods of chronic stress load induce plastic changes in the actions of adrenoceptors on vagal brainstem neurocircuits.

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The α2-adrenoceptor agonist dexmedetomidine increases the apparent potency of the volatile anesthetic isoflurane in rats in vivo and in hippocampal slice in vitro

Brain Research ◽

10.1016/0006-8993(91)91101-6 ◽

1991 ◽

Vol 548 (1-2) ◽

pp. 23-28 ◽

Cited By ~ 20

Author(s):

M.K.T. Savola ◽

M.B. MacIver ◽

V.A. Doze ◽

J.J. Kendig ◽

M. Maze

Keyword(s):

Hippocampal Slice ◽

Volatile Anesthetic ◽

Α2 Adrenoceptor ◽

Adrenoceptor Agonist

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Desensitization of platelet α2-adrenoceptors after short term infusions of adrenoceptor agonist in man

Clinical Science ◽

10.1042/cs0700147 ◽

1986 ◽

Vol 70 (2) ◽

pp. 147-153 ◽

Cited By ~ 18

Author(s):

C. R. Jones ◽

M. Giembcyz ◽

C. A. Hamilton ◽

I. W. Rodger ◽

K. Whyte ◽

...

Keyword(s):

Binding Sites ◽

Human Platelet ◽

Short Term ◽

Α2 Adrenoceptor ◽

Adrenoceptor Agonist ◽

Adrenoceptor Agonists ◽

Adrenaline Infusion ◽

And Function

1. The effect of intravenous infusion of catecholamines and related drugs on human platelet α2-adrenoceptor number and function was investgated. 2. Short (60–120 min) infusions of catecholamines with α2 agonist activity in vivo produced attenuation of the platelet responses to adrenaline in vitro. This desensitization was specific for the adrenaline induced aggregatory response. 3. The maximum number of [3H]yohimbine binding sites on platelets was not altered by adrenaline infusion. 4. The ability of adrenaline to reduce platelet cyclic AMP levels was significantly reduced after the infusions. 5. Acute infusions of α2-adrenoceptor agonists may alter the coupling of the platelet α2-adrenoceptor to adenylate cyclase.

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Significance of Platelet β-Adrenoceptors for Platelet Responses In Vivo and In Vitro

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646345 ◽

1992 ◽

Vol 68 (06) ◽

pp. 687-693 ◽

Cited By ~ 24

Author(s):

P T Larsson ◽

N H Wallén ◽

A Martinsson ◽

N Egberg ◽

P Hjemdahl

Keyword(s):

Ex Vivo ◽

High Dose ◽

Platelet Aggregability ◽

Adrenoceptor Agonist ◽

Dose Infusion ◽

Von Willebrand ◽

Willebrand Factor ◽

Factor Antigen

SummaryThe significance of platelet β-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the β-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed α- and β-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma β-thromboglobulin levels. Adrenaline levels were 3–4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels β-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that β-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an α-adrenoceptor mediated proaggregatory action.

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Vasopressin as a neuroendocrine regulator of anterior pituitary hormone secretion

Acta Endocrinologica ◽

10.1530/acta.0.1290489 ◽

1993 ◽

Vol 129 (6) ◽

pp. 489-496 ◽

Cited By ~ 33

Author(s):

Andreas Kjær

Keyword(s):

Arginine Vasopressin ◽

Mode Of Action ◽

Anterior Pituitary ◽

Hormone Secretion ◽

Pituitary Hormones ◽

Pituitary Hormone ◽

Anterior Pituitary Hormones ◽

Anterior Pituitary Hormone

Secretion of the anterior pituitary hormones adrenocorticotropin (ACTH), β-endorphin and prolactin (PRL) is complex and involves a variety of factors. This review focuses on the involvement of arginine-vasopressin (AVP) in neuroendocrine regulation of these anterior pituitary hormones with special reference to receptor involvement, mode of action and origin of AVP. Arginine-vasopressin may act via at least two types of receptors: V1− and V2−receptors, where the pituitary V1−receptor is designated V1b. The mode of action of AVP may be mediating, i.e. anterior pituitary hormone secretion is transmitted via release of AVP, or the mode of action may be permissive, i.e. the presence of AVP at a low and constant level is required for anterior pituitary hormones to be stimulated. Under in vivo conditions, the AVP-induced release of ACTH and β-endorphin is mainly mediated via activation of hypothalamic V1− receptors, which subsequently leads to the release of corticotropin-releasing hormone. Under in vitro conditions, the AVP-stimulated release of ACTH and β-endorphin is mediated via pituitary V1b− receptors. The mode of action of AVP in the ACTH and β-endorphin response to stress and to histamine, which is involved in stress-induced secretion of anterior pituitary hormones, is mediating (utilizing V1− receptors) as well as permissive (utilizing mainly V1− but also V2−receptors). The AVP-induced release of PRL under in vivo conditions is conveyed mainly via activation of V1−receptors but V2−receptors and probably additional receptor(s) may also play a role. In stress- and histamine induced PRL secretion the role of AVP is both mediating (utilizing V1 −receptors) and permissive (utilizing both V1− and V2− receptors). Arginine-vasopressin may be a candidate for the PRL-releasing factor recently identified in the posterior pituitary gland. Arginine-vasopressin of both magno- and parvocellular origin may be involved in the regulation of anterior pituitary hormone secretion and may reach the corticotrophs and the lactotrophs via three main routes: the peripheral circulation, the long pituitary portal vessels or the short pituitary portal vessels.

