Academic literature on the topic 'AT2 receptor antagonist'
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Journal articles on the topic "AT2 receptor antagonist"
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Widdop, R. E., S. M. Gardiner, P. A. Kemp, and T. Bennett. "Differential blockade of central effects of angiotensin II by AT2-receptor antagonists." American Journal of Physiology-Heart and Circulatory Physiology 265, no. 1 (July 1, 1993): H226—H231. http://dx.doi.org/10.1152/ajpheart.1993.265.1.h226.
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In conscious, chronically instrumented, male Long-Evans rats, we showed previously that central administration (intracerebroventricular) of the AT1-receptor antagonist EXP-3174 (1 microgram) caused a rapid-onset marked, but transient, blockade of the regional hemodynamic responses to intracerebroventricular angiotensin II (ANG II). In contrast, the AT2-receptor antagonist PD-123319 (80 micrograms) caused a slow-onset, but marked and persistent, antagonism of the effects of intracerebroventricular ANG II. In the present study we attempted to mimic the actions of PD-123319 by giving a supramaximal dose of EXP-3174 (10 micrograms), and we also assessed the effects of PD-123177 (80 micrograms), an AT2-receptor antagonist that differs from PD-123319 only by a dimethyl group. The higher dose of EXP-3174 did not exert prolonged antagonistic effects against responses to intracerebroventricular ANG II, and PD-123177 was without inhibitory effects in this model. The results indicate important functional differences between putative AT2-receptor antagonists, when assessed in vivo, that are not apparent from binding studies.
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Louis, Sherif, Laura Saward, and Peter Zahradka. "Both AT1 and AT2 receptors mediate proliferation and migration of porcine vascular smooth muscle cells." American Journal of Physiology-Heart and Circulatory Physiology 301, no. 3 (September 2011): H746—H756. http://dx.doi.org/10.1152/ajpheart.00431.2010.
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Angiotensin receptor antagonists have shown clinical promise in modulating vascular disease, in part by limiting smooth muscle cell proliferation and migration. The majority of studies examining the contribution of these receptors have been undertaken in cells derived from rat aorta, which primarily express the ANG II type 1 (AT1) receptor. This investigation studied the relative contribution of AT1 and ANG II type 2 (AT2) receptors to the mitogenic program of porcine smooth muscle cells. Smooth muscle cells were derived from porcine coronary artery explants. The presence of both AT1 and AT2 receptors was demonstrated through ligand binding and RT-PCR analysis. Biochemical and cellular markers of proliferation were monitored in the presence of selective receptor antagonists. Smooth muscle cell migration was measured using both wound healing and Boyden chamber migration assays. Visualization of the AT1 and AT2 receptors in growing and quiescent porcine smooth muscle cells with epifluorescence microscopy demonstrated that their subcellular distribution varied with growth state. An examination with several growth assays revealed that both AT1-specific losartan and AT2-specific PD-123319 receptor antagonists inhibited ANG II-stimulated RNA and DNA synthesis, PCNA expression, and hyperplasia. ANG II induced both directional and nondirectional cell migration. AT1 receptor antagonist treatment significantly decreased ANG II-induced directional migration only, whereas AT2 receptor antagonist treatment significantly reduced both modes of migration. Interestingly, the focal adhesion kinase inhibitor PF-573228 also blocked migration but not proliferation. Furthermore, focal adhesion kinase activation in response to ANG II was prevented only by PD-123319, indicating that this activation is downstream of the AT2 receptor. The observed role of the AT2 receptor in ANG II-induced migration was confirmed with smooth muscle cells depleted of the AT2 receptor with short hairpin RNA treatment.
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Le Noble, F. A., N. H. Schreurs, H. W. van Straaten, D. W. Slaaf, J. F. Smits, H. Rogg, and H. A. Struijker-Boudier. "Evidence for a novel angiotensin II receptor involved in angiogenesis in chick embryo chorioallantoic membrane." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 264, no. 2 (February 1, 1993): R460—R465. http://dx.doi.org/10.1152/ajpregu.1993.264.2.r460.
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Angiotensin II acts as a growth factor in the cardiovascular system and has been implicated in angiogenesis. The existence of at least two types of angiotensin II receptors, the AT1 and the AT2 receptors, has been suggested by ligand binding studies. We used three different AT receptor antagonists to study the receptor mediating angiotensin II-induced angiogenesis in the chorioallantoic membrane (CAM) of the chick embryo. Angiotensin II caused pronounced angiogenesis of pre- and postcapillary vessels of 30-40%. This response could only be blocked by adding the peptidergic AT2 antagonist CGP-42112A. The nonpeptidergic AT2 antagonist PD123319 and AT1 antagonist losartan (DuP 753) were not effective. In addition, we used radioligand binding studies with a range of ligands to define the nature of the receptor. Our results show a high density of specific single class AT receptor with a total number of binding sites of 1,190 fmol/mg protein and an affinity constant for angiotensin II of 2.7 nM. The inhibitory concentrations (IC50) for CGP-42112A, PD 123319 and losartan were 724, > 100,000, and 59,000 nM, respectively. Our studies suggest that these binding sites act as receptors for angiotensin II-induced angiogenesis. Both functional and radioligand binding studies suggest that the receptor is different from the classical mammalian AT1 and AT2 receptors.
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Naito, Takashi, Li-Jun Ma, Haichun Yang, Yiqin Zuo, Yiwei Tang, Jee Young Han, Valentina Kon, and Agnes B. Fogo. "Angiotensin type 2 receptor actions contribute to angiotensin type 1 receptor blocker effects on kidney fibrosis." American Journal of Physiology-Renal Physiology 298, no. 3 (March 2010): F683—F691. http://dx.doi.org/10.1152/ajprenal.00503.2009.
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Angiotensin type 1 (AT1) receptor blocker (ARB) ameliorates progression of chronic kidney disease. Whether this protection is due solely to blockade of AT1, or whether diversion of angiotensin II from the AT1 to the available AT2 receptor, thus potentially enhancing AT2 receptor effects, is not known. We therefore investigated the role of AT2 receptor in ARB-induced treatment effects in chronic kidney disease. Adult rats underwent 5/6 nephrectomy. Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into four groups with equivalent glomerulosclerosis: no further treatment, ARB, AT2 receptor antagonist, or combination. By week 12 after nephrectomy, systolic blood pressure was decreased in all treatment groups, but proteinuria was decreased only with ARB. Glomerulosclerosis increased significantly in AT2 receptor antagonist vs. ARB. Kidney cortical collagen content was decreased in ARB, but increased in untreated 5/6 nephrectomy, AT2 receptor antagonist, and combined groups. Glomerular cell proliferation increased in both untreated 5/6 nephrectomy and AT2 receptor antagonist vs. ARB, and phospho-Erk2 was increased by AT2 receptor antagonist. Plasminogen activator inhibitor-1 mRNA and protein were increased at 12 wk by AT2 receptor antagonist in contrast to decrease with ARB. Podocyte injury is a key component of glomerulosclerosis. We therefore assessed effects of AT1 vs. AT2 blockade on podocytes and interaction with plasminogen activator inhibitor-1. Cultured wild-type podocytes, but not plasminogen activator inhibitor-1 knockout, responded to angiotensin II with increased collagen, an effect that was completely blocked by ARB with lesser effect of AT2 receptor antagonist. We conclude that the benefical effects on glomerular injury achieved with ARB are contributed to not only by blockade of the AT1 receptor, but also by increasing angiotensin effects transduced through the AT2 receptor.
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Hakam, Amer C., and Tahir Hussain. "Angiotensin II AT2 receptors inhibit proximal tubular Na+-K+-ATPase activity via a NO/cGMP-dependent pathway." American Journal of Physiology-Renal Physiology 290, no. 6 (June 2006): F1430—F1436. http://dx.doi.org/10.1152/ajprenal.00218.2005.
