To see the other types of publications on this topic, follow the link: 1-adrenergic receptors.
Dissertations / Theses on the topic '1-adrenergic receptors'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 44 dissertations / theses for your research on the topic '1-adrenergic receptors.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Broso, Francesca. "Alpha-1-Adrenergic receptors as new targets in Neuroblastoma." Doctoral thesis, Università degli studi di Trento, 2021. http://hdl.handle.net/11572/318323.
Full textAbstract:
High-risk neuroblastoma (NB) is an aggressive childhood tumor that originates from progenitor neural crest cells. Even if the therapeutic protocol for NB is articulate and aggressive, the outcome remains dismal, with the 5-year disease-free overall survival below rating 50%. A novel drug combination strategy can possibly provide a new solution to this unmet therapeutic need. 13-cis retinoic acid (13-cis-RA, isotretinoin) is an anti-proliferative and pro-differentiative agent currently used in the post-consolidation phase of NB therapy. To identify molecules able to potentiate the anti-proliferative activity of 13-cis-RA, NB cells were treated with a library of 169 naturally occurring polyphenols in combination with the retinoid. This in vitro screen led to the identification of isorhamnetin as a synergistic partner of 13-cis-RA, producing an 80% reduction in cell viability. At the molecular level, this synergistic effect is followed by a marked increase in the expression of a member of the catecholamine receptor superfamily: the adrenergic receptor alpha-1B (ADRA1B) suggesting that this receptor might represent a key mediator of the synergistic effect of 13-cis-RA and isorhamnetin observed in vitro. This finding redirected our attention to the class of adrenergic receptors (ARs) as novel targets in NB. To investigate the role of ADRA1B in the synergism, we generated CHP134 NB cell lines knocked-out (KO) for the receptor and observed that exposure of CHP134 KO cell to 13-cis-RA leads to a reduction of cell viability and neural differentiation. We, therefore, substituted the genetic KO strategy with the alpha-1B adrenergic antagonist, L765,314, obtaining the same results. Subsequently, we extended the analysis on the role of adrenergic receptors (AR) performing a biased screen using two libraries of AR-ligands. The screen results confirm that the molecules working as alpha-1-ARs antagonists are those that greatly increase cell sensitivity to 13-cis-RA with reduction of cell viability and increase in differentiation. We confirmed our observation in NB xenograft mice models in vivo, treating mice with a combination of 13-cis-RA and the FDA approved alpha-1 AR antagonist doxazosin. The proposed pharmacological treatment was effective in slowing tumor growth, leading to tumors of smaller size. From our results, we can conclude that the deletion or inhibition of alpha-1-AR sensitizes NB cells to 13-Cis-RA, both in terms of induction of apoptosis and neural differentiation. Since NB is a catecholamine-rich tumor, we propose that antagonization of alpha-1-AR disrupts the established autocrine pro-survival circuit generated by catecholamines in NB and restores the ability of the cells to follow the pro-differentiative and pro-apoptotic programs endorsed by 13-cis-RA. Considering the druggable nature of the alpha-1-AR receptors, we indicate this class of receptors as a novel pharmacological target for the treatment of neuroblastoma.
2
Broso, Francesca. "Alpha-1-Adrenergic receptors as new targets in Neuroblastoma." Doctoral thesis, Università degli studi di Trento, 2021. http://hdl.handle.net/11572/318323.
Full textAbstract:
High-risk neuroblastoma (NB) is an aggressive childhood tumor that originates from progenitor neural crest cells. Even if the therapeutic protocol for NB is articulate and aggressive, the outcome remains dismal, with the 5-year disease-free overall survival below rating 50%. A novel drug combination strategy can possibly provide a new solution to this unmet therapeutic need. 13-cis retinoic acid (13-cis-RA, isotretinoin) is an anti-proliferative and pro-differentiative agent currently used in the post-consolidation phase of NB therapy. To identify molecules able to potentiate the anti-proliferative activity of 13-cis-RA, NB cells were treated with a library of 169 naturally occurring polyphenols in combination with the retinoid. This in vitro screen led to the identification of isorhamnetin as a synergistic partner of 13-cis-RA, producing an 80% reduction in cell viability. At the molecular level, this synergistic effect is followed by a marked increase in the expression of a member of the catecholamine receptor superfamily: the adrenergic receptor alpha-1B (ADRA1B) suggesting that this receptor might represent a key mediator of the synergistic effect of 13-cis-RA and isorhamnetin observed in vitro. This finding redirected our attention to the class of adrenergic receptors (ARs) as novel targets in NB. To investigate the role of ADRA1B in the synergism, we generated CHP134 NB cell lines knocked-out (KO) for the receptor and observed that exposure of CHP134 KO cell to 13-cis-RA leads to a reduction of cell viability and neural differentiation. We, therefore, substituted the genetic KO strategy with the alpha-1B adrenergic antagonist, L765,314, obtaining the same results. Subsequently, we extended the analysis on the role of adrenergic receptors (AR) performing a biased screen using two libraries of AR-ligands. The screen results confirm that the molecules working as alpha-1-ARs antagonists are those that greatly increase cell sensitivity to 13-cis-RA with reduction of cell viability and increase in differentiation. We confirmed our observation in NB xenograft mice models in vivo, treating mice with a combination of 13-cis-RA and the FDA approved alpha-1 AR antagonist doxazosin. The proposed pharmacological treatment was effective in slowing tumor growth, leading to tumors of smaller size. From our results, we can conclude that the deletion or inhibition of alpha-1-AR sensitizes NB cells to 13-Cis-RA, both in terms of induction of apoptosis and neural differentiation.
Since NB is a catecholamine-rich tumor, we propose that antagonization of alpha-1-AR disrupts the established autocrine pro-survival circuit generated by catecholamines in NB and restores the ability of the cells to follow the pro-differentiative and pro-apoptotic programs endorsed by 13-cis-RA. Considering the druggable nature of the alpha-1-AR receptors, we indicate this class of receptors as a novel pharmacological target for the treatment of neuroblastoma.
3
Zolty, Ronald. "Beta 1 and Alpha 2C adrenergic receptor polymorphisms and response to beta blockers in heart failure patients /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
Find full textAbstract:
Thesis (Ph.D. in Clinical Science) -- University of Colorado Denver, 2007.<br>Typescript. Includes bibliographical references (leaves 130-142). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
4
Stamer, William Daniel 1964. "Characterization of alpha(2)-adrenergic receptors and aquaporin-1 water channels in the human eye." Diss., The University of Arizona, 1996. http://hdl.handle.net/10150/282123.
Full textAbstract:
In most cells, water moves across the plasma membrane by simple diffusion. However, there are specialized epithelia, such as the kidney proximal tubules, that secrete or absorb water faster than simple diffusion predicts. While the identification of a proteinacious pore that transports water was elusive for many years, the recent discovery of aquaporin-1 (AQP-1) provides a molecular mechanism for the extraordinarily high permeability to water of epithelial cells in these tissues. Like the kidney, the human eye has several epithelial-lined structures that have a high permeability to water. One of these structures, the ciliary process, secretes aqueous humor (comprised mostly of water) into the eye and is regulated therapeutically by activating α₂-adrenergic receptors (α₂-AR) on its plasma membrane. The studies presented in this dissertation are structured to address four specific aims that were designed to test the hypothesis that the AQP-1 water channels are present in the human eye and are functionally regulated by α₂-ARs. Specific aim 1 characterized the distribution of AQP-1 in the human eye by immunofluorescence microscopy using affinity purified antibodies against purified AQP-1 protein. Using standard techniques in molecular biology, specific aim 2 generated antibodies to three fusion proteins; each containing a specific region of AQP-1. After screening several cell lines from the eye and the kidney with anti-AQP-1 and anti-α₂-AR IgY, specific aim 3 identified a cell line, human trabecular meshwork (HTM) cells, that contains both the AQP-1 water channels and α₂-ARs. Lastly, specific aim 4 investigated the functional relationship between the α₂-ARs and AQP-1 water channels. Using HTM cells as a model, the activation of α₂-ARs did not measurably affect AQP-1 messenger RNA or AQP-1 protein levels as compared to control. However, since the α₂-ARs primarily couple to cyclic AMP (cAMP) and several other aquaporins are regulated by cAMP, the effect of cAMP on AQP-1 was investigated. Using Xenopus oocytes expressing AQP-1 as a model, stimulation of oocytes with forskolin, a drug which increases intracellular cAMP, increased the permeability of AQP-1 to water. This observation provided evidence that is consistent with the general hypothesis that AQP-1 water channels and α₂-ARs are functionally coupled.
5
Al-Khairi, Irina. "Characterization of signal transduction pathways of alpha-1 adrenergic receptors in neonatal ventral hippocampus lesion rat model." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112374.
Full textAbstract:
Neonatal ventral hippocampus (nVH) lesioned animals show molecular and behavioral abnormalities analogous to those described in schizophrenia. As an extension to previous studies that showed an increase in ligand binding of cortical alpha-1 adrenergic receptors (AR) and a dysfunction in alpha-1 AR regulation of mesolimbic dopamine functions in post-pubertal nVH lesioned rats, we investigated the subcellular expression and activity of protein kinase C (PKC)---a second messenger in alpha-1 AR signaling---in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) of post-pubertal nVH lesioned rats. Western blot analysis of membrane and cytosolic fractions showed complex changes in lesioned animals in the expression of different PKC subtypes following saline or alpha-1 AR agonist (cirazoline i.p.) injection. Among these changes, nVH lesioned animals showed a significant increase in membrane bound PKC alpha and phospho-PKC, and a decrease in cytosolic PKC gamma and PKC betaII in the PFC in comparison to sham-lesioned controls following saline. Cirazoline increased membrane bound PKC alpha in controls but decreased it in lesioned animals. In the NAcc, lesioned animals showed an increase in membrane bound and cytosolic PKC epsilon and PKC lambda levels following saline. Following cirazoline, lesioned animals showed a decrease in membrane bound PKC epsilon and PKC lambda, while controls showed an increase in cytosolic and membrane fractions of PKC epsilon with no change in PKC lambda. In vitro PKC activity assays showed increased basal activity in PFC slices of lesioned animals compared to controls, with no difference in NAcc slices. alpha-1 AR stimulation by the agonist phenylephrine (PE) increased PKC activity in PFC of controls while decreasing activity substantially in lesioned animals. In the NAcc, high concentrations of PE increased activity in controls, but decreased activity in lesioned animals. This abnormal expression and activity of PKC in the PFC and NAcc of nVH lesioned animals may be related to abnormal alpha-1 AR functions and may modulate some of the abnormal neuronal functions in these animals, such as working memory deficits and hyper neuronal excitability of the PFC and the NAcc.
6
Raji, Ismaila. "Effect of Tulbaghia violacea on the blood pressure and heart rate in male spontaneously hypertensive wistar rats." Thesis, University of the Western Cape, 2011. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_5212_1367481132.
Full textAbstract:
<p>Tulbaghia violacea Harv. (Alliaceae) is a small bulbous herb which belongs to the family, Alliaceae, most commonly associated with onions and garlic. In South Africa (SA), this <br>herb has been traditionally used in the treatment of various ailments, including fever, colds, asthma, paralysis, hypertension (HTN) and stomach problems. The aim of this study <br>was to evaluate the effect of methanol leaf extracts (MLE) of T. violacea on the blood pressure (BP) and heart rate (HR) in anaesthetized male spontaneously hypertensive rats<br> <br>and to find out the mechanism(s) by which it acts. The MLE of T. violacea (5 - 150 mg/kg), angiotensin I (ang I, 3.1 - 100 &mu<br>g/kg), captopril (10 mg/kg), angiotensin II (ang II, 3.1 - 50 <br>g/kg), losartan (30 mg/kg), phenylephrine (0.01 &ndash<br>0.16 mg/kg), prazosin (1 mg/kg), dobutamine (0.2 &ndash<br>10.0 &mu<br>g/kg), propranolol (0.1 - 12.8 mg/kg), muscarine (0.16 -10 &mu<br>g/kg), <br>and atropine (0.02 - 20.48 mg/kg) were administered intravenously into male spontaneously hypertensive rats (SHR) weighing between 300 g and 350 g and aged less than 5 <br>months. The MLE of T. violacea and/or the standard drugs were infused alone, simultaneously, or separately into each animal. The BP and HR were measured via a pressure <br>transducer connecting the femoral artery and the Powerlab. The vehicle (0.2 mls of a mixture of dimethylsulfoxide and normal saline), T. violacea (60 mg/kg) and captopril (10 <br>mg/kg) were injected intraperitoneally into some SHR for 21 days to investigate the chronic effect of these agents on plasma levels of aldosterone. The mean change, the mean <br>of the individual percentage changes and the percentage difference (in mean) observed with each intervention was calculated and statistically analyzed using the Student&rsquo<br>s t test <br>for significant difference (p <<br>0.05). The Microsoft Excel software was used for statistical analysis. T. violacea significantly (p <<br>0.05) reduced the systolic, diastolic, and mean <br>arterial BP<br>and HR dose-dependently. In a dose-dependent manner, ang I, ang II, phenylephrine significantly (p <<br>0.05) increased the BP, while propranolol, muscarine and <br>atropine reduced the BP. The increases in BP due to dobutamine were not dose-dependent. In a dose dependent manner, phenylephrine and propranolol reduced the HR, while dobutamine increased the HR. The effect of ang I, ang II, muscarine and atropine on HR were not dose-dependent<br>with both increases as well as decreases observed with ang <br>I, and II and atropine, while decreases were seen with muscarine. Captopril produced <br>significant (p <<br>0.05) reduction in BP which were not associated with any change in HR. The co-infusion of ang I with the MLE produced significant (p <<br>0.05) reduction in BP, which were not associated with significant changes in HR. The co-infusion of ang II with the <br>MLE did not produce any significant changes in BP or HR when compared to the infusion of the standard drug alone. The co-infusion of phenylephrine with the MLE did not <br>produce any significant change in BP or HR when compared to the values obtained with the infusion of the standard drug alone, in both the absence and presence of prazosin. <br>The co-infusion of dobutamine with T. violacea produced siginificant (p <<br>0.05) increases in DBP which were associated with significant (p <<br>0.05) reductions in HR, when <br>compared to the values obtained with the infusion of the standard drug alone. Theco-infusion of atropine with the MLE did not produce any significant change in BP or HR when <br>compared to the values obtained with the infusion of atropine alone. However, the infusion of T. violacea, 20 minutes after pre-treating animals with atropine (5.12 mg/kg) lead to <br>dose dependent significant (p <<br>0.05) increases in BP, which were associated with dose-dependent increases in HR. The chronic treatment of animals with T. violacea or <br>captropril produced (a) signicant (p <<br>0.05) reductions in the plasma levels of aldosterone when compared to the values obtained in the vehicle-treated group, (b) produced <br>signifiant (p <<br>0.05) reduction in BP in the captopril treated group when compared to the vehicle-treated, (c) did not produce any signficant change in BP in the T. violacea-treated <br>group when compared to the vehicle-treated group and (d) did not produce any signifiant change in HR or body weight in any of the groups. The result obtained in this study <br>suggests that T. violacea reduced BP and HR in the SHR. Secondly, the BP and HR reducing effect of the MLE may involve a) the inhibition of the ACE, b) the inhibition of the &beta<br>1 <br>adrenoceptors, c) the stimulation of the muscarinic receptors and d) the reduction of the levels of aldosternone in plasma. The results also <br>suggest that the MLE may not act <br>through the angiotensin II receptors or the &alpha<br>1 adrenergic receptors. <br></p>
7
Walker, Mollie. "Characterisation of α-1 adrenergic receptors in peripheral blood mononuclear cells of complex regional pain syndrome". Thesis, Walker, Mollie (2017) Characterisation of α-1 adrenergic receptors in peripheral blood mononuclear cells of complex regional pain syndrome. Honours thesis, Murdoch University, 2017. https://researchrepository.murdoch.edu.au/id/eprint/38078/.
Full textAbstract:
Complex regional pain syndrome (CRPS) is a chronic pain condition that may occur after injury or trauma to a limb. The underlying pathophysiology of CRPS is largely undetermined, although CRPS patients commonly present with a persisting inflammatory response in the early stage of the condition and overexpress the α-1 adrenergic receptor (α-1AR) on nociceptors and keratinocytes in the affected limb. In other chronic inflammatory conditions, increased α-1AR mRNA expression in peripheral blood mononuclear cells (PBMCs) has been shown, and is thought to contribute to persisting inflammation. The α-1AR are expressed on a range of cells, including nerve, smooth muscle, skin and immune cells, and bind to adrenaline and noradrenaline released after activation of the sympathetic nervous system. The aims of this project were to examine the mRNA expression of α-1AR subtypes (α-1A, α-1B and α-1D) by qPCR in PBMCs isolated from fractionated blood of CRPS patients, and to quantify the percentages of various PBMC subpopulations compared to healthy controls. Subpopulations of PBMCs were determined by flow cytometry using a panel of fluorescent antibodies that identified CD4+ T cells, CD8+ T cells, CD4+ CD8+ T cells, CD4+ CD25+ T cells, CD8+ CD25+ T cells, B cells, natural killer (NK) cells, NKT cells, and subsets of monocytes. No differences in expression of α- 1AR subtypes in PBMCs of CRPS patients were found when compared to healthy controls. However, a significant increase in the concentration of total PBMCs isolated per mL of blood in CRPS patients and a shift from CD16- to CD16+ monocyte subpopulations was identified when compared to healthy controls. These results show there is an inflammatory component to CRPS and provide preliminary evidence that the persisting inflammation in CRPS patients may originate from over-proliferation of PBMC progenitors in the bone marrow, which is sympathetically modulated by α-1AR, and/or an expansion of other PBMC cell types that were not examined in this project.
8
Kamath, Aarthi. "Alterations in responsiveness and mRNA expression of alpha-1 adrenergic receptors in neonatal ventral hippocampus lesioned rats." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=18675.
Full textAbstract:
Neonatal ventral hippocampus (nVH) lesion in rats is a widely accepted animal model of schizophrenia due to the exclusively post-pubertal emergence of many schizophrenia-like abnormalities. Previous studies have shown increased ligand binding of a-1 adrenergic receptors (AR) in the frontal cortex of post-pubertal nVH lesioned rats, compared to sham-operated control rats. Also, pretreatment with a-1 AR antagonist prazosin reversed amphetamine-induced hyperlocomotion in controls, but failed to do so in lesioned animals. In order to investigate the hypothesis that nVH lesions may lead to hyperactivity of a-1 AR, we studied locomotor behavior and prepulse inhibition (PPI) in post-pubertal (PD56-90) sham and lesioned animals in response to different doses of a-1 AR agonist cirazoline. Results showed that 0.6 mg/kg cirazoline significantly increased locomotor activity in both groups of animals, without any differential effect on nVH lesioned animals. However, lesioned animals showed a substantial decrease in PPI in response to an intermediate dose of 0.45 mg/kg cirazoline that did not significantly reduce PPI in control animals. This deficit was blocked by pretreatment with prazosin, demonstrating that the effect of cirazoline was through activation of a-1 ARs. Together, these results suggest that nVH lesioned animals show a hyperactive a-1 AR system that may regulate at least some behaviors that are abnormal in these animals. In situ hybridization using digoxigenin-labeled, subtype-specific oligonucleotide probes for a-1 AR mRNA revealed a significantly higher number of cells labeled for a-1A AR mRNA, a lower number of cells labeled for a-1D AR mRNA, and no difference in the number of cells labeled for a-1B AR mRNA in the medial prefrontal cortex of nVH lesioned rats. These results suggest that alterations at the level of transcription of genes encoding for some a-1 AR subtypes may be responsible for the abnormal adrenergic system in nVH lesioned animals.<br>La lésion ventrale néonatale de l'hippocampe (nVH) chez les rats est largement admise comme modèle animal de la schizophrénie. Des études antérieures ont montré une augmentation de liaison aux récepteurs adrénergiques (AR) a-1 dans le cortex frontal des rats post-pubères ayant des lésions au niveau du nVH (nVHL) comparativement aux rats contrôles. De plus, l'hyperlocomotion normalement induite chez les rats contrôles par l'amphétamine est abolit par le prétraitement de ces rats avec le prazosin, un antagoniste du AR a-1, alors que ce dernier est sans effet sur les rats avec lésions.. Afin d'investiguer l'hypothèse que des lésions au niveau du nVH peuvent mener à l'hyperactivité du AR a-1, nous avons étudié les comportements locomoteurs et la «prepulse inhibition» (PPI) chez les rats contrôles (PD56-90) et les nVHL, en réponse à différentes doses de l'agoniste adrénergique a-1 cirazoline. Les résultats montrent qu'une dose de 0.6 mg/kg de cirazoline augmente significativement l'activité motrice dans les deux groupes d'animaux, sans effet différentiel chez les nVHL. Cependant, les nVHL présentent une diminution substantielle du PPI suite à l'administration de 0.45 mg/kg de cirazoline, laquelle dose ne réduit pas de manière significative la PPI chez les contrôles. Ce déficit a été bloqué par le prétraitement avec le prazosin, démontrant que les effets de la cirazoline sont médiés via l'activation du AR a-1. Ensemble, ces résultats suggèrent que les nVHL ont une hyperactivité du système adrénergique a-1, laquelle peut mener à certains comportements anormaux chez ces animaux. Nous avons utilisé des sondes marquées avec digoxigenin pour faire de l'hybridation in situ. Les sondes étaient spécifiques pour différents sous-types d'oligonucléotides d'ARNm de AR a-1. Les resultats ont indiqué un nombre sensiblement plus élevé de cellules marquées par l'ARNm a-1A, un nombre inférieur de cellules marquées par l'ARN
9
McLean, Alison Jane. "Ligand regulation of #beta#â†1- and #beta#â†2- adrenergic receptors and their GFP-tagged forms." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323436.
Full text
10
Manion, Sean T. "Amygdala, anxiety & alpha-1 adrenoreceptors : investigations utilizing a rodent model of traumatic stress /." Download the thesis in PDF, 2006. http://www.lrc.usuhs.mil/dissertations/pdf/Manion2006.pdf.
Full text
11
Harrigan, Tom. "The effects of central I¦1-imidazoline and æ2-adrenergic receptors on body temperature regulation in conscious rats." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ53047.pdf.
Full text
12
Nagabhushan, Sahana. "Neural Mechanisms Underlying Stress-Induced Depression and Its Prevention." Kent State University Honors College / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors1304462392.
Full text
13
Hakalahti, A. (Anna). "Human β1-adrenergic receptor:biosynthesis, processing and the carboxyl-terminal polymorphism". Doctoral thesis, Oulun yliopisto, 2011. http://urn.fi/urn:isbn:9789514295263.
Full textAbstract:
Abstract The β1-adrenergic receptor (β1AR) belongs to the large family of G protein-coupled receptors. It is activated by epinephrine and norepinephrine and thus has a central role in mediating the effects of the sympathetic nervous system. β1AR is the predominant adrenergic receptor in the heart, where it mediates positive inotropy and chronotropy. Thus, it is the most important target receptor for β-adrenergic antagonists, which are widely used in the treatment of cardiovascular diseases. Furthermore, β1AR is also expressed in the brain, where it has a crucial role in regulating memory formation and synaptic plasticity. Human β1AR (hβ1AR) has two polymorphisms, one at each terminus. The carboxyl-terminal (C-terminal) Arg389Gly8.56 polymorphism has previously been shown to have functional significance. Despite the clinical importance of hβ1AR, its biosynthetic profile and post-translational processing have not been well characterized to date. The aims of the present study were to shed light on these events, focusing on the limited proteolysis of hβ1AR and the impact of β-adrenergic ligands on receptor processing. In addition, the C-terminal polymorphism and its associations with certain parameters were investigated in a population consisting of survivors of acute myocardial infarction (AMI). By using a heterologous expression system, hβ1AR biosynthesis was revealed to be efficient and rapid. The N-terminus of the mature receptor was modified with O-glycans and one N-glycan, but despite these modifications it was subject to cleavage at the cell surface that resulted in two C-terminal fragments. The cleavage was mediated by a metalloproteinase, and importantly, it also occurred in vivo. Moreover, receptor activation enhanced the cleavage, which suggests that it represents a novel regulatory mechanism of hβ1AR. Interestingly, those ligands that enhanced the cleavage stabilized intracellular hβ1AR precursors, possibly via a pharmacological chaperone activity. Thus, the present study demonstrates that β-adrenergic ligands can have different regulatory effects on distinct hβ1AR forms. Among the AMI survivors, the Arg3898.56 homozygotes had significantly increased left ventricular mass indexes, when compared to the Gly3898.56 carriers, which suggests an association between Arg3898.56 and left ventricular hypertrophy (LVH). When euglycemic and diabetic patients were analyzed separately, the association existed among the euglycemic patients but was not present in diabetic patients. Diabetes is one of several risk factors that have previously been shown to influence the progression of LVH. Here, diabetes was shown to have a stronger effect on the development of LVH, when compared with the Arg3898.56 variant of hβ1AR<br>Tiivistelmä β1-adrenerginen reseptori (β1AR) kuuluu laajaan G-proteiineihin kytkettyjen reseptorien perheeseen. β1AR on tärkeässä asemassa sympaattisen hermoston toiminnassa. Sydämessä β1AR on vallitseva adrenerginen reseptori, ja sydänlihaksen supistusvireys sekä -taajuus voimistuvat β1AR:n aktivaation kautta. Siten se edustaa sydän- ja verisuonisairauksissa käytettävien β-salpaajien tärkeintä kohdereseptoria. β1AR:n luontaisia agonisteja ovat lisämunuaisytimestä ja hermopäätteistä vapautuvat adrenaliini ja noradrenaliini. Sydänlihaksen lisäksi β1AR:a ilmennetään myös aivoissa, jossa reseptorilla on keskeinen asema muistin ja synaptisen muovautuvuuden kannalta. Ihmisen β1AR (hβ1AR) sisältää kaksi polymorfismia, joista toinen (Arg389Gly8.56) sijaitsee reseptorin karboksyyli- (C-) terminaalissa solulimassa. Tällä polymorfismilla on havaittu olevan toiminnallista merkitystä. Vaikka hβ1AR:n kliininen merkitys on huomattava, sen biosynteesistä ja translaationjälkeisestä muokkauksesta ei ole tähän mennessä ollut juurikaan tutkimustietoa. Tämän väitöskirjatyön tavoite oli kuvata näitä tapahtumia ja erityisesti keskittyä hβ1AR:n solunulkoisen amino- (N-) terminaalin rajoitettuun proteolyysiin. Lisäksi haluttiin tutkia, onko β-adrenergisillä ligandeilla vaikutusta reseptorin prosessointiin. Tutkimuksen kliinisessä osiossa kartoitettiin C-terminaalisen polymorfian yhteyttä valikoituihin muuttujiin aineistossa, joka koostui akuutin sydäninfarktin (AMI) sairastaneista potilaista. hβ1AR:n biosynteesin havaittiin olevan tehokas ja nopea heterologisessa systeemissä. Kypsän reseptorin N-terminaalissa havaittiin useita O-kytkennäisiä ja yksi N-kytkennäinen glykaani. Glykosyloinnista huolimatta N-terminaali pilkkoutui solun pinnalla, mikä tuotti kaksi solukalvolla sijaitsevaa, C-terminaalista reseptoripalasta. Pilkkoutumista, joka havaittiin myös in vivo, katalysoi metalloproteinaasi. Reseptorin aktivaatio kiihdytti pilkkoutumista, joka siten todennäköisesti edustaa uudenlaista hβ1AR:n säätelymekanismia. Ligandit, jotka kiihdyttivät pilkkoutumista, toisaalta stabiloivat solunsisäisiä hβ1AR:n epäkypsiä muotoja toimien luultavasti ns. farmakologisina kaperoneina. Näin ollen väitöskirjatyö osoittaa, että β-adrenergisillä ligandeilla voi olla erilaisia säätelyvaikutuksia eri hβ1AR-muotoihin. Kliinisessä tutkimuksessa Arg3898.56-homotsygooteilla potilailla havaittiin merkittävästi suurentunut vasemman kammion massaindeksi Gly3898.56-kantajiin verrattuina, mikä puoltaa Arg3898.56-polymorfismin ja vasemman kammion hypertrofian (LVH) välistä yhteyttä. Kun euglykeemisiä potilaita ja diabeetikkoja tutkittiin erikseen, yhteys ilmeni vain euglykeemisessä ryhmässä. Diabetes on riskitekijä, joka vaikuttaa LVH:n kehittymiseen. Tässä tutkimuksessa diabeteksellä havaittiin olevan voimakkaampi vaikutus LVH:n kehittymiseen Arg3898.56 -polymorfismiin verrattuna
14
Janota, Danielle Marie. "Alpha1-Adrenergic Receptor Activation Mimics Ischemic Postconditioning in Cardiac Myocytes." Kent State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=kent1406562863.
Full text
15
Wang, Jingping. "Contribution of ߦ1- and ߦ2-adrenergic receptors to the sympathetic stimulation of L-type calcium current in isolated guinea pig ventricular cardiomyocytes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq24939.pdf.
Full text
16
Marcus, Monica M. "Mechanism of action of antipsychotic drugs: focus on the nucleus accumbens and the prefrontal cortex : an experimental study /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-284-5/.
Full text
17
Sun, Ruoyu [Verfasser], Reinhard [Akademischer Betreuer] Nießner, Peter B. [Gutachter] Luppa, and Reinhard [Gutachter] Nießner. "Nanodiscs incorporating functional human beta-1 adrenergic receptors as novel diagnostic approach for autoimmune dilated cardiomyopathy / Ruoyu Sun ; Gutachter: Peter B. Luppa, Reinhard Nießner ; Betreuer: Reinhard Nießner." München : Universitätsbibliothek der TU München, 2018. http://d-nb.info/1185069569/34.
Full text
18
Reader, Brenda Faye. "Social Stress Induces Immunoenhancement During Allergic Airway Inflammation and Infection." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385475903.
Full text
19
Hoque, Nina. "Inhibition of æ1 adrenergic effects by adenosine A¦1 receptor activation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0001/MQ30725.pdf.
Full text
20
Vela, Jose David. "Beta adrenergic modulation of peripheral nociceptors a dissertation /." San Antonio : UTHSC, 2008. http://proquest.umi.com.libproxy.uthscsa.edu/pqdweb?did=1588778261&sid=1&Fmt=2&clientId=70986&RQT=309&VName=PQD.
Full text
21
Linnér, Love. "Noradrenergic augmentation strategies in the pharmacological treatment of depression and schizophrenia : an experimental study /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-253-1.
Full text
22
Ananthakrishnan, Kameswari, та Kameswari Ananthakrishnan. "Improved β-Cell Targeting and Therapeutics Using Multivalent Glucagon-Like Peptide-1 (GLP-1) Linked to the α2AR Antagonist Yohimbine (YHB): Evaluating the Binding, Selectivity and Signaling". Diss., The University of Arizona, 2016. http://hdl.handle.net/10150/623004.
Full textAbstract:
Diabetes Mellitus (DM) is a metabolic disorder in which the body fails to achieve glucose homeostasis, due to either insulin resistance or reduced insulin secretion or both. This inadequate glucose control leads to hyperglycemia which, if left unchecked, leads to secondary complications like nephropathy, neuropathy, retinal degeneration and other serious conditions. In non-disease state, normal glucose level in the blood is maintained by pancreatic β-cells, which secrete insulin. However, during diabetes development, there is loss of β-cell mass and function; resulting in decreased insulin secretion which is the ultimate cause of hyperglycemia. The ability to non-invasively monitor changes in the β-cell mass during the development or treatment of diabetes would be a significant advance in diabetes management. However, a primary limitation for analysis of β-cell mass and developing dysfunction is the lack of specificity of β-cell targeting agents. Our novel approach for achieving the required specificity for a usable β-cell targeted contrast agent is to target a set of receptors on the cell surface that, as a combination, are unique to that cell. Through genetic screening, Glucagon Like Peptide-1 Receptor (GLP-1R) and α2Adrenergic Receptor (α2AR) were chosen as a potential molecular barcode for β-cells since their combination expression is relatively unique to the β-cells. GLP-1R and α2AR are both G-protein couple receptors (GPCRs) that, apart from being a β-cell specific combination, play an important role in regulating fundamental downstream signaling pathways in β-cells. To target these receptors effectively, we synthesized a multivalent ligand composed of Yohimbine (Yhb), an α2 adrenergic receptor (α2AR) antagonist, linked to an active Glucagon-like Peptide 1 analog (GLP-1₇₋₃₆). In this manuscript, I describe the synthesis and characterization of binding selectivity and signaling ability of GLP-1/Yhb at the cellular level. Using high throughput binding assays, we observed high affinity binding of GLP-1/Yhb to βTC3 cells, a β-cell mimetic line expressing both receptors, at a Kd of ~3 nM. Using microscopy, we observed significant Cy5-tagged GLP-1/Yhb binding and rapid internalization in cells expressing the complementary receptor pair at low concentrations, as low as 1 nM and 5 nM. When one of the receptors was made inaccessible due to presence of saturating quantities of a single unlabeled monomer, GLP-1/Yhb-Cy5 failed to bind to the cells at low concentrations (<10 nM). Similarly, in cells where either GLP-1R or α2AR were knocked down (using shRNA), binding of GLP-1/Yhb was significantly reduced (≤half of cells with both receptors), indicating strong selectivity of the ligand to cells expressing the combination of receptors. We also observed that GLP-1/Yhb construct modulates downstream signaling inβ TC3 cells resulting in enhanced Glucose Stimulated Insulin Secretion (GSIS). In presence of stimulatory glucose, GLP-1/Yhb significantly potentiated GSIS with a half-maximal effective dose of 2.6 nM. Compared to GLP-1₇₋₃₆ alone or GLP-1₇₋₃₆ and Yhb monomers added together, only GLP-1/Yhb could significantly potentiate GSIS at 1 nM, demonstrating that GLP-1/Yhb could translate high affinity binding to increased efficacy for GSIS potentiation. Unlike for insulin secretion, high affinity divalent binding did not translate to increased cAMP production at low concentrations, with significant increases above baseline seen only at 10 nM and higher. Nevertheless, these data show that GLP-1/Yhb binds selectively to β-cells and affects signaling, demonstrating its potential for targeted β-cell imaging and therapy. Overall, our work indicates that synthetic heterobivalent ligands, such as GLP-1/Yhb can be developed to increase cellular specificity and sensitivity making them a strong candidate for both noninvasive imaging and targeted therapy.
23
Gonçalves, Andrezza Neves. "Investigação do mecanismo bioquímico in vitro da interação da metaloprotease da matriz 2 (MMP-2) com o receptor beta 1 adrenérgico." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/17/17131/tde-01022019-102035/.
Full textAbstract:
As metaloproteases da matriz (MMPs) são enzimas proteolíticas que participam da degradação da matriz extracelular no organismo de vertebrados. Estudos mostram a grande importância dessas enzimas no processo de remodelação do tecido cardíaco, além de sugerirem a participação da MMP-2 em doenças cardiovasculares. Em estudo recente foi demonstrado que as MMPs clivam o receptor ?2-adrenérgico, contribuindo para o aumento do tônus arteriolar de ratos espontaneamente hipertensos (SHR). Acredita-se que processo semelhante possa ser verificado em relação ao receptor ?-1 adrenérgico e proteínas das junções, que são fundamentais para o funcionamento do coração. As análises in sílico realizadas mostraram regiões prováveis de clivagem pela metaloprotease da matriz 2 humana recombinante (rhMMP-2) na porção extracelular, especificamente na região Nterminal deste receptor, no entanto, as análises de comparação de similaridade de substratos não apresentaram resultados significativos, embora os resultados preliminares obtidos no teste in vitro mostraram que houve hidrolise logo no início do peptídeo sintético ASPPASLLPPAS, entre os resíduos alanina e serina, entre as duas prolinas e por fim entre o resíduo de prolina e alanina, regiões com grandes chances de ocorrer a hidrólise, pois o substrato nativo desta enzima é o colágeno que é composto por uma cadeia polipeptídica com uma sequência de repetições onde geralmente temos glicina-X-Y, onde X normalmente é uma prolina e Y frequentemente uma hidroxiprolina, e raramente lisina e hidroxilisina, no entanto a replicação deste experimento não apresentou o mesmo resultado. Já os resultados obtidos no western blotting mostraram que a expressão do receptor é diminuída quando os cardiomiócitos são previamente tratados com 40mM e 120mM de rhMMP- 2 e esse efeito tem uma reversão significativa quando as células são previamente tratadas com inibidores doxiciclina ou ONO-4817, corroborando com os trabalhos apresentados na literatura em que a rhMMP-2 atua no receptor ?1adrenérgico.<br>Matrix metalloproteinases (MMPs) are proteolytic enzymes that participate in the degradation of the extracellular matrix in the vertebrate organism. Studies show the great importance of these enzymes in the remodeling process of cardiac tissue, besides suggesting the participation of MMP-2 in cardiovascular diseases. In a recent study, MMPs were shown to cleave the ?2-adrenergic receptor, contributing to the increase in arteriolar tone of spontaneously hypertensive rats (SHR). It is believed that a similar process can be verified also in the ?-1 adrenergic receptor and junction proteins, which are fundamental to the heart function. The in situ analyzes performed revealed sections prone to be cleaved by matrix metalloproteinase 2 recombinant human (rhMMP-2) in the extracellular portion, specifically in the Nterminal region of this receptor, however, the comparative analyzes of the similarity of substrates did not present significant results, but those obtained in the in vitro test showed that there was hydrolysis right at the beginning of the synthetic peptide ASPPASLLPPAS, between alanine and serine residues, between the two proline and finally between the proline residue and alanine. Hydrolysis among proline residues was expected, even though it was not predicted for in silica cleavage, since the native substrate of this enzyme is collagen, which is composed of a polypeptide chain with a sequence of repetitions in which it usually has glycine-XY, where X usually is a proline and Y often a hydroxyproline, and rarely lysine and hydroxylysine, however the replication of this experiment di not present the same result. The obtained results in western blotting have presented that receptor expression is decreased when cardiomyocytes are pretreated with 40mM and 120mM rhMMP-2 and this effect has a significant reversion when cells are pretreated with doxycycline or ONO-4817 inhibitors, supporting previous studies which demonstrate that rhMMP- 2 acts on the ? 1 adrenergic receptor.
24
VALLARINO, GIULIA. "A new formulation of ellagic acid and pomegranate peel extract for dietary supplementation in an animal model of multiple sclerosis." Doctoral thesis, Università degli studi di Genova, 2023. https://hdl.handle.net/11567/1105298.
Full textAbstract:
My Ph.D. project was dedicated to evidentiate beneficial effects elicited by the therapeutic administration of a new formulation of ellagic acid (Ellagic Acid microdispersion, EAm) and pomegranate peel extract (Pomegranate peel Extract microdispersion, PEm) in an animal model of multiple sclerosis (the EAE mice), with particular attention to its impact on “in vivo” and “in vitro” parameters at the acute stage of disease, to support its translation to clinical studies in patients suffering from multiple sclerosis.
My thesis was composed of two different sections: the first one focuses on the characterization of the EAE model and the analysis of the healthy properties of the formulations on it; the second one investigates a potential therapeutic target of ellagic acid.
The study led to two recent publications in Molecules and Antioxidants and was exposed in the poster section of national and international congresses reported in the last part of the thesis.
The thesis would also briefly describe other studies I was involved in during the 3 years Ph.D. program.
25
Ana, Yuliana. "Study on the regulatory mechanism for Uncoupling protein 1 (Ucp1) expression in beige adipocytes." Kyoto University, 2019. http://hdl.handle.net/2433/244554.
Full text
26
Santos, Kelly Teixeira dos. "Estudo do polimorfismo Ser49Gly do gene do receptor beta adrenérgico 1 (β-adr 1) na população do estado do Rio de Janeiro, Brasil estratificada por cor da pele e ancestralidade genômica." Universidade do Estado do Rio de Janeiro, 2012. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=5469.
Full textAbstract:
Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro<br>As doenças cardiovasculares possuem a maior taxa de óbitos no mundo, e notavelmente nos últimos anos as pesquisas genéticas sobre as mesmas estão baseadas em estudos de associação, no qual o gene suspeito que esteja em maior frequência entre os pacientes passa a ser considerado um possível fator causal. Os polimorfismos genéticos que ocorrem no receptor beta-adrenérgico podem resultar em mudanças significativas na função do receptor, podendo acarretar fisiopatologias. Neste trabalho, o objetivo foi estimar a diversidade e a frequência do polimorfismo Ser49Gly do gene do receptor beta-adrenérgico 1 a partir de uma amostra de 188 indivíduos da população do Estado do Rio de Janeiro. As frequências também foram analisadas a partir da estratificação da amostra por critério fenotípico em função do padrão de cor da pele em (negros e não negros) ou ancestralidade genética em (afrodescendente e não afrodescendente), definida através da informação dos marcadores de ancestralidade Indels e SNP de cromossomo Y, para avaliar se os padrões de ancestralidade ou cor da pele são fundamentais para a diferenciação e distanciamento genético. Fragmentos de interesse foram amplificados por PCR (reação de cadeia de polimerase) com primers específicos para o marcador Ser49Gly e as reações de genotipagem foram realizadas com enzimas de restrição Eco0109I. Os valores da heterozigosidade variaram entre 0,25-0,50 e 0,20-0,41 nos grupos estratificados por ancestralidade e cor da pele, respectivamente. No que diz respeito à análise do equilíbrio de Hardy-Weinberg, não houve um desvio significativo na distribuição do marcador nas amostras gerais do Estado do Rio de Janeiro, ou mesmo nas amostras estratificadas. A distribuição dos alelos na amostra dos 188 indivíduos da população geral do Rio de Janeiro (AC_RJ) mostrou uma frequência de 80,30% e 19,70% para o alelo selvagem e mutado Ser49Gly, respectivamente. A comparação das análises sobre a distribuição das frequências alélicas para este marcador mostrou a ocorrência de diferenças significativas na distribuição das frequências alélicas entre negros e não negros e afrodescendentes e não afrodescendentes. A diferença significativa observada entre os negros e afrodescendentes, foi em menor grau de distanciamento. A informação obtida em relação à ancestralidade foi crucial para a obtenção dos dados sobre o aumento da variável mutada do polimorfismo Ser49Gly nas populações negras e afrodescendentes do Estado Rio de Janeiro. Tal evidência, em combinação com estudos clínicos podem contribuir para uma análise pormenorizada do padrão de susceptibilidade à doença em questão, em falhas do mecanismo deste receptor.<br>Cardiovascular diseases have the highest death rate in the world, and notably in recent years genetic research about them are based on association studies, in which the gene suspected to be at a higher frequency among patients is now considered a possible causal factor. Genetic polymorphisms that occur in the beta adrenergic receptor can result in significant changes in the receptor function that may trigger physiopathologies. The main aim of this study was to estimate the diversity and the frequency of Ser49Gly polymorphism of Βeta adrenergic 1 receptor gene in a sample of 188 individuals of the population of Rio de Janeiro. The frequencies were also analyzed from the sample stratification by phenotypic criteria due to skin color pattern (blacks and non-blacks) or by genetic ancestry (African descent and non-African descent), defined by ancestry information SNP and Indels markers from Y chromosome, to evaluate whether the ancestry criteria and/or skin color are crucial to the pattern of differentiation and genetic distance. Fragments of interest were amplified by PCR (polymerase chain reaction) with specific primers for the marker Ser49Gly and genotyping reactions performed by restriction with the enzyme Eco0109I. The values of heterozygosity ranged from 0.25 to 0.50 and 0.20 to 0.41 in the groups stratified by ancestry and skin color, respectively. Regarding the analysis of EHW, there was no significant deviation from this marker genotype distribution in Rio de Janeiro sample or even the stratified sample. The distribution of alleles in the sample of 188 individuals from the general population of Rio de Janeiro (AC_RJ) shows a frequency of 80.30% and 19.70% for the wild-type allele mutated Ser49 and Gly49, respectively. The comparison analysis showed the occurrence of significant differences in the distribution of allele frequencies of this marker between blacks and non-blacks and African descent and non-African descent. A significant difference was also observed between blacks and African descent, with a lesser degree of detachment. The information obtained in relation to ancestry was crucial for obtaining data on the increase in variable mutated polymorphism Ser49Gly in the black populations and African descent in Rio de Janeiro State. Such evidence, in combination with clinical studies may contribute to a detailed analysis of the pattern of susceptibility to disease involved in mechanism crashes of this receptor.
27
Cherian, Thomas. "A functional study of the ureter : relevance of myogenic and neurogenic functions and the role of post-synaptic alpha 1 and alpha 2 adrenergic recepters in ureteral motility." Thesis, University of Sunderland, 2014. http://sure.sunderland.ac.uk/4895/.
Full text
28
Memetzidis, Georgios. "Pharmacochimie de la tetrahydro-5,6,13,13a 8h-dibenzo (a, g) quinolizine ou berbine." Université Louis Pasteur (Strasbourg) (1971-2008), 1988. http://www.theses.fr/1988STR13159.
Full text
29
Breuiller, Michelle. "Les recepteurs adrenergiques dans le myometre humain gravide : implication des recepteurs beta-adrenergiques chez la rate au moment de la parturition." Paris 7, 1988. http://www.theses.fr/1988PA077019.
Full text
30
Christoff, Jeffrey J. "Part 1. Synthesis of arylalkylguanidines as dopamine agonists. Part 2. Modifications of trimetoquinol and the effects on ?-adrenergic and thromboxane A[subscript 2] receptor systems : approaches to the asymmetic synthesis of irreversibly... /." The Ohio State University, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487847761305873.
Full text
31
KAVERI, SRINIVAS-VENKATESH. "Etude immunologique des recepteurs beta-adrenergiques." Paris 7, 1987. http://www.theses.fr/1987PA077217.
Full textAbstract:
Caracterisation des recepteurs beta -adrenergiques humains a ete realisee par des methodes immunologiques (anticorps polyclonaux et anticorps monoclonaux ont ete developpes. Un anticorps anticodytypique ab2b4 reconnait egalement le recepteur beta -adrenergique et stimule l'activite de l'adenylate cyclase comme des ligands agonistes. Au cours de certaines maladies autoimmunes, l'existence d'autoanticorps diriges contre les recepteurs beta -adrenergiques ont ete detectes dans le serum de patients atteints de la maladie de chagas. Le developpement des groupes d'anticorps anti-recepteur obtenus permettront une etude structurale et fonctionnelle du systeme beta-adrenergique
32
Laurent, Anne-Coline. "Rôles et mécanismes d’action de la protéine Epac dans l’hypertrophie cardiaque." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T044/document.
Full textAbstract:
Les catécholamines induisent la synthèse d’AMPc par une stimulation des récepteurs β-adrénergiques et contrôlent ainsi la fonction cardiaque en activant une pléiade de voies de signalisation intracellulaires. Les protéines Epac sont des facteurs d’échange pour les petites protéines G et sont directement activés par l’AMPc. Devant l’importance de la voie β-adrénergique dans la physiopathologie cardiaque et dans le but de mieux comprendre la régulation des processus cellulaires dépendants de l’AMPc dans le cœur, il apparaît essentiel de caractériser le rôle des facteurs d’échange Epac dans le myocarde. Dans une première partie, cette étude démontre que les effets de Epac sur l’hypertrophie des cardiomyocytes ventriculaires de rats nouveaux nés requièrent les GTPases H-Ras et Rap2B. Epac active la voie PLC/IP3/Ca2+ qui est nécessaire pour l’activation de H-Ras. Au niveau transcriptionnel, Epac induit l’export nucléaire de HDAC4 permettant l’activation d’un programme génique d’hypertrophie. Dans une deuxième partie, cette étude révèle l’implication de Epac1 dans l’hypertrophie des cardiomyocytes in vivo, chez la souris. La délétion de Epac1 protège du remodelage cardiaque induit par l’activation prolongée des récepteurs β-adrénergiques et améliore la fonction cardiaque. La surexpression de Epac1 spécifiquement dans le myocarde entraîne une hypertrophie des cardiomyocytes. Par ailleurs, la voie β-AR/Epac1 induit l’accumulation de protéines ubiquitinylées et provoque l’activation du processus d’autophagie in vitro et in vivo. L’autophagie protège des effets délétères de la voie β-adrénergique/Epac en participant à l’élimination des agrégats protéiques et en contrant les effets hypertrophiques de Epac1. Ces résultats ouvrent de nouvelles perspectives pour le traitement de l’hypertrophie et de l’insuffisance cardiaque<br>Catecholamines regulate cardiac function by stimulating β-adrenergic receptors (β-AR), leading to cAMP production and activation of a multiplicity of signaling pathways. Epac proteins are exchange factors for small G proteins which are directly activated by cAMP. Given the importance of the β-adrenergic pathway in cardiac physiopathology, it becomes essential to characterize functions of Epac protein in myocardium. In a first part, this study shows that H-Ras and Rap2B GTPases are involved in Epac-induced neonatal rat cardiac myocytes hypertrophy. Epac induces activation of the PLC/IP3/Ca2+ pathway which is necessary for H-Ras activation. At the transcriptional level, Epac causes HDAC4 nuclear export leading to activation of a hypertrophic gene program. In a second part, this study reveals implication of Epac1 in cardiac hypertrophy in vivo. Deletion of Epac1 in mice protects from cardiac remodeling induced by chronic isoproterenol infusion and enhances cardiac function. Cardiac specific overexpression of Epac1 in mice induces cardiac myocytes hypertrophy. Interestingly, β-AR/Epac1 pathway triggers ubiquitinated proteins accumulation and activation of autophagy both in vitro and in vivo. By eliminating aggregates and by counteracting hypertrophic effects of Epac, autophagy protects from deleterious effects of the β-AR/Epac pathway. These results open news insights into the treatment of cardiac hypertrophy and heart failure
33
EL-ETR, MATHIS MARTINE. "Cooperation neuro-gliale pour l'expression de l'effet potentialisateur de l'adenosine sur la reponse mediee par un recepteur muscarinique couple a la phospholipase c." Paris 6, 1988. http://www.theses.fr/1988PA066224.
Full text
34
Boutayeb, Soraya. "Etude des effets d'une ischémie régionale sur le coeur isolé de rat : essais de protection pharmacologique." Grenoble 1, 1988. http://www.theses.fr/1988GRE10073.
Full text
35
Florent, Romane. "Intérêt de la modulation pharmacologique des voies de signalisation calcique pour restaurer le contrôle de l'apoptose dans les cancers ovariens chimiorésistants Inhibition of store-operated channels by carboxyamidotriazole sensitizes ovarian carcinoma cells to anti-BclxL strategies through Mcl-1 down-regulation Drug Repositioning of the α1-Adrenergic Receptor Antagonist Naftopidil: A Potential New Anti-Cancer Drug? Bim, Puma and Noxa upregulation by Naftopidil sensitizes ovarian cancer to the BH3-mimetic ABT-737 and the MEK inhibitor Trametinib". Thesis, Normandie, 2020. http://www.theses.fr/2020NORMC413.
Full textAbstract:
Le sombre pronostic du cancer de l’ovaire s’explique notamment par une fréquence importante de résistance à la chimiothérapie conventionnelle présentée par les patientes. La mise en place de stratégies thérapeutiques alternatives à la chimiothérapie, mais aussi la découverte de biomarqueurs prédictifs de la réponse à ce traitement, représentent donc un enjeu majeur pour améliorer la prise en charge de cette pathologie. La chimiorésistance des cellules cancéreuses ovariennes s’explique principalement par leur résistance à l’apoptose, résultant d’un déséquilibre entre les membres pro- et anti-apoptotiques de la famille Bcl-2 qui contrôlent cette mort cellulaire. De ce fait, toutes stratégies capables de moduler le ratio [pro ]/[anti apoptotiques] en faveur des [pro-] restaure efficacement l’apoptose de ces cellules. Or, la signalisation calcique est connue pour réguler l’expression de ces protéines et apparait ainsi comme une cible pertinente pour restaurer l’apoptose des cellules cancéreuses ovariennes chimiorésistantes. Dans ce contexte, nous avons mis en évidence que trois modulateurs du signal calcique sont capables d’induire la mort de ces dernières en association à l’ABT-737, un BH3-mimétique ciblant l’activité de l’anti apoptotique Bcl-xL. Cette sensibilisation à l’ABT-737 est permise par le fait que le carboxyamidotriazole réprime l’expression de l’anti apoptotique Mcl-1 via l’inhibition des courants SOCE, le naftopidil augmente l’expression des protéines pro apoptotiques via l’induction d’un stress du RE ou l’activation de JNK et que la thapsigargine semble préparer à la mort cellulaire grâce à une augmentation de la concentration calcique intracellulaire via STIM1 et, peut-être, via l’induction de l’expression de Noxa. En outre, les acteurs de la signalisation calcique, connus pour subir un remodelage au cours des processus de cancérogenèse pourraient se révéler comme des outils de prédiction de réponse à la chimiothérapie. Dans ce contexte, nous avons mis en évidence que l’expression de la pompe calcique SERCA2 semble jouer le rôle de biomarqueur prédictif de la réponse à la chimiothérapie des patientes atteintes d’un cancer de l’ovaire<br>The poor prognosis of ovarian cancer is mainly explained by a high rate of resistance to conventional chemotherapy presented by patients. Therefore, discovery of both alternative therapeutic strategies to chemotherapy and predictive biomarkers for response to this treatment represent a major challenge for improving the management of this pathology. Chemoresistance of ovarian cancer cells is mainly due to their resistance to apoptosis, resulting from an imbalance between the pro- and anti-apoptotic members of the Bcl-2 family that control this type of cell death. Thus, all strategies able to modulate the [pro]/[anti-apoptotic] protein ratio in favor of [pro-] effectively restore apoptosis in these cells. However, calcium signaling is known to regulate the expression of these proteins and thus appears to be a relevant target for restoring apoptosis in chemoresistant ovarian cancer cells. In this context, we have shown that three calcium signal modulators are able to induce the death of these cells in association with ABT-737, a BH3-mimetic targeting the activity of the anti-apoptotic Bcl-xL. This sensitization to ABT-737 is enabled by the fact that carboxyamidotriazole represses the expression of the anti apoptotic Mcl-1 via the inhibition of SOCE currents, naftopidil increases pro-apoptotic protein expression via ER stress induction or JNK activation and thapsigargin seems to prepare cell death through increasing intracellular calcium concentration via STIM1 and, maybe, through Noxa expression induction. In addition, players of the calcium signaling toolkit, known to undergo remodeling during carcinogenesis could be proven as tools for predicting response to chemotherapy. In this context, we have shown that the expression of the calcium pump SERCA2 seems to play a role as a predictive biomarker for response to chemotherapy of patients with ovarian cancer
36
Holland, Patrick. "DRUGS, DIMERS, AND MUTATIONS: INVESTIGATING THE EFFECTS OF LIGANDS AND A ?2-ADRENERGIC POLYMORPHISM ON HOMO/HETERODIMERIZATION OF ?2-ADRENERGIC AND ANGIOTENSIN II TYPE 1 RECEPTORS." Thesis, 2012. http://hdl.handle.net/10222/15245.
Full textAbstract:
GPCRs are known to form dimeric structures, and this affects their pharmacological properties. The ?2AR and AT1aR are GPCRs that are involved the regulation of the adrenergic and renin-angiotensin systems. The ?2AR is polymorphic at position 164, affecting its responsiveness to adrenergic ligands. Both receptors have been shown to form dimers, but little is known on how dimerization affects their trafficking and signalling following ligand treatments. Plasma membrane localization, arrestin-2 recruitment, and G-protein interactions were determined between receptor dimers using molecular biological techniques. This study demonstrates that the formation of heterodimers can change the expected response to ligand treatments, along with associated trafficking events. It was determined that ligands bind to dimers, resulting in conformational changes to the dimeric complexes. Both the ?2AR and AT1aR are targeted in cardiovascular disease and this research demonstrates the importance of dimerization when prescribing drug therapies to avoid potential unwanted drug side effects.
37
Liptáková, Andrea. "Úloha beta 1 adrenergních receptorů v srdci chladově adaptovaného potkana." Master's thesis, 2020. http://www.nusl.cz/ntk/nusl-433989.
Full textAbstract:
During cold acclimation the heat production is shifted from shivering to non-shivering thermogenesis, which is mediated by adrenergic signaling. It has also been observed, that cold acclimation may increase the organismal resistence to pathological stimuli and may affect functional parameters of cardiovascular system. However, acute exposure to sever cold is often associated with detrimental effects on the body. We have recently shown that chronic exposure to cold increases the heart's resistance to ischemia-reperfusion injury without negative side effects when mild temperatures are used, however the mechanism of protection is not yet known. The aim of this work was to determine whether: i) if the sensitivity of the heart to ischemia changes already after the first day of cold exposure and does not show any negative effects, ii) if β1-adrenergic signaling plays a role in chronic regimen of cold-induced cardioprotection. The results of this work showed that i) one day of exposure to mild cold did not change the sensitivity of the heart to ischemia and ii) metoprolol treatment reduced the infarct size in the control group, but did not affect the heart of cold-adapted rats. Key words : Heart, rat, beta 1 adrenergic receptors, cold acclimation
38
Cannavo, A., G. Rengo, D. Liccardo та ін. "β1-Adrenergic Receptor and Sphingosine- 1-Phosphate Receptor 1 Reciprocal Down-Regulation Influences Cardiac Hypertrophic Response and Progression Toward Heart Failure: Protective Role of S1PR1 Cardiac Gene Therapy". 2013. http://hdl.handle.net/10454/7923.
Full textAbstract:
Yes<br>The Sphingosine-1-phosphate receptor 1 (S1PR1) and β1-adrenergic receptor
(β1AR) are G protein-coupled receptors (GPCRs) expressed in the heart. These two GPCRs have
opposing actions on adenylyl cyclase due to differential G protein-coupling. Importantly, both of
these receptors can be regulated by the actions of GPCR kinase-2 (GRK2), which triggers
desensitization and down-regulation processes. Although, classical signaling paradigms suggest
that simultaneous activation of β1ARs and S1PR1s in a myocyte would simply be opposing action
on cAMP production, in this report we have uncovered a direct interaction between these two
receptors with a regulatory involvement of GRK2.
In HEK293 cells overexpressing both β1AR and S1PR1, we
demonstrate that β1AR down-regulation can occur after sphingosine 1-phosphate (S1PR1 agonist)
stimulation while S1PR1 down-regulation can be triggered by isoproterenol (βAR agonist)
treatment. This cross-talk between these two distinct GPCRs appears to have physiological
significance since they interact and show reciprocal regulation in mouse hearts undergoing chronic
βAR stimulation and also in a rat model of post-ischemic heart failure (HF).
We demonstrate that restoring cardiac plasma membrane levels of S1PR1
produce beneficial effects counterbalancing deleterious β1AR overstimulation in HF.
39
Harrigan, Tom. "The effects of central I|1-imidazoline and A|2-adrenergic receptors on body temperature regulation in conscious rats." 2000. http://hdl.handle.net/1993/1852.
Full textAbstract:
Clonidine, an _2-adrenergic receptor agonist, is a classic pharmacological tool used to study the sympathetic control of cardiovascular and thermoregulatory processes. Clonidine's ability to inhibit sympathetic output may be linked more to its affinity for non-adrenergic I1-imidazoline receptors than for _2-adrenoceptors. Previous research has focused on the role of medullary _2-adrenergic and I 1-imidazoline receptors in regulating blood pressure; yet, structures rostral to the brainstem also influence sympathetic output. What role I 1-imidazoline receptors located in the medulla, or those located in the region of the third ventricle, exert towards the regulation of body temperature is largely unexplored. The present study assessed the relative contributions of diencephalic and medullary _2-adrenergic and I1-imidazoline receptors on core body temperature in conscious rats. In Experiment 1, 24 rats received chronically indwelling thermistors, for recording body temperature, and intracerebroventricular (ICV)cannulae targeted to the third ventricle, an area near the hypothalamus, for drug administration. In a repeated measures design, 12 rats were pretreated with central administration of 4 [mu]l of saline or efaroxan, an I1-antagonist; 20-min later moxonidine, an I1 agonist, was centrally administered in l of 3 doses (0, 1, 10 nmol) delivered in a 4 [mu]l saline over 45-60 s. The other 12 rats were similarly pretreated with saline or SK&F 86466, an _2 -adrenergic receptor antagonist, followed 20 min later with 1 of 3 doses (0, 1, 10 nmol) of UK 14304, an a2-adrenergic receptor agonist. Body temperature was monitored at 30-min intervals for 4 hr. The result were contrary to what might have been predicted from reports of moxonidine-induced reductions in blood pressure in that 10-nmol of moxonidine increased core body temperature (>1.5C, 'p' < .02). However, the increase in body temperature was reversed with efaroxan. UK 14304 did not alter body temperature. In Experiment 2, 24 rats underwent the same procedure as described above, except the drugs were delivered to the fourth ventricle, an area near the medulla. In this case, neither moxonidine nor UK 14304 had any significant effect on body temperature. These findings support the notion that I 1-imidazoline and _2-adrenergic receptors in the diencephalon and medulla are functionally distinct, and that the thermoregulatory contribution of diencephalic I1-imidazoline receptors is different from what would be predicted from their sympathoinhibitory action exhibited in the medulla.
40
Hammad, Maha. "CHARACTERIZATION OF THE ANGIOTENSIN TYPE 1 RECEPTOR AND THE BETA2 ADRENERGIC RECEPTOR PROPERTIES: THE INVOLVEMENT OF ARRESTIN2, RAB1 AND SOME MOLECULAR CHAPERONES IN THE ASSEMBLY AND TRAFFICKING OF GPCRS." 2010. http://hdl.handle.net/10222/13068.
Full textAbstract:
Current drugs used to treat Congestive Heart Failure target the renin-angiotensin and adrenergic systems. Studies showed increased mortality rates in patients treated with a combination of these medications. Angiotensin-AT1 and ?2-Adrenergic receptors were shown to form receptor heteromers. Blockade of one receptor in the complex can affect the signal transmitted by the other; suggesting that ligand-based therapy is not as selective as we might think. Modulating receptor trafficking after synthesis might prove to be a valid therapeutic strategy. Unfortunately, little is known about receptor assembly and transport from Endoplasmic Reticulum to Plasma Membrane. The objectives of this study are to identify the proteins that participate in the assembly of AT1R-?2AR heteromer and the regulators of the anterograde trafficking of G-Protein Coupled Receptors. This thesis introduces the role of important targets in those poorly understood processes. The identification of such targets could lead to developing better drugs with fewer adverse effects.
41
Lai, Lick Pui. "Gene regulation in growth plate chondrocytes by the parathyroid hormone 1 receptor and the beta2-adrenergic receptor." 2008. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=742616&T=F.
Full text
42
Dangerfield, Aran Lindsay. "The effect of AT1 or [beta]-adrenergic receptor blockade on cardiotrophin-1 expression in the infarcted rat heart." 2007. http://hdl.handle.net/1993/20476.
Full text
43
Pillay, Visva. "Variants of inflammatory mediators: alpha-1-protease inhibitors, cortisol binding globulin, interleukin-1-receptor antagonist and beta-2-adrenergic receptor genes in atopic asthmatic and non-asthmatic South Africans." Thesis, 2014.
Find full textAbstract:
According to current concepts asthma is primarily an inflammatory condition of the
bronchi which results from the complex interactions between heterogenous genetic and
environmental factors. Although the environmental allergens are fairly well known, little
information concerning the genetic differences between atopic and non-atopic individuals
is available, A number of candidate genes have been proposed, including genes for
protease inhibitors, interleukins and the beta-2-adrenergic receptor ((32AR) The present
study was undertaken in order to determine whether molecular variation of certain atopy
candidate genes (alpha-1-protease inhibitor, cortisol binding globulin, interleukin-1-
receptor antagonist and p2AR) may be associated with atopic asthma in black and white
asthmatic South Africans. Alpha-1-protease inhibitor (ctjPI) has been implicated in the
pathogenesis of emphysema, if it is present in one of its deficient phenotypic forms. Given
that a ^ I is also an acute phase reactant in humans, it is possible that an association exists between the manifestations of asthma and a,PI or its deficiency. This investigation looked at the various phenotypes of cqPI in black and white asthmatic and control individuals by making use of isoelectric focusing as well as to make use of the polymerase chain reaction (PCR) which allowed for the identification of two haplotypes of the Ml phenotype ipf a,PI,viz. Ml (Ala213) and MI (Val213), There was a significant increase in the M l (Ala213) haplotype in the black groups as compared to a white groups. A novel finding was the identification of a new variant, the M1E(j0HANNESBURG)_ A significant difrerence was also found when comparing patients with severe asthma who had the rarer variants of a,PI as compared to mild or moderate asthmatic patients with the M1M1 phenotype indicating that UjPI plays a role in the pathogenesis of asthma.No mutation was found in exon 2 (an amino acid substitution in this exon was shown to be responsible for abnormal CBG steroid binding activity) of the cortisol binding
globulin (CBG), (as determined by sequencing analysis) in black and white asthmatic and
control individuals in the present study. However, taking the fact that CBG and oqPI share
more than 40% homology of amino acid sequence, it would be advisable to continue the
search for possible mutations in other exons of the gene which might act as markers for
mutations in other genes that are closely linked to the CBG and which play a role in
asthma.An important role player in the control of the inflammatory process could be the
IL-1 Ra since it is a powerful endogenous anti-inflammatory molecule that competitively
inhibits IL-1 a and IL-ip. The allelic frequency of the polymorphism in intron 2 of the IL-1
Ra gene was studied in black and white patients with asthma and control individuals, The
plasma IL1 Ra concentration was also determined using a standardised Elisa kit. No
significant differences in IL-1 Ra VNTR allelic frequencies were noted in the clinical
groups and controls in each of the two population groups, However the 410 bp allele was
increased in all black subjects as compared to all white subjects while the 240 bp allele was markedly reduced in all black subjects as compared to all white subjects. Significant
differences were observed when we compared the levels of severe patients with patients
classified as having mild astlima. Significant differences were also observed when
comparing moderate asthmatic children with the mild asthmatic children. Our results
indicate, a distinct racial difference in the EL-1 Ra gene polymorphism and although this
polymorphism is unlikely to be an important determinant of overall disease susceptibility
in asthma the IL-1 Ra plasma concentrations could act as a marker of disease severity in
asthmatic patients.The p2 adrenergic receptor (p2AI<) is an important factor in the control of the inflammatory process in asthma. The gly 16 polymorphism of the (32AR which appears to impart enhanced down regulation of receptor numbers has been found to have a higher prevalence in nocturnal white asthmatics. The allelic frequencies of the gly 16
polymorphism was studied in black and white asthmatic children control individuals.
Genotyping was performed by making use of PGR and the presence of the mutation was
analysed on agarose gels using ethidium bromide staining and confirmed by DNA
sequencing. There was no difference in the prevalence of the gly 16 polymorphism of the
(32AR between the black and white control individuals. There was a significant increase
in the frequency ofthe gly 16 polymorphism of the P2AR between severe and moderate
asthmatics. There was also a significant increase in the prevalence of the gly 16
polymorphism in those patients who required a long acting beta stimulant to gain
symptomatic control, We did not find a difference- in the prevalence of the gly 16
polymorphism between nocturnal vs. non-nocturnal asthmatics. The gly 16 polymorphism
of p2AR was predictive of more severe asthma in this study. It was also predictive for
those patients who needed a long acting beta stimulant to attain symptomatic control. This
polymorphism may act as a disease modifier in asthma and represents one of the many
genetic variables involved in the pathogenesis of asthma.
In conclusion, the present study demonstrates the extent and complexity of genetic
susceptibility to atopic asthma and it highlights the need for more refined association and
functional studies that will identify additional atopy'loci and their association with asthma.
Part of the work in this dissertation was the subject of conference p resentations.
Pillay V, Gaillard M.C., Dewar J.B, Hirsch G.P and Song E, “Differences in the
Interleukin-1 Receptor Antagonist (IL-IRa) Gene Polymorphism In Black And White
Patients With Asthma Or Rheumatoid Arthritis And Control Individuals.” 37"' Annual
Congress of the Federation of South African Societies of Pathology. Sea Point, Cape
Town. 29 June - 2 July 1997.
Pillay V, Gaillard M.C, Halkas A and Song E. “The GLY 16 Polymorphism of the P2
Adrenergic Receptor in South African Asthmatic Children.” Biochemistry In Africa: 2nd
Of) FASBMB and 15,h SASBMB. Potchefstroom, South Africa. 29 September - 3 October
1998.
44
Rivard, Katy. "Remodelage électrique cardiaque dans des modèles murins de cardiomyopathies." Thèse, 2010. http://hdl.handle.net/1866/4880.
Full textAbstract:
Les cardiomyopathies sont une atteinte du myocarde qui se présente sous différentes formes telles que l’hypertrophie ou la dilatation des chambres cardiaques. Ces maladies du muscle cardiaque peuvent affecter la contraction cardiaque et dégénèrer en insuffisance cardiaque. Aussi, l’hypertrophie et l’insuffisance cardiaques sont associées à une augmentation de la morbidité et de la mortalité cardiovasculaires principalement due au remodelage électrique et à la survenue d’arythmies. De plus, le retard de repolarisation, associé à une diminution des courants K+, est un des troubles cardiaques les plus couramment observés lors de ces pathologies cardiaques.
L’angiotensine II (Ang II) et la norépinéphrine, principaux effecteurs du système rénine-angiotensine et du système nerveux sympathique, peuvent tous deux agir directement sur le cœur en liant les récepteurs de type 1 de l’Ang II (AT1) et les récepteurs adrénergiques. L’Ang II et la norépinéphrine sont associées au développement des cardiomyopathies, au remodelage cardiaque et à une prolongation de la durée du potentiel d'action cardiaque. Deux modèles de souris trangéniques surexprimant spécifiquement au niveau cardiaque les récepteurs AT1 (la souris AT1R) ou les récepteurs α1B-adrénergiques (la souris α1B-AR) ont été créés afin d’étudier les effets de ces stimuli sur le cœur. Ces deux modèles de souris développent du remodelage cardiaque, soit de l’hypertrophie chez les souris AT1R (cardiomyopathie hypertrophique) ou une dilatation des chambres cardiaques chez les souris α1B-AR (cardiomyopathie dilatée). Au stade avancé de la maladie, les deux modèles de souris transgéniques sont insuffisants cardiaques. Des données préliminaires ont aussi montré que les souris AT1R et les souris α1B-AR ont une incidence accrue d’arythmies ainsi qu’une prolongation de la durée du potentiel d’action. De plus, ces deux modèles de souris meurent subitement et prématurément, ce qui laissait croire qu’en conditions pathologiques, l’activation des récepteurs AT1 ou des récepteurs α1B-adrénergiques pouvait affecter la repolarisation et causer l’apparition d’arythmies graves. Ainsi, l’objectif de ce projet était de caractériser la repolarisation ventriculaire des souris AT1R et α1B-AR afin de déterminer si la suractivation chronique des récepteurs de l’Ang II ou des récepteurs 1B-adrénergiques pouvait affecter directement les paramètres électrophysiologiques et induire des arythmies.
Les résultats obtenus ont révélé que les souris AT1R et les souris α1B-AR présentent un retard de repolarisation (prolongation de l’intervalle QTc (dans l’électrocardiogramme) et de la durée du potentiel d’action) causé par une diminution des courants K+ (responsables de la repolarisation). Aussi, l’incidence d’arythmies est plus importante dans les deux groupes de souris transgéniques comparativement à leur contrôle respectif. Finalement, nous avons vu que les troubles de repolarisation se produisent également dans les groupes de souris transgéniques plus jeunes, avant l’apparition de l’hypertrophie ou du remodelage cardiaque. Ces résultats suggèrent qu’en conditions pathologiques, l’activation chronique des récepteurs de l’Ang II ou des récepteurs α1B-adrénergiques peut favoriser le développement d’arythmies en retardant la repolarisation et cela, indépendamment de changements hémodynamiques ou du remodelage cardiaque. Les résultats de ces études pourront servir à comprendre les mécanismes responsables du développement d’arythmies cardiaques lors du remodelage et de l’insuffisance cardiaques et pourraient aider à optimiser le choix des traitements chez ces patients atteints ou à risque de développer de l’hypertrophie ou du remodelage cardiaque.<br>Cardiomyopathies are diseases of the myocardium that may have several causes and comes in different forms such as cardiac hypertrophy or dilatation. Cardiomyopathies are often progressive diseases that cause a loss of heart function and lead to heart failure. In addition, hypertrophy and heart failure are associated with increased morbidity and mortality mainly due to electrical remodeling and arrhythmias. Delayed repolarization associated with a decrease of K+ currents, is one of the most common cardiac disorders associated with cardiac remodeling.
Angiotensin II (Ang II) and norepinephrine, the main effectors of the renin-angiotensin system and of the sympathetic nervous system, can both act directly on the heart by binding the Ang II type 1 receptor (AT1) and the adrenergic receptors. Ang II and norepinephrine are both associated with the development of cardiomyopathy, cardiac remodeling and prolongation of action potential duration. Two transgenic mouse models overexpressing the AT1 receptors (AT1R mouse) or the α1B-adrenergic receptors (α1B-AR mouse) specifically in the myocardium have been developed to study the effects of these stimuli on the heart. These two mouse models developed cardiac remodeling such as hypertrophy for the AT1R mice (hypertrophic cardiomyopathy) and dilatation of cardiac chambers for α1B-AR mice (dilated cardiomyopathy). In advanced stage of the disease, the two transgenic mouse models exhibit heart failure. Preliminary data showed that both transgenic mouse models experience cardiac arrhythmias and have a prolongation of the action potential duration. Moreover, AT1R and α1B-AR mice die suddenly and prematurely, which suggested that in pathological conditions, activation of the Ang II type 1 receptor or of the α1B-adrenergic receptor may affect repolarization and can be responsible for the incidence of serious arrhythmias causing the death of these mice. Base on these informations, the objective of this project was to characterize the ventricular repolarization in AT1R and α1B-AR mice to see if an increase of the activation of the Ang II type 1 receptor or of the 1B-adrenergic receptor could directly affect electrophysiological parameters and lead to severe arrhythmias.
Results showed that both AT1R mice and α1B-AR mice have a delayed ventricular repolarization (prolongation of the QTc interval and action potential duration) caused by a decrease in outward K+ currents (responsible for the repolarization). In addition, the incidence of arrhythmias is higher in both groups of transgenic mice compared with their respective control. Finally, we have seen that repolarization disorders also occur in younger mice of both models of cardiomyopathy that do not present sign of hypertrophy and cardiac remodeling. These results suggest that under pathological conditions, the overactivation of the Ang II type 1 receptor or of the α1B-adrenergic receptor can directly promote the development of arrhythmias by delaying the repolarization independently of hemodynamic variations and pathological phenotype. The results of these studies can be useful to understand the mechanisms underlying the development of cardiac arrhythmias in patients suffering from cardiac hypertrophy or failure and may help to choose the best treatment for these patients.