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Zinc oxide microrods and nanorods: different antibacterial activity and their mode of action against Gram-positive bacteria

RSC Advances ◽

10.1039/c4ra08462d ◽

2014 ◽

Vol 4 (99) ◽

pp. 56031-56040 ◽

Cited By ~ 42

Author(s):

Ilaria Rago ◽

Chandrakanth Reddy Chandraiahgari ◽

Maria P. Bracciale ◽

Giovanni De Bellis ◽

Elena Zanni ◽

...

Keyword(s):

Zinc Oxide ◽

Antibacterial Activity ◽

Mode Of Action ◽

Gram Positive ◽

Gram Positive Bacteria

ZnO micro and nanorods, produced through simple and inexpensive techniques, resulted to be strong antimicrobials against Gram-positive bacteria, in vitro as well as in vivo, by altering cell outer structures like membrane and exopolysaccharides.

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Mechanism of Action of Progestins in the Treatment of Hormone-dependent Breast Cancer.

Tumori Journal ◽

10.1177/030089167506100601 ◽

1975 ◽

Vol 61 (6) ◽

pp. 501-508 ◽

Cited By ~ 5

Author(s):

Francesco Di Carlo ◽

Giovanni Pacilio ◽

Giuseppe Conti

Keyword(s):

Breast Cancer ◽

Estrogen Receptors ◽

Mechanism Of Action ◽

Mode Of Action ◽

Binding Capacity ◽

Specific Receptors ◽

High Concentrations ◽

Good Agreement

The in vitro interference of some gestagens with the binding of 3H-17 β-oestradiol to cytosol specific receptors was investigated with a view to elucidating the mechanism of action of progestins in the treatment of human hormone-dependent breast cancer. A decrease (up to 85 %) of oestradiol binding capacity was observed with high concentrations of progesterone, clogestone and medrogestone. These findings are in good agreement with those previously obtained by the same progestins in our laboratory on rat uterine estrogen receptors in vitro or in vivo. These results provide support for the hypothesis that the mode of action of progestins in the therapy of mammary and perhaps uterine carcinomas is to some extent related to the inhibition of oestradiol binding to cytosol specific receptors.

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L-750355, a human ß3-adrenoceptor agonist; in vitro pharmacology and profile of activity in vivo in the rhesus monkey

European Journal of Pharmacology ◽

10.1016/s0014-2999(00)00724-x ◽

2000 ◽

Vol 407 (1-2) ◽

pp. 175-181 ◽

Cited By ~ 3

Author(s):

Michael J Forrest ◽

Gary Hom ◽

Tom Bach ◽

Mari Rios Candelore ◽

Margaret A Cascieri ◽

...

Keyword(s):

Rhesus Monkey ◽

Adrenoceptor Agonist ◽

In Vitro Pharmacology

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Gene Expression Profiles in Rat Liver Slices Exposed to Hepatocarcinogenic Enzyme Inducers, Peroxisome Proliferators, and 17α-Ethinylestradiol

International Journal of Toxicology ◽

10.1080/10915810600846963 ◽

2006 ◽

Vol 25 (5) ◽

pp. 379-395 ◽

Cited By ~ 6

Author(s):

Gisela Werle-Schneider ◽

Andreas Wölfelschneider ◽

Marie Charlotte von Brevern ◽

Julia Scheel ◽

Thorsten Storck ◽

...

Keyword(s):

Gene Expression ◽

Rat Liver ◽

Mode Of Action ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Peroxisome Proliferators ◽

Liver Slices ◽

Enzyme Inducers

Transcription profiling is used as an in vivo method for predicting the mode-of-action class of nongenotoxic carcinogens. To set up a reliable in vitro short-term test system DNA microarray technology was combined with rat liver slices. Seven compounds known to act as tumor promoters were selected, which included the enzyme inducers phenobarbital, α-hexachlorocyclohexane, and cyproterone acetate; the peroxisome proliferators WY-14,643, dehydroepiandrosterone, and ciprofibrate; and the hormone 17 α-ethinylestradiol. Rat liver slices were exposed to various concentrations of the compounds for 24 h. Toxicology-focused TOXaminer™ DNA microarrays containing approximately 1500 genes were used for generating gene expression profiles for each of the test compound. Hierarchical cluster analysis revealed that (i) gene expression profiles generated in rat liver slices in vitro were specific allowing classification of compounds with similar mode of action and (ii) expression profiles of rat liver slices exposed in vitro correlate with those induced after in vivo treatment (reported previously). Enzyme inducers and peroxisome proliferators formed two separate clusters, confirming that they act through different mechanisms. Expression profiles of the hormone 17 α-ethinylestradiol were not similar to any of the other compounds. In conclusion, gene expression profiles induced by compounds that act via similar mechanisms showed common effects on transcription upon treatment in vivo and in rat liver slices in vitro.

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