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Angiotensin II AT2 receptors act as a functional antagonist for the AT1 receptors in various tissues. We previously reported that activation of the renal AT2 receptors promotes natriuresis and diuresis; however, the mechanism is not known. The present study was designed to investigate whether activation of AT2 receptors affects the activity of Na+-K+-ATPase (NKA), an active tubular sodium transporter, in the proximal tubules isolated from Sprague-Dawley rats. The AT2 receptor agonist CGP-42112 (10−10-10−7 M) produced a dose-dependent inhibition of NKA activity (9–38%); the inhibition was attenuated by the presence of the AT2 receptor antagonist PD-123319 (1 μM), suggesting the involvement of the AT2 receptors. The AT1 receptor antagonist losartan (1 μM) did not affect the CGP-42112 (100 nM)-induced inhibition of NKA activity. The presence of guanylyl cyclase inhibitor ODQ (10 μM) and the nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME; 100 μM) abolished the CGP-42112 (100 nM)-induced NKA inhibition. ANG II (100 nM), in the presence of losartan, significantly inhibited NKA activity; the inhibition was attenuated by PD-123319. CGP-42112 also, in a dose-dependent manner, stimulated NO production (∼0–230%) and cGMP accumulation (∼25–100%). The CGP-42112 (100 nM)-induced NO and cGMP increases were abolished by the AT2 receptor antagonist PD-123319, ODQ, and l-NAME. The data suggest that the activation of the AT2 receptor via stimulation of the NO/cGMP pathway causes inhibition of NKA activity in the proximal tubules. This phenomenon provides a plausible mechanism responsible for the AT2 receptor-mediated natriuresis-diuresis in rodents.
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Johansson, Berndt, Mathias Holm, Sara Ewert, Anna Casselbrant, Anders Pettersson, and Lars Fändriks. "Angiotensin II type 2 receptor-mediated duodenal mucosal alkaline secretion in the rat." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 6 (June 1, 2001): G1254—G1260. http://dx.doi.org/10.1152/ajpgi.2001.280.6.g1254.
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The aims of this study were to elucidate the distribution of angiotensin receptors (AT1and AT2) in the duodenal wall and to investigate whether AT2 receptors are involved in the regulation of duodenal mucosal alkaline secretion, which is of importance for the mucosal defense against gastric acid. Immunohistochemistry was used to locate AT1 and AT2 receptors in chloralose-anesthetized rats. Duodenal mucosal alkaline output was measured by use of in situ pH-stat titration. Immunohistochemistry demonstrated a distinct staining for both AT1 and AT2 receptors in the lamina propria of the villi and also for AT1 receptors in the muscularis interna. When angiotensin II was infused in the presence of the AT1receptor antagonist losartan, mucosal alkaline secretion increased by ∼50%. This response was inhibited by the AT2 receptor antagonist PD-123319. The AT2 receptor agonist CGP-42112A increased mucosal alkaline secretion by ∼50%. This increase was absent in the presence of PD-123319 but not in the presence of losartan or the local anesthetic lidocaine. We conclude that angiotensin II stimulates duodenal mucosal alkaline secretion by activation of AT2 receptors located in the duodenal mucosa/submucosa.
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Shimizu-Hirota, Ryoko, Hiroyuki Sasamura, Mizuo Mifune, Hideaki Nakaya, Mari Kuroda, Matsuhiko Hayashi, and Takao Saruta. "Regulation of Vascular Proteoglycan Synthesis by Angiotensin II Type 1 and Type 2 Receptors." Journal of the American Society of Nephrology 12, no. 12 (December 2001): 2609–15. http://dx.doi.org/10.1681/asn.v12122609.
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ABSTRACT. Recent studies have shown that proteoglycans play an important role in the development of vascular disease and renal failure. In this study, the effects of angiotensin II (AngII) type 1 (AT1) and type 2 (AT2) receptor stimulation on glycosaminoglycan and proteoglycan core protein synthesis in vascular smooth muscle cells (VSMC) were examined. Treatment of AT1 receptor-expressing VSMC with AngII resulted in a dose-dependent and time-dependent increase (2- to 4-fold) in 3H-glucosamine/35S-sulfate incorporation, which was abolished by pretreatment with the AT1 receptor antagonist, losartan. The effects of AngII were inhibited by the epidermal growth factor receptor inhibitor, AG1478, and the mitagen-activated protein kinase kinase inhibitor, PD98059, but not the protein kinase C inhibitors, chelerythrine and staurosporine. AngII treatment also resulted in significant increases in the mRNA of the core proteins, versican, biglycan, and perlecan. The effects of AT2 receptor stimulation were examined by retroviral transfection of VSMC with the AT2 receptor. Stimulation of the AT2 receptor in these VSMC-AT2 cells resulted in a significant (1.3-fold) increase in proteoglycan synthesis, which was abolished by the AT2 receptor antagonist, PD123319, and attenuated by pretreatment with pertussis toxin. These results implicate both AT1 and AT2 receptors in the regulation of proteoglycan synthesis and suggest the involvement of epidermal growth factor receptor-dependent tyrosine kinase pathways and Gαi/o-mediated mechanisms in the effects of the two receptors.
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Vázquez, Erika, Israel Coronel, Rocio Bautista, Eunice Romo, Carlos M. Villalón, M. Carmen Avila-Casado, Virgilia Soto, and Bruno Escalante. "Angiotensin II-dependent induction of AT2 receptor expression after renal ablation." American Journal of Physiology-Renal Physiology 288, no. 1 (January 2005): F207—F213. http://dx.doi.org/10.1152/ajprenal.00216.2004.
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Angiotensin (ANG) II can be associated with gene expression regulation. Thus we studied the possible role of ANG II in the regulation of AT2 mRNA and protein expression. We utilized sham-operated renal ablation rats as well as renal ablation rats pretreated during the first 7 days of the development of renal damage with either the angiotensin-converting inhibitor ramipril, the AT1 receptor antagonist losartan, or the AT2 receptor antagonist PD-123319. Renal tissue was analyzed for histological changes and expression of AT2 receptor mRNA (by RT-PCR) and protein (by immunohistochemistry). To explore the physiological role of AT2 receptor overexpression in the development of renal damage, blood pressure, urinary protein excretion, and renal damage were evaluated. A time-dependent increase in the expression of AT2 receptor mRNA and protein was observed at 7, 15, and 30 days after renal ablation. Because these effects were already evident at day 7, the effects of ramipril, losartan, or PD-123319 were tested at this time. The ramipril group and the PD-123319-pretreated group showed inhibition of AT2 receptor expression, whereas the losartan-pretreated group showed a further increase in AT2 receptor expression. Inhibition of the AT2 receptor during renal ablation was associated with increased renal damage and a further increase in the blood pressure. This suggests that overexpression of AT2 receptors after renal ablation is modulated by ANG II through its own AT2 receptor and that functional expression of this effect may represent a counterregulatory mechanism to modulate the renal damage induced by renal ablation.
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Casselbrant, Anna, Anders Edebo, Peter Hallersund, Emma Spak, Herbert F. Helander, Claes Jönson, and Lars Fändriks. "Angiotensin II receptors are expressed and functional in human esophageal mucosa." American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 5 (November 2009): G1019—G1027. http://dx.doi.org/10.1152/ajpgi.00255.2009.
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Only few studies have been devoted to the actions of the renin-angiotensin system (RAS) in the human gastrointestinal tract. The present study was undertaken to elucidate the expression and action of RAS in the human esophageal mucosa. Mucosal specimens with normal histological appearance were obtained from healthy subjects undergoing endoscopy and from patients undergoing esophagectomy due to neoplasm. Gene and protein expressions of angiotensin II (Ang II) receptor type 1 (AT1) and type 2 (AT2) and angiotensin-converting enzyme (ACE) were analyzed. In vivo functionality in healthy volunteers was reflected by assessing transmucosal potential difference (PD). Ussing chamber technique was used to analyze the different effects of Ang II on its AT1 and AT2 receptors. Immunoreactivity to AT1 and AT2 was localized to stratum superficiale and spinosum in the epithelium. ACE, AT1, and AT2 were found in blood vessel walls. Transmucosal PD in vivo increased following administration of the AT1 receptor antagonist candesartan. In Ussing preparations mean basal transmural PD was −6.4 mV, epithelial current ( Iep) 34 μA/cm2, and epithelial resistance ( Rep) 321 Ω·cm2. Serosal exposure to Ang II increased PD as a result of increased Iep, whereas Rep was constant. Ang II given together with the selective AT1-receptor antagonist losartan, or AT2 agonist C21 given alone, resulted in a similar effect. Ang II given in presence of the AT2-receptor antagonist PD123319 did not influence PD, but Iep decreased and Rep increased. In conclusion, Ang II receptors and ACE are expressed in the human esophageal epithelium. The results suggest that AT2-receptor stimulation increases epithelial ion transport, whereas the AT1 receptor inhibits ion transport and increases Rep.
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Mifune, Mizuo, Hiroyuki Sasamura, Hideaki Nakaya, Ryoko Shimizu-Hirota, Matsuhiko Hayashi, and Takao Saruta. "Effects of Angiotensin II Type 2 Receptor Stimulation on Collagen Synthesis in Vascular Smooth Muscle Cells." Hypertension 36, suppl_1 (October 2000): 709. http://dx.doi.org/10.1161/hyp.36.suppl_1.709.
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P84 Previously, we and others have shown that angiotensin II enhances vascular smooth muscle cell extracellular matrix synthesis via stimulation of the type 1 angiotensin (AT1) receptor. Recently, expression of the type 2 (AT2) receptor has been confirmed in the adult vasculature, but its role in vascular remodeling has not yet been fully defined. In particular, conflicting data from in vivo studies have reported that AT2 receptor inhibition may either attenuate or enhance vascular hypertrophy and fibrosis. The aim of this study was to clarify the effects of direct stimulation of AT2 receptors on collagen synthesis in vascular smooth muscle cells in vitro. Firstly, retroviral gene transfer was used to supplement adult vascular smooth muscle cells with AT2 receptors to mimic the vasculature in vivo. Treatment of these cells with the AT2 receptor agonist CGP42212A (10-7 mol/L) alone did not cause a significant change in p42/p44 MAP kinase activity, but caused a modest (33%) decrease in protein tyrosine phosphatase activity. Treatment with CGP42112A also caused a dose- and time-dependent increase in both cell-associated and secretory collagen synthesis (148+17% of control at 48 h, p<0.05) which was completely inhibited by the AT2 receptor antagonist PD123319, but unaffected by the AT1 receptor antagonist losartan. The AT2 receptor-mediated stimulation of collagen synthesis was unaffected by tyrosine phosphatase inhibitors sodium orthovanadate and okadaic acid, but attenuated by pretreatment with pertussis toxin or Galphai antisense oligonuclotides. These results suggest that direct AT2 receptor stimulation can increase rather than decrease collagen synthesis in vascular smooth muscle cells, and suggest a role for Galphai in the AT2 receptor-mediated effects.
Dissertations / Theses on the topic "AT2 receptor antagonist"
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Wallinder, Charlotta. "Design, Synthesis and Biological Evaluation of Selective Nonpeptide AT2 Receptor Agonists and Antagonists." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9213.
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Foulquier, Sébastien. "Récepteurs AT1-AT2 de l'angiotensine II et propriétés particulières des antagonistes AT1 sur la circulation cérébrale chez le rat." Thesis, Université de Lorraine, 2012. http://www.theses.fr/2012LORR0002.
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Le Système Rénine Angiotensine tient une place prépondérante au sein de la circulation cérébrale. Les Antagonistes des Récepteurs AT1 à l'Angiotensine II (ARAII) ont prouvé leur efficacité dans la prévention de l'Accident Vasculaire Cérébral (AVC), indépendamment de leur effet anti-hypertenseur. Plusieurs mécanismes pourraient être impliqués dans cette cérébroprotection. D'une part, en bloquant les récepteurs AT1, les ARAII favorisent la stimulation des récepteurs AT2 à l'angiotensine II. Le caractère bénéfique lié à la stimulation des récepteurs AT2 s'oppose au caractère délétère lié à la stimulation des récepteurs AT1. Nous avons montré que cet équilibre AT1 - AT2 est modifié au niveau cérébrovasculaire suite à un régime hypersodé. En effet, la vasodilatation des artérioles cérébrales médiée par les récepteurs AT2 est abolie, ce qui pourrait constituer un élément délétère lors de la survenue d'un évènement ischémique. D'autre part, certains ARAII présentent une affinité pour les récepteurs PPAR-gamma. Cette activité, démontrée comme protectrice à différents niveaux vasculaires, pourrait également être bénéfique pour la circulation cérébrale. Nous avons en particulier montré que l'activation PPAR-gamma améliore les effets des ARAII au niveau de la circulation cérébrale (diamètre artériolaire, réactivité à l'angiotensine II). Les mécanismes en jeu semblent impliquer des modifications de la fonction des récepteurs AT1-AT2, indépendamment de leur expression. La stimulation des récepteurs AT2 et l'activation PPAR-gamma constituent donc deux propriétés particulières des ARAII. Ces propriétés pourraient participer au caractère cérébroprotecteur des ARAII, au-delà du seul blocage des récepteurs AT1. Le développement de molécules duales regroupant les activités antagoniste AT1 - agoniste PPAR-gamma pourrait constituer un avenir thérapeutique intéressant dans le traitement de l'hypertension en apportant une protection cérébrovasculaire supérieure aux traitements actuelsThe Renin Angiotensin System plays a major role in cerebral circulation. AT1 receptor blockers (ARBs) afford protection against cerebrovascular complications that go beyond that to be expected from their blood pressure lowering action. Several mechanisms could explain such beneficial effects. Firstly, by blocking AT1 receptors, ARBs promote AT2 receptor stimulation by angiotensin II. The beneficial effect related to stimulation of AT2 receptors (vasodilation) counterbalances the deleterious actions of AT1 receptors stimulation. Changes in this ratio may then alter cerebral circulation. We demonstrated that the AT1- AT2 ratio is modified at the cerebrovascular level during high salt intake, which is a risk factor for stroke. The AT2-mediated vasodilation of pial arterioles is abolished. Secondly, some ARBs act as partial agonists of PPAR-gamma. Such an activity, which has been demonstrated to protect extracerebral vessels, could also be beneficial for cerebral circulation. Our results showed that PPAR-gamma activation improves ARB effects on cerebral circulation (arteriolar diameter, angiotensin II reactivity). The underlying mechanisms could imply functional regulation of AT1-AT2 receptors without any change in expression status. AT2 receptor stimulation and PPAR-gamma activity are two special properties of ARBs. These properties could contribute to the cerebroprotection induced by ARBs, beyond the AT1-receptor blockade. Development of new molecules with AT1-receptor blockade and PPAR-gamma activity could take part into the future therapeutic management of hypertension, providing a better cerebrovascular protection
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Avgoustou, Paris. "Developing small molecule antagonists against AM2 receptor for the treatment of pancreatic cancer." Thesis, University of Sheffield, 2018. http://etheses.whiterose.ac.uk/21421/.
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Pancreatic cancer is the 11th most common cancer type in the UK. The survival rates are among the lowest in the UK which is directly reflected by its mortality rates that keep raising. Existing therapies include surgical removal and cytotoxic chemotherapeutic cocktails which have minimal improvement in life expectancy. Adrenomedullin (AM) is a multifunctional peptide that exerts its actions through activation of AM receptor a member of GPCR superfamily. The physiological role of AM as an important regulator of blood pressure is well established. However, emerging data suggest its involvement in several aspects of tumour development including cancer cell growth, angiogenesis, cell survival and the communication between the tumour cells and the host microenvironment. This study aims to develop novel small molecule antagonists against AM2 receptor. Using a structure/knowledge-based drug modelling program, based on published crystal structures of CGRP and AM1 receptors and recently developed CGRP receptor small molecule antagonists we were able to design and screen a large library of potential antagonists. Novel compounds were screened for their ability to inhibit cAMP production in CGRPr, AM1r, AM2r AMY1r and AMY3r overexpressing cells. This resulted in the development of a primary structural family with high potency and selectivity against AM2 and CGRP receptors. Several members of this family such as SHF-638, showed high selectivity for AM2 receptor when compared with CGRP. Pharmacological evaluation of SHF-638, using Schild regression analysis, suggested a competitive mode of antagonism. Moreover, SHF-638 was proven as an excellent tool for in-vitro and in-vivo use. In-vivo administration of SHF-638 resulted in significant decrease of breast and pancreatic cancer subcutaneous tumour growth. Inhibition of AM resulted in decrease proliferation, vessel development and increase in necrosis. Decrease in the presence of pancreatic stellate cells was also observed suggesting involvement of AM in the development of desmoplastic structures. Overall, the findings of this study suggest that blocking the effects of AM not only influences the development and growth of tumors but is also affecting the tumour microenvironment, feature that could potentially be used for overcoming chemotherapeutic resistance.
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Helms, Nick. "Wechselwirkungen von Agonisten und kompetitiven Antagonisten mit der Ligandenbindungsstelle des schnell desensitisierenden P2X3-Rezeptors." Doctoral thesis, Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-197364.
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Purinerge P2X3-Rezeptoren spielen eine bedeutende Rolle in der Vermittlung chronischer Schmerzen, welche ein führendes Problem des Gesundheitswesens mit vielen sozioökonomischen Konsequenzen darstellen. Die Tatsache, dass P2X3-Rezeptoren fast ausschließlich von
nozizeptiven Neuronen exprimiert werden, macht sie trotz ihres besonderen Desensitisierungsverhaltens zu vielversprechenden Angriffspunkten zukünftiger Schmerztherapien, beispielsweise mithilfe kompetitiver Antagonisten an diesen Rezeptoren. Zur Analyse der Wechselwirkungen zwischen Agonist und kompetitivem Antagonist wird meist der Schild-Plot benutzt. Jedoch ist dieser im Falle der sehr schnell desensitisierenden P2X3-Rezeptoren ungeeignet, da die Vorbedingung
eines stabilen Gleichgewichts zwischen Agonist und Antagonist aufgrund der Desensitisierung nicht erfüllt ist.
Ziel der vorliegenden Arbeit war es, eine neue Methode zur Analyse der Interaktion kompetitiver Antagonisten mit ihrer Bindungsstelle am Beispiel des P2X3-Rezeptors zu entwickeln und so für die Antagonistenbindung bedeutende Aminosäuren der Bindungsstelle zu identifizieren.
Mittels der Patch-Clamp-Technik wurden die Effekte der Antagonisten A-317491, TNP-ATP und PPADS auf die vom P2X1,3-Rezeptor-selektiven Agonisten α,β-MeATP induzierten Ströme am P2X3-Wildtyp-Rezeptor und an fünf Rezeptormutanten mit veränderter Ligandenbindungsstelle
untersucht. Alle Rezeptoren wurden in HEK293-Zellen exprimiert. Anhand der gemessenen Daten wurde ein Hidden Markov Model (HMM) erstellt, welches die sequentiellen Übergänge des Rezeptors von geschlossen zu offen und desensitisiert in An- und Abwesenheit des Antagonisten miteinander kombiniert. Die am P2X3-Rezeptor induzierten Ströme konnten mithilfe dieses Modells korrekt gefittet und die für die Antagonistenbindung wichtigen Aminosäuren innerhalb der Bindungsstelle bestimmt werden. Als Resultat dieser Arbeit konnte außerdem gezeigt werden, dass das HMM eine geeignete Methode zur Analyse der Wirkung kompetitiver Antagonisten an schnell desensitisierenden Rezeptoren darstellt. Die untersuchten Antagonisten A-317491 und TNP-ATP haben einen kompetitiven Wirkmechanismus, während PPADS eine pseudoirreversible Blockade verursacht.
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Price, Andrew George. "Physiological and pathophysiological roles of angiotensin II in the rat knee joint: Therapeutic potential of AT1 receptor antagonism." Thesis, University of the West of Scotland, 2006. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.748540.
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Carmo, Marta Regina Santos do. "Efeito do PPADS, antagonista do receptor P2, sobre a lesÃo cerebral, comportamento e memÃria de camundongos submetidos à isquemia cerebral focal permanente." Universidade Federal do CearÃ, 2010. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=4924.
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Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgicoApÃs isquemia cerebral, o Trifosfato de Adenosina (ATP) atinge altas concentraÃÃes no espaÃo extracelular e pode atuar como agente tÃxico, que causa degeneraÃÃo celular e morte, mediada atravÃs de receptores P2X e P2Y. No presente estudo, foram investigados os efeitos do PPADS, um antagonista nÃo-seletivo dos receptores P2, sobre o comportamento e dano neuronal apÃs isquemia induzida por oclusÃo permanente da artÃria cerebral mÃdia por eletrocoagulaÃÃo. Os animais receberam PPADS (0,1, 0,5 e 1,0 nmols/1μL) ou fluÃdo cerebroespinhal artificial (FCE) por injeÃÃo intracerebroventricular 10 min antes da isquemia. Os parÃmetros estudados foram funÃÃo sensÃrio-motora, aquisiÃÃo e retenÃÃo de memÃria, Ãrea de infarto cerebral e atividade da MPO, como marcador para infiltraÃÃo granulocÃtica. ApÃs isquemia, verificou-se atravÃs de avaliaÃÃo neurolÃgica, uma diminuiÃÃo significante do desempenho motor e funÃÃo sensorial dos animais. A percentagem da Ãrea de infarto nos animais falso-operados foi significantemente menor que naqueles submetidos à isquemia (FO: 0,89  0,18%; FO + PPADS 1,0: 1,18  0,1%; ISQ: 9,06  1,2%; ISQ + PPADS 0,5: 2,2  0,32%; ISQ + PPADS 1,0: 1,86  0, 18%). Foi observado ainda um aumento da atividade exploratÃria vertical (n de Rearings) nos animais tratados com PPADS quando comparados aos animais do grupo isquemiado (ISQ: 9,5  1,8; ISQ + PPADS 0,5: 26,9  2,9; ISQ + PPADS 1,0: 20,6  3,7; Kruskall-Wallis, p<0.05). O tratamento com PPADS melhorou de forma significante os dÃficits na memÃria operacional induzidos pela isquemia, avaliado no teste do Labirinto em Y (FO: 73,8  1,9%; ISQ: 56,7  2,9%; ISQ + PPADS 0,5: 76,7  3,2%; ISQ + PPADS 1,0: 72,6  4,0%). Um resultado semelhante foi observado na memÃria aversiva (teste da esquiva passiva) no qual o PPADS melhorou a aquisiÃÃo de memÃria de curta duraÃÃo. Os animais isquemiados demonstraram um aumento nos nÃveis de MPO no estriado (FO: 3,6  0,63; ISQ: 16,24  4,86) e cÃrtex temporal (FO: 6,16  1,23; ISQ: 22,33  4,98), e o tratamento com PPADS (1,0 nmols/1μL) reverteu significantemente esse efeito (ISQ + PPADS â estriado: 6,13  0,65; cÃrtex: 6,28  0,38). Os resultados demonstram o envolvimento dos receptores P2 na fisiopatologia da isquemia cerebral. A inibiÃÃo dos receptores P2 pelo PPADS mostrou um significante efeito neuroprotetor sobre o dano neuronal, comportamento motor e memÃria apÃs isquemia e indicam que este efeito pode estar relacionado pelo menos em parte a uma atividade antiinflamatÃria deste composto.
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Hachem, Maryam. "Characterization of [18F]FPyKYNE-Losartan as a Novel PET Tracer for Imaging AT1 Receptors." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32417.
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The Angiotensin II Type I Receptor (AT1R) is the main receptor that produces most of the physiological actions of the Renin Angiotensin System (RAS). Alterations of AT1R expression in renal and cardiovascular diseases make this receptor an attractive target for developing an imaging agent to monitor its expression in disease states. [18F]FPyKYNE-Losartan has been developed as a derivative of the clinically used AT1R blocker Losartan. The aim of this work was to characterize this tracer and evaluate its potential as an imaging agent for AT1Rs, thereby, progressing towards human imaging of the AT1R. MicroPET imaging in rats and PET imaging in pigs displayed specific AT1R binding, high kidney-to-blood and image contrast, and slow clearance from kidneys. [18F]FPyKYNE-Losartan was shown to have 2 types of labeled metabolites in rat plasma and kidneys: hydrophilic and hydrophobic, whereas, only hydrophilic metabolite(s) in pig plasma. Plasma protein binding of [18F]FPyKYNE-Losartan was determined, by an in vitro ultrafiltration method, to be 97% which is very similar to that of Losartan (98%). FPyKYNE-Losartan displayed full antagonism of Ang II pressor effect in rats in vivo, with an ED50 of 25.5 mg/Kg and 4-times (25%) less potency than Losartan. In vitro binding studies confirmed the binding selectivity of [18F]FPyKYNE-Losartan. Bmax and Kd parameters were determined to be 348 ± 112 fmol/mm2 and 49.4 nM, respectively. Rat dosimetry studies exhibited that the sex averaged effective doses of [18F]FPyKYNE-Losartan according to ICRP 60 and 103 protocols are 2.97E-02 (mSv/MBq) and 3.06E-02 (mSv/MBq), respectively, which are within an acceptable range compared with other F-18 labeled tracers and within the safety limits of the FDA. In conclusion, [18F]FPyKYNE-Losartan has an excellent potential for translation towards human imaging to monitor AT1R expression and guide therapy.
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Fitoussi, Mathieu. "Intérêt des inhibiteurs de l' enzyme de conversion de l' angiotensine et des antagonistes des récepteurs AT1 de l' angiotensine dans le traitement de l' insuffisance cardiaque." Paris 5, 1995. http://www.theses.fr/1995PA05P214.
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Helms, Nick. "Wechselwirkungen von Agonisten und kompetitiven Antagonisten mit der Ligandenbindungsstelle des schnell desensitisierenden P2X3-Rezeptors." Doctoral thesis, 2015. https://ul.qucosa.de/id/qucosa%3A14492.
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Purinerge P2X3-Rezeptoren spielen eine bedeutende Rolle in der Vermittlung chronischer Schmerzen, welche ein führendes Problem des Gesundheitswesens mit vielen sozioökonomischen Konsequenzen darstellen. Die Tatsache, dass P2X3-Rezeptoren fast ausschließlich von
nozizeptiven Neuronen exprimiert werden, macht sie trotz ihres besonderen Desensitisierungsverhaltens zu vielversprechenden Angriffspunkten zukünftiger Schmerztherapien, beispielsweise mithilfe kompetitiver Antagonisten an diesen Rezeptoren. Zur Analyse der Wechselwirkungen zwischen Agonist und kompetitivem Antagonist wird meist der Schild-Plot benutzt. Jedoch ist dieser im Falle der sehr schnell desensitisierenden P2X3-Rezeptoren ungeeignet, da die Vorbedingung
eines stabilen Gleichgewichts zwischen Agonist und Antagonist aufgrund der Desensitisierung nicht erfüllt ist.
Ziel der vorliegenden Arbeit war es, eine neue Methode zur Analyse der Interaktion kompetitiver Antagonisten mit ihrer Bindungsstelle am Beispiel des P2X3-Rezeptors zu entwickeln und so für die Antagonistenbindung bedeutende Aminosäuren der Bindungsstelle zu identifizieren.
Mittels der Patch-Clamp-Technik wurden die Effekte der Antagonisten A-317491, TNP-ATP und PPADS auf die vom P2X1,3-Rezeptor-selektiven Agonisten α,β-MeATP induzierten Ströme am P2X3-Wildtyp-Rezeptor und an fünf Rezeptormutanten mit veränderter Ligandenbindungsstelle
untersucht. Alle Rezeptoren wurden in HEK293-Zellen exprimiert. Anhand der gemessenen Daten wurde ein Hidden Markov Model (HMM) erstellt, welches die sequentiellen Übergänge des Rezeptors von geschlossen zu offen und desensitisiert in An- und Abwesenheit des Antagonisten miteinander kombiniert. Die am P2X3-Rezeptor induzierten Ströme konnten mithilfe dieses Modells korrekt gefittet und die für die Antagonistenbindung wichtigen Aminosäuren innerhalb der Bindungsstelle bestimmt werden. Als Resultat dieser Arbeit konnte außerdem gezeigt werden, dass das HMM eine geeignete Methode zur Analyse der Wirkung kompetitiver Antagonisten an schnell desensitisierenden Rezeptoren darstellt. Die untersuchten Antagonisten A-317491 und TNP-ATP haben einen kompetitiven Wirkmechanismus, während PPADS eine pseudoirreversible Blockade verursacht.
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Bemme, Sebastian. "Bedeutung der Blockade des lokalen Angiotensinsystems für die chronisch progrediente Niereninsuffizienz im Rahmen der Alport-Nephritis." Doctoral thesis, 2012. http://hdl.handle.net/11858/00-1735-0000-000D-F001-7.
Full textBooks on the topic "AT2 receptor antagonist"
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Lambert, David G. Mechanisms and determinants of anaesthetic drug action. Edited by Michel M. R. F. Struys. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199642045.003.0013.
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This chapter is broken into two main sections: a general description of the principles of ligand receptor interaction and a discussion of the main groups of ‘targets’; and explanation of some common pharmacological interactions in anaesthesia, critical care, and pain management. Agonists bind to and activate receptors while antagonists bind to receptors and block the effects of agonists. Antagonists can be competitive (most common) or non-competitive/irreversible. The main classes of drug target are enzymes, carriers, ion channels, and receptors with examples of anaesthetic relevance interacting with all classes. There are many examples in anaesthesia where multiple interacting drugs are co-administered—polypharmacology. To give an example: neuromuscular blockade. Rocuronium is a non-depolarizing neuromuscular blocker acting as a competitive antagonist at the nicotinic acetylcholine receptor. Rocuronium competes with endogenous acetylcholine to shift the concentration–response curve for contraction to the right. The degree of contractility is less for a given concentration of acetylcholine (agonist) in the presence of rocuronium. Using the same principle, the rightward shift can be compensated by increasing the amount of acetylcholine (as long as the amount of rocuronium presented to the receptor as an antagonist remains unchanged, its action can be overcome by increased agonist). Acetylcholine at the effect site is increased by acetylcholinesterase inhibition with neostigmine. One of the side-effects of neostigmine is that it acts as an indirect parasympathomimetic. In the cardiovascular system this would lead to muscarinic receptor-mediated bradycardia; these effects are routinely reversed by the competitive muscarinic antagonist glycopyrrolate.
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Feng, Alexander J., George C. Chang Chien, and Alan D. Kaye. NMDA Receptor Antagonists, Gabapentinoids, Alpha-2 Agonists, and Dexamethasone. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190457006.003.0002.
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Surgical pain is a major obstacle in the recovery of patients. Effective pain management is of upmost importance to optimize a patient’s recovery, decrease medical complications, and increase patient satisfaction. Traditional pain management with opioids and nonsteroidal anti-inflammatory drugs have significant side effect profiles leading to medical complications or insufficient pain management from reluctance of use. Adjuvant analgesic can provide improved pain management with significantly less side effect profile. In addition, the clinician can, with synergistic effects of adjuvant medications, lower the total dosages used, thus lessening the likelihood of the side effects that occur when medications are used alone at a higher dosage. This chapter presents several adjuvant analgesics—NMDA receptor antagonists, gabapentinoids, alpha-2 agonists, and dexamethasone—and evidence for their use. Ultimately, through the use of traditional pain management options along with adjuvant analgesics, the effectiveness of acute pain management can be increased while adverse outcomes are reduced and functional recovery and quality of life improved.
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Jones, Alison L. Management of opioid poisoning. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199600830.003.0319.
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Opioids are ‘morphine like’ substances that have actions at specific opioid receptors (especially µ receptors) in the central nervous system (CNS). Tolerance of respiratory depression develops at a slower rate than analgesic tolerance, placing patients with a long history of opioid use at particular risk for respiratory depression. If chronic users abruptly stop taking opioids, they develop an acute withdrawal syndrome. Most opioid toxicity is the result of inadvertent overdosage during recreational use or in self-harm, but it can also be due to medication misuse and drug errors. It is characterized by three main clinical features (all may not be consistently present); depressed respiratory rate (the sine qua non of opioid poisoning) and respiratory volume, and reduced arterial oxygen desaturation, CNS depression, and small or pin-point pupils. Opioid-poisoned patients require early clinical assessment, appropriate administration of intravenous naloxone (competitive opioid antagonist) and meticulous respiratory supportive care, with close observation. Because of the longer half-life of opioids than naloxone, repeated doses may be needed for long-acting opioids or large doses of shorter acting opioids. If opioid antagonists are given to regular opioid users in excess, they can precipitate acute withdrawal symptoms. The need for ITU admission usually occurs as a result of a complication of the opioid toxicity.
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Iversen, Leslie. The Pharmacology of Delta-9-Tetrahydrocannabinol (THC). Oxford University Press, 2018. http://dx.doi.org/10.1093/oso/9780190846848.003.0002.
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The 19th century was a great era for plant chemistry. Many complex drug molecules, known as alkaloids, were isolated and identified from plants. This chapter discusses the history of the discovery of delta-9-tetrahyrocannabinol (THC) as the psychoactive substance in cannabis products and also the discovery of the cannabinoid receptors CB-1 and CB-2 in the body and brain. The mechanism of action of cannabinoids on such receptors to inhibit neurotransmitter release or other actions is also discussed. In addition, various methods for the ingestion of cannabis, such as smoking and vaping, are reviewed. Synthetic agonists and antagonists at cannabinoid receptors and the proliferation of synthetic agonists as novel psychoactive agents are also discussed.
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Nutt, David J., and Liam J. Nestor. The opioid system and addiction. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198797746.003.0010.
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The opioid system of the brain is the major target for opiate drugs such as morphine and heroin, and has been implicated in processes such as pain, stress and reward. Many of these effects take place at the mu opioid receptor (mOR), which is distributed throughout the brain. Significantly, genetic polymorphisms at the mOR may confer a greater dopamine response to the reinforcing effects of alcohol, and it has been suggested that addiction per se may be associated with alterations to the opioid system. There is evidence for the potential efficacy of mOR antagonists (e.g. naltrexone) in reducing drug and alcohol relapse, increasing treatment retention and attenuating the subjective effects of substances of abuse. Medications with partial agonist activity at the kappa opioid receptor (e.g. nalmefene) may also confer an additional clinical advantage by reducing binging following relapse.
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Vimalesvaran, Kavitha, and Michael Marber. Myocardial Remodelling after Myocardial Infarction. Oxford University Press, 2014. http://dx.doi.org/10.1093/med/9780199653461.003.0031.
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This chapter focuses on myocardial remodelling, a process that affects the heart’s shape, structure, and function, following myocardial injury (MI). Post-MI remodelling can be divided into three phases, with the first phase 0–72 hours beginning at the time of ischaemic injury, the second phase 72 hours to 6 weeks, and the third and last phase 6 weeks and beyond. During post-infarction remodelling, hypertrophy is an adaptive response that compensates for the increased load, reduces the effect of progressive dilatation, and balances contractile function. The chapter discusses the factors involved in ventricular remodelling and its association with heart failure progression. The effects of therapies designed to prevent or attenuate post-infarction left ventricular remodelling, with reference to the pathophysiological mechanisms involved, are then considered. Therapies specifically discussed include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β-adrenoreceptor blockers, and aldosterone receptor antagonists.
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Eastman, Brad, and Larry Field. Opioid and Benzodiazepine Overdose. Edited by Matthew D. McEvoy and Cory M. Furse. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190226459.003.0092.
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This chapter, “Opioid and Benzodiazepine Overdose,” reviews the pathophysiology of disease state pertaining to overdose as well as the molecular mechanisms involved with drug receptor binding. It discusses common presenting signs and symptoms of opioid and benzodiazepine overdose in the context of a clinical scenario. It also discusses specific patient populations that are at increased risk of opioid and benzodiazepine overdose. Initial and subsequent treatment options are thoroughly examined while allowing the reader to engage in clinical discussions to open-ended questions provided throughout the chapter. The use of opioid and benzodiazepine antagonists as antidotes is reviewed in detail along with common doses and regimens.
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Erlinge, David, and Göran Olivecrona. Diagnosis and management of non-STEMI coronary syndromes. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199600830.003.0146.
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Acute coronary syndromes are classified as ST segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) or unstable angina. Most patients with NSTEMI present with a history of chest pain that has subsided spontaneously before or soon after arrival at the emergency room, but with positive cardiac markers (usually troponin T or I) indicative of myocardial infarction. NSTEMI has a risk of recurrent myocardial infarction of 15–20% and a 15% chance of 1-year mortality. Patients with non-STE-acute coronary syndromes are at similar risk as a STEMI patient at 1 year. The strongest objective signs of NSTEMI are a positive troponin and ST segment depression. NSTEMI should be acutely treated with aspirin, an adenosine diphosphate-receptor antagonist, and an anticoagulant (fondaparinux or low molecular weight heparins). NSTEMI should be investigated with coronary angiography within 72 hours. Curative treatment is percutaneous coronary intervention or coronary artery bypass grafting.
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Hider, Samantha, and Edward Roddy. Epidemiology of gout. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199668847.003.0038.
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Gout is the most prevalent inflammatory arthritis in men. Data from epidemiological studies conducted in several countries suggest that the prevalence and incidence of gout have risen over the last few decades, although incidence may have stabilized recently. Dietary factors (animal purines, alcohol, and fructose), co-morbid medical conditions (obesity, metabolic syndrome, hypertension, and chronic kidney disease), and medications (diuretics, aspirin, beta blockers, angiotensin converting-enzyme inhibitors, and non-losartan angiotensin II receptor blockers) have been confirmed to be risk factors for both hyperuricaemia and gout. In contrast, low-fat dairy products, coffee, vitamin C, calcium channel antagonists, and losartan appear to reduce the risk of developing gout. People with gout are themselves at increased risk of developing cardiovascular disease and chronic kidney disease, independent of traditional risk factors for these conditions.
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Opie, Lionel. Optimal Medical Therapy Post-AMI. Oxford University Press, 2011. http://dx.doi.org/10.1093/med/9780199544769.003.0006.
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• The management of an acute myocardial infarction can be divided into four phases: (a) The initial acute ischaemia causes severe prolonged chest pain when the patient is rushed to a Coronary or Intensive Care Unit; (b) Within the next few hours as ischaemia changes into infarction, the aim at this step is to restore blood flow in the occluded artery by thrombolysis or by percutaneous coronary intervention (PCI); (c) Next, the infarct is established and the left ventricle undergoes early remodeling; (d) Finally, follows the post-AMI post-hospital phase when continued left ventricular remodeling takes place• The therapeutic management of each of these steps can be optimized using appropriate medical therapy including antiplatelet and antithrombotic therapy, beta-blockers, ACE-inhibitors and angiotensin receptor blockers, lipid-lowering drugs, aldosterone antagonists, omega-3 fatty acids and so on.
Book chapters on the topic "AT2 receptor antagonist"
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de Gasparo, M. "AT1 Receptor Antagonists: Pharmacology." In Angiotensin Vol. II, 417–51. Berlin, Heidelberg: Springer Berlin Heidelberg, 2004. http://dx.doi.org/10.1007/978-3-642-18497-0_18.
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Inagami, Tadashi, Satoru Eguchi, Satoshi Tsuzuki, and Toshihiro Ichiki. "Angiotensin II Receptors AT1 and AT2: New Mechanisms of Signaling And Antagonistic Effects of AT1 and AT2." In Progress in Experimental Cardiology, 129–39. Boston, MA: Springer US, 1998. http://dx.doi.org/10.1007/978-1-4615-5743-2_11.
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Ito, H., K. Takemori, J. Kawai, and T. Suzuki. "AT1 Receptor Antagonist Prevents Brain Edema Without Lowering Blood Pressure." In Brain Edema XI, 141–45. Vienna: Springer Vienna, 2000. http://dx.doi.org/10.1007/978-3-7091-6346-7_29.
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Azizi, M., and J. Ménard. "Combined Blockade of the Renin Angiotensin System with ACE Inhibitors and AT1 Receptor Antagonists." In Angiotensin Vol. II, 485–516. Berlin, Heidelberg: Springer Berlin Heidelberg, 2004. http://dx.doi.org/10.1007/978-3-642-18497-0_20.
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Champion, Hunter C., David G. Lambert, Trinity J. Bivalacqua, Dennis B. Mcnamara, and Philip J. Kadowitz. "Comparison of the Inhibitory Actions of Angiotensin AT1 Receptor Antagonists in the Peripheral Vascular Bed." In Progress in Experimental Cardiology, 65–86. Boston, MA: Springer US, 1998. http://dx.doi.org/10.1007/978-1-4615-5743-2_6.
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Funke-Kaiser, Heiko, Ulrike Steckelings, and Thomas Unger. "Stimulation of AT2 receptors." In Angiotensin II Receptor Antagonists, 31–46. CRC Press, 2006. http://dx.doi.org/10.1201/b14355-4.
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van Zwieten, Peter. "Comparative pharmacology of angiotensin II (AT1) receptor antagonists." In Angiotensin II Receptor Antagonists, 13–30. CRC Press, 2006. http://dx.doi.org/10.1201/b14355-3.
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"Effect of AT1-Receptor Antagonists on Endothelial Function." In Vascular Protection, 99–109. CRC Press, 2002. http://dx.doi.org/10.1201/b12626-14.
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Becker, Richard C., and Frederick A. Spencer. "Platelet Glycoprotein IIb/IIIa Receptor Antagonists." In Fibrinolytic and Antithrombotic Therapy. Oxford University Press, 2006. http://dx.doi.org/10.1093/oso/9780195155648.003.0014.
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The glycoprotein (GP) IIb/IIIa (αIIb/β3) receptor totalling 50,000 to 70,000 copies per platelet represents a common pathway for platelet aggregation in response to a wide variety of biochemical and mechanical stimuli. Accordingly, it represents an attractive target for pharmacologic inhibition that can be applied to patients with acute coronary syndromes. The evolution of GPIIb/IIIa receptor antagonists began with murine monoclonal antibodies and subsequently expanded to include small peptide or nonpeptide molecules with structural similarities to fibrinogen. There are three intravenous GPIIb/IIIa receptor antagonists that have been approved by the U.S. Food and Drug Administration: . . . • Abciximab (ReoPro) . . . . . . • Tirofiban (Aggrastat) . . . . . . • Eptifibatide (Integrilin) . . . Abciximab (ReoPro) is the Fab fragment of the chimeric human–murine monoclonal antibody c7E3. Following an intravenous bolus, free plasma concentrations of abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second-phase half-life of 30 minutes, representing rapid binding to the platelet GPIIb/IIIa receptor. Abciximab remains in the circulation for 10 or more days in the platelet-bound state. Intravenous administration of abciximab in doses ranging from 0.15 mg/kg to 0.3 mg/kg produces a rapid dose-dependent inhibition of platelet aggregation in response to adenosine diphosphate (ADP). At the highest dose, 80% of platelet GPIIb/IIIa receptors are occupied within 2 hours and platelet aggregation, even with 20 μM ADP, is completely inhibited. Sustained inhibition is achieved with prolonged infusions (12 to 24 hours) and low-level receptor blockade is present for up to 10 days following cessation of the infusion; however, platelet inhibition during infusions beyond 24 hours has not been well characterized. Platelet aggregation in response to 5 μM ADP returns to greater than or equal to 50% of baseline within 24 hours of drug cessation. In nearly 2,100 patients undergoing either balloon coronary angioplasty or atherectomy at high risk for ischemic (thrombotic) complications, a bolus of abciximab (0.25 mg/kg) followed by a 12-hour continuous infusion (10 μg/min) reduced the occurrence of death, the occurrence myocardial infarction (MI), or the need for an urgent intervention (repeat angioplasty, stent placement, balloon pump insertion, or bypass grafting) by 35% (EPIC Investigators, 1994).
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Becker, Richard C., and Frederick A. Spencer. "Platelet Antagonists." In Fibrinolytic and Antithrombotic Therapy. Oxford University Press, 2006. http://dx.doi.org/10.1093/oso/9780195155648.003.0039.
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Antithrombotic and fibrinolytic drugs impair normal hemostasis and, as a result, increase the risk for hemorrhage. It is important to consider that many treatment strategies include agents of differing classes (platelet antagonists, anticoagulants, fibrinolytics) and categories (aspirin, clopidogrel, glycoprotein [GP] IIb/IIIa receptor antagonists), creating a multisite and/or hemostatic phase defect. Platelet antagonists, by impairing primary hemostasis, are associated most often with hemorrhage involving the skin and mucous membranes; however, the gastrointestinal and genitourinary tracts may occasionally be involved. Fixed-dose unfractionated heparin (UFH) therapy is a modifiable risk factor associated with hemorrhage in patients receiving GPIIb/IIIa receptor antagonists. The Evaluation of c7E3 Fab in Preventing Ischemic Complications of High-Risk Angioplasty (EPIC) trial was a prospective, randomized, placebo-controlled trial examining the efficacy of treatment with abciximab (EPIC Investigators, 1994). A total of 2,099 patients were scheduled for coronary angioplasty or direct atherectomy and were considered to be at high risk for abrupt closure. The primary composite endpoint of the study at 30 days was death from any cause, nonfatal myocardial infarction (MI), coronary artery bypass grafting (CABG) or repeat percutaneous coronary intervention (PCI), or placement of an intraaortic balloon pump to relieve refractory ischemia. All patients received therapy with 325 mg of aspirin and bolus dosing of UFH between 10,000 and 12,000 U followed by additional boluses of 3,000 U every 15 minutes to maintain an activated clotting time (ACT) between 300 and 350 seconds. Patients were randomized to receive either abciximab 0.25 mg/kg as a bolus followed by placebo infusion, or a placebo bolus and infusion. A significant increase in the incidence of major hemorrhage was demonstrated in patients receiving abciximab bolus and infusion compared to placebo bolus and infusion. A total of 14% of patients receiving abciximab bolus and infusion experienced a major bleeding complication as compared to 7% in the placebo bolus and infusion group (p = .001). Analysis of major hemorrhage in patients treated with abciximab bolus and infusion as a function of UFH dose revealed a dose-dependent increased risk.
Conference papers on the topic "AT2 receptor antagonist"
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Johnson, G. J., P. C. Dunlop, M. J. Rabiet, L. A. Leis, and AH L. From. "THE DIHYDROPYRIDINE CALCIUM CHANNEL AGONIST, BAY K 8644, AND THE ANTAGONIST, NIFEDIPINE, INHIBIT U46619-INDUCED HUMAN PLATELET ACTIVATION BY COMPETITIVE BINDING TO THE THROMBOXANE A22/PGH2 RECEPTOR." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643756.
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The dihydropyridine (DP) Ca2+ channel antagonist, nifedipine (NF), inhibits platelet aggregation .in vitro and ex vivo by an undefined mechanism. Inhibition of Ca2+ influx via Ca2+ channels is a postulated mechanism, but voltage-dependent Ca2+ channels have not been demonstrated in platelets. We previously observed that NF blocked thromboxane A2 (TXA2)-induced platelet aggregation and secretion. In order to further evaluate the mechanism of DP inhibition of platelet activation, we studied the effects of NF and BAY K 8644, (BAY), a DP with opposite (agonist) effects on muscle cells, on human platelet aggregation and secretion induced by the TXA2 mimic, U46619. We also observed the effects of DP on biochemical consequences of platelet activation: cytoplasmic ionized Ca2+ ([Ca2+]i) by fura-2 fluorescence; phosphorylation of 40,000 Dalton protein (40KP) substrate of protein kinase C by SDS-PAGE and [32p] counting; TXA2 formation by RIA of TXB2. 1μM BAY and 10μM NF inhibited the 2nd wave of platelet aggregation and secretion induced by ADP or epinephrine and blocked aggregation and secretion induced by U46619. A Schild plot gave a slope of -1 indicating competitive inhibition of U46619 by BAY (K1[=0.7μM).BAY and NF also blocked U46619-induced phosphorylation of 40KP, rise in [Ca2+]i and TXB2 formation. The (+)-(R) enantiomer of BAY (BAY+) was responsible for BAY inhibition. BAY, BAY(+), and the R enantiomer of another DP, 202-791, all functioned as competitive antagonists of [3H]-U4661 9 binding (K1[ for BAY=2.8 μM-comparable to known receptor antagonists, 13-azaprostanoic acid and BM 13.177; K1 for BAY(+)=0.69μM). Neither BAY nor NF inhibited[3H]-yohimbine binding to α adrenergic receptors.NF, BAY, BAY(+) and BAY(-) in nM concentrations slightly stimulated platelet aggregation,secretion and biochemical events induced by U46619 similar to their effects on muscle. Therefore, DP's do not inhibit platelet activation by blocking voltage-dependent Ca2+ channels. The mechanism of DP inhibition of TXA2-induced platelet activation is stereoselective, competitive binding to the TXA2/PGH2 receptor. DP's may exert similar effects on TXA2-induced vascular smooth muscle contraction.
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Champaigne, Kevin D., Sarette N. Jenderny, and Jiro Nagatomi. "Electrophysiological Investigation of Hydrostatic Pressure Mechanotransduction by Urothelial Cell Lines." In ASME 2011 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2011. http://dx.doi.org/10.1115/sbc2011-53518.
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The urothelium is the epithelial lining of the ureters, urinary bladder, and urethra. Recent discoveries have suggested that in addition to providing a barrier function to urine, the urothelium actively participates in sensory functions related to thermal, chemical, and mechanical stimuli, and releases chemical signals in response[1]. In addition to a sensitivity to cell membrane stretch caused by wall tension upon bladder filling, in vitro studies by our group have shown that urothelial cells may be sensitive to hydrostatic pressure directly without requiring membrane stretching [2]. Specifically, primary cultures of rat bladder urothelial cells exposed to 10 cmH2O pressure on rigid substrates released significantly greater amounts of ATP compared to the baseline control without exposure to pressure. Moreover, this ATP response by rat urothelial cells to pressure was inhibited by pre-treatment of cells with ruthenium red, a non-specific antagonist of transient receptor potential (TRP) channels, suggesting a potential involvement of these channels in pressure mechanotransduction. Further understanding of the mechanisms, however, is needed to improve treatment of bladder dysfunction such as overactive bladder.
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Jefferson, J. R., J. T. Harmon, and G. A. Jamieson. "ADP-BINDING SITES IN PLATELETS: CHARACTERIZATION BY PHOTOAFFINITY LABELING AND BINDING STUDIES WITH FIXED PLATELETS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644463.
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Attempts to photoaffinity label platelet ADP receptors with 2-azidoADP have not been successful possibly due to the absence of a spacer arm between the nucleotide and the photolabile group. We have synthesized a probe having a long spacer arm by coupling 2-(3-aminopropylthio)-ADP to succinimidyl 4-3H-azidobenzoate. Labeling competable by ADP could not demonstrated with intact platelets. With isolated platelet membranes, three bands (Mr 140,000, 110,000 and 46,000) were labeled that were not competed by ADP while three other bands (Mr 188,000, 92,000 and 51,000) were competable by 100 uM ADP.Another problem in characterizing ADP receptors has been complications due to ADP metabolism and secretion from the dense granules. To avoid this problem we have measured the binding of ADP and analogues to formalin-fixed platelets. ADP bound to two sites (Kl, 0.35 ± 0.04 uM; R1, 160,000 ± 20,000 sites/platelet; K2 7.9 ± 2.0 uM; R2, 400,000 ± 40,000 sites/platelet) with low non-specific binding: these values are in agreement with ADP concentrations required for activation. Affinity at the high affinity site was in the sequence ADP(0.35 uM)=ATP(0.4 uM)›2-MeS.ADP(6.8 uM)› GDP(49 uM) › AMP(360 uM); adenosine did not compete. Binding at the high affinity site was blocked by pMBS (EC50 250 uM) and 5-fluoro-sulfonylbenzoyladenosine (EC50 1 mM). This is the first report of photoaffinity labeling of putative ADP receptors. Our experiments with fixed platelets suggest that they may be useful in testing agonists, antagonists and inhibitors in the absence of complications due to secretion and metabolism.
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Nagata, H., S. Nomura, K. Oda, T. Kokawa, and K. Yasunaga. "ANALYSIS OF THE FUNCTIONAL ROLE OF PLATELET MEMBRANE GLYCOPROTEINS WITH MONOCLONAL ANTIBODIES." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643509.
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Eight monoclonal antibodies were obtained which recognized platelet surface antigens of these, 5 (NNKYl-32, NNKY2-5, NNKY2-6, NNKY2-11, NNKY2-18 ) recognized GP IIb-IIIa complex, 2 (NNKY5-4, NNKY5-5 ) recognized GP lb and 1 (NNKYl-19) recognized CD 9 antigen. They were used to research the platelet membrane antigens.Monoclonal antibodies that recognize CD 9 antigen, which exists on the surface of platelets, acute lymphoblastic leukemia cells, eosinophils and other tissue, are known to act as an aggregating agent to platelets and NNKYl-19 was fond to induce platelet aggregation accompanied by ATP release. NNKY5-4 had no effect on platelet functions. NNKY5-5 inhibited aggregation induced by ristocetin but had no effect on aggregation induced by ADP, collagen, thrombin, and NNKYl-19. NNKYl-32, 2-5, 2-6, 2-11, and 2-18 inhibited aggregation induced by ADP, collagen, thrombin, and NNKYl-19, although slight release of ATP was recognized when NNKYl-19-induced aggregation was completely inhibited by NNKYl-32. Mutual inhibition of binding to platelet membranes between the 3 groups of monoclonal antibodies was not recognizedNNKYl-19-induced aggregation was associated with a lag time that was plo-longed in inverse proportion to antibody concentration. Aspirin had almost no effect on NNKYl-19-induced aggregation. A TXA2 receptor antagonist, a calci-um-channel blocking drug and EDTA inhibited NNKYl-19-induced aggregation. These results indicate that GP I b, GP IIb-IIIa complex and the cyclooxygenase pathway are not involved in NNKYl-19-induced platelet activation, that the target of NNKYl-19 on the platelet membrane is same as that of TXA2, and that the mechanism of activation by NNKYl-19 is related to calcium flux.
Reports on the topic "AT2 receptor antagonist"
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Idakwo, Gabriel, Sundar Thangapandian, Joseph Luttrell, Zhaoxian Zhou, Chaoyang Zhang, and Ping Gong. Deep learning-based structure-activity relationship modeling for multi-category toxicity classification : a case study of 10K Tox21 chemicals with high-throughput cell-based androgen receptor bioassay data. Engineer Research and Development Center (U.S.), July 2021. http://dx.doi.org/10.21079/11681/41302.
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Deep learning (DL) has attracted the attention of computational toxicologists as it offers a potentially greater power for in silico predictive toxicology than existing shallow learning algorithms. However, contradicting reports have been documented. To further explore the advantages of DL over shallow learning, we conducted this case study using two cell-based androgen receptor (AR) activity datasets with 10K chemicals generated from the Tox21 program. A nested double-loop cross-validation approach was adopted along with a stratified sampling strategy for partitioning chemicals of multiple AR activity classes (i.e., agonist, antagonist, inactive, and inconclusive) at the same distribution rates amongst the training, validation and test subsets. Deep neural networks (DNN) and random forest (RF), representing deep and shallow learning algorithms, respectively, were chosen to carry out structure-activity relationship-based chemical toxicity prediction. Results suggest that DNN significantly outperformed RF (p < 0.001, ANOVA) by 22–27% for four metrics (precision, recall, F-measure, and AUPRