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

1986 ◽  
Vol 70 (2) ◽  
pp. 147-153 ◽  
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.

Acute and chronic regulation of α2-adrenoceptor number and function in man

1985 ◽  
Vol 68 (s10) ◽  
pp. 129s-132s ◽  
Author(s):  
C. R. Jones ◽  
C. A. Hamilton ◽  
K. F. Whyte ◽  
H. L. Elliott ◽  
J. L. Reid
Keyword(s):  
Radioligand Binding ◽  
Plasma Catecholamines ◽  
Platelet Response ◽  
Dynamic Regulation ◽  
Α2 Adrenoceptor ◽  
Adrenoceptor Agonist ◽  
Adrenoceptor Agonists ◽  
Receptor Inactivation ◽  
And Function

1. Agonist regulation of platelet α2-adrenoceptors was examined in human volunteers after acute elevations of adrenoceptor agonist and during chronic elevation of plasma catecholamines in two patients with phaeochromocytoma. 2. Platelet α2-adrenoceptor number was measured by radioligand binding ([3H]yohimbine) and α2-adrenoceptor function measured by turbidimetric platelet aggregation. 3. Short term infusion of adrenoceptor agonists with α2 activity caused reductions in the platelet response to adrenaline in vitro; conversely an increase in activity was observed postoperatively in two patients after removal of phaeochromocytoma. 4. The changes in platelet response were not accompanied by changes in α2-adrenoceptor number. 5. It is proposed that a process of receptor inactivation occurs during desensitization and this is responsible for the dynamic regulation of platelet responses.

α-Adrenoceptor Changes after Oestrogen Treatment in Platelets and other Tissues in Female Rabbits

1985 ◽  
Vol 69 (2) ◽  
pp. 235-238 ◽  
Author(s):  
N. Mishra ◽  
C. A. Hamilton ◽  
C. R. Jones ◽  
C. Leslie ◽  
J. L. Reid
Keyword(s):  
Radioligand Binding ◽  
Blood Platelets ◽  
Rabbit Platelet ◽  
Oestrogen Treatment ◽  
Α2 Adrenoceptor ◽  
Adrenoceptor Agonists ◽  
Receptor Number ◽  
And Function

1. α2-Adrenoceptors on blood platelets have been widely used as a model for α-adrenoceptors in less accessible tissues. 2. The effect of oestrogen (200 μg/day intramuscularly) on α2-adrenoceptor number and function was studied in immature female rabbits. α2-Adrenoceptor number was measured in whole platelets, and membrane preparations of forebrain, hindbrain, spleen and kidney by radioligand binding. α2-Adrenoceptor function was examined by measuring platelet aggregation in vitro and circulatory responses to selective α2-adrenoceptor agonists in vivo. 3. Oestrogen treatment resulted in a significant decrease in platelet α2-adrenoceptor number and function. However, no changes were observed either in receptor number in other tissues or in responses to α2-agonists in vivo. 4. The results suggest that oestrogen modulation of rabbit platelet α2-adrenoreceptor number and function may be different from that of brain, kidney and spleen. Caution should be exercised in extrapolating results from platelets to α-adrenoceptors at other sites.

α-Adrenoceptor regulation in vivo and in vitro in the rabbit

1985 ◽  
Vol 68 (s10) ◽  
pp. 125s-128s ◽  
Author(s):  
C. A. Hamilton ◽  
C. R. Jones ◽  
J. L. Reid
Keyword(s):  
Radioligand Binding ◽  
Receptor Activation ◽  
Oestrogen Treatment ◽  
Α2 Adrenoceptor ◽  
Adrenoceptor Agonists ◽  
Organ Response ◽  
Adrenoceptor Regulation ◽  
Adrenaline Infusion

1. The relationship between α-adrenoceptor number and response has been studied in rabbits under a range of physiological and pathological conditions. 2. The effects of irreversible α-adrenoceptor blockade, maturation, ageing, oestrogen treatment, adrenaline infusion, perinephritis hypertension and sinoaortic denervation on α-adrenoceptor number and response were examined. 3. α-Adrenoceptor number was measured by radioligand binding. [3H]Prazosin and [3H]clonidine were used as ligands to measure α1- and α2-adrenoceptor number in spleen and [3H]yohimbine to measure α2-adrenoceptor number on platelets. Responses in vivo were studied by examining the pressor responses to a range of α-adrenoceptor agonists. The functional response of platelets was examined in vitro by using the aggregatory response to adrenaline. 4. Reductions in α2-adrenoceptor ligand binding were consistently accompanied by equivalent reductions in α2-adrenoceptor-mediated responses. In contrast large reductions in [3H]prazosin binding were observed with little or no change in α1-adrenoceptor-mediated responses. 5. These results would be consistent with a large receptor reserve for α1-adrenoceptors but few if any spare α2-adrenoceptors in the vasculature or on platelets. 6. Increased responses to both α1- and α2-adrenoceptor agonists were observed in animals with sinoaortic denervation and to α1-adrenoceptor agonists in rabbits with perinephritis hypertension. These increases in response were not accompanied by increases in radioligand binding and may be related to alterations in the coupling of receptor activation to end-organ response.

scholarly journals Vagally mediated gastric effects of brain stem α2-adrenoceptor activation in stressed rats

2018 ◽  
Vol 314 (4) ◽  
pp. G504-G516 ◽  
Author(s):  
Yanyan Jiang ◽  
Kirsteen N. Browning ◽  
Luca Toti ◽  
R. Alberto Travagli
Keyword(s):  
Chronic Stress ◽  
Acute Stress ◽  
Gastric Tone ◽  
Α2 Adrenoceptor ◽  
Adrenoceptor Agonist ◽  
Cholinergic Tone ◽  
Relevant Role ◽  
In Vivo Effects

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.

scholarly journals Prognostic Value and Function of KLF5 in Papillary Thyroid Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 185
Author(s):  
Poyil Pratheeshkumar ◽  
Abdul K. Siraj ◽  
Sasidharan Padmaja Divya ◽  
Sandeep Kumar Parvathareddy ◽  
Sarah Siraj ◽  
...  
Keyword(s):  
Binding Sites ◽  
Specific Inhibitor ◽  
Papillary Thyroid ◽  
Self Renewal ◽  
Functional Correlation ◽  
Xenograft Growth ◽  
Molecular Therapeutic ◽  
And Function

The Krüppel-like factor 5 (KLF5), a zinc-finger transcriptional factor, is highly expressed in several solid tumors, but its role in PTC remains unclear. We investigated the expression of KLF5 protein in a large cohort of PTC patient samples and explored its functional role and mechanism in PTC cell lines in vitro and in vivo. KLF5 overexpression was observed in 65.1% of all PTC cases and it was significantly associated with aggressive clinico-pathological parameters and poor outcome. Given the significant association between KLF5 and HIF-1α overexpression in PTC patients, we investigated the functional correlation between KLF5 and HIF-1α in PTC cells. Indeed, the analysis revealed the co-immunoprecipitation of KLF5 with HIF-1α in PTC cells. We also identified KLF5-binding sites in the HIF-1α promoter that specifically bound to KLF5 protein. Mechanistically, KLF5 promoted PTC cell growth, invasion, migration, and angiogenesis, while KLF5 downregulation via specific inhibitor or siRNA reverses its action in vitro. Importantly, the silencing of KLF5 decreases the self-renewal ability of spheroids generated from PTC cells. In addition, the depletion of KLF5 reduces PTC xenograft growth in vivo. These findings suggest KLF5 can be a possible new molecular therapeutic target for a subset of PTC.

scholarly journals The modulation of ureteral smooth muscle contractile responses by α1- and α2-adrenoceptor activation

2018 ◽  
Vol 105 (3) ◽  
pp. 225-232
Author(s):  
DR Monks ◽  
SJ Bund
Keyword(s):  
Smooth Muscle ◽  
Contractile Function ◽  
Contractile Responses ◽  
Α2 Adrenoceptor ◽  
Adrenoceptor Agonist ◽  
Adrenoceptor Agonists ◽  
Muscle Contractile

Purpose This study was performed to investigate the influence of α-adrenoceptor subtypes upon ureteral smooth muscle contractile responses. Methods Rat ureters were challenged in vitro with noradrenaline (NA), the α1-adrenoceptor agonist phenylephrine (PE), and the α2-adrenoceptor agonist clonidine (CLON). The influences of the agonists on the magnitude and frequency of acetylcholine (ACh)-stimulated phasic contractile responses were recorded. Results The magnitude of the phasic contractile responses effected by ACh was not significantly influenced by the adrenoceptor agonists, but the frequency of the response was significantly enhanced by all three agonists (p < 0.05). Idazoxan and prazosin abolished the rise in frequency effected by CLON and PE, respectively, whereas both antagonists in combination were required to abolish the increase in frequency effected by NA. Conclusions It has been demonstrated that α1- and α2-adrenoceptors modulate the contractile function of rat ureteral smooth muscle by increasing the frequency, but not the magnitude, of phasic contractile responses. The enhancement of contractile function by NA is mediated by mechanisms dependent upon both α1- and α2-adrenoceptors.

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

2008 ◽  
Vol 599 (1-3) ◽  
pp. 65-71 ◽  
Author(s):  
Jyrki Lehtimäki ◽  
Tiina Leino ◽  
Ari Koivisto ◽  
Timo Viitamaa ◽  
Tarja Lehtimäki ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Local Mode ◽  
Α2 Adrenoceptor ◽  
Adrenoceptor Agonist

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

1992 ◽  
Vol 68 (06) ◽  
pp. 687-693 ◽  
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.

Half-Life of Platelet Factor 4 (PF-4) in Plasma and Platelets from Macaca Mulatta

1977 ◽  
Vol 37 (01) ◽  
pp. 073-080 ◽  
Author(s):  
Knut Gjesdal ◽  
Duncan S. Pepper
Keyword(s):  
Macaca Mulatta ◽  
Half Life ◽  
Human Platelet ◽  
Gel Filtration ◽  
Platelet Factor 4 ◽  
Active Protein ◽  
Platelet Factor ◽  
Membrane Bound

SummaryHuman platelet factor 4 (PF-4) showed a reaction of complete identity with PF-4 from Macaca mulatta when tested against rabbit anti-human-PF-4. Such immunoglobulin was used for quantitative precipitation of in vivo labelled PF-4 in monkey serum. The results suggest that the active protein had an intra-platelet half-life of about 21 hours. In vitro 125I-labelled human PF-4 was injected intravenously into two monkeys and isolated by immuno-precipita-tion from platelet-poor plasma and from platelets disrupted after gel-filtration. Plasma PF-4 was found to have a half-life of 7 to 11 hours. Some of the labelled PF-4 was associated with platelets and this fraction had a rapid initial disappearance rate and a subsequent half-life close to that of plasma PF-4. The results are compatible with the hypothesis that granular PF-4 belongs to a separate compartment, whereas membrane-bound PF-4 and plasma PF-4 may interchange.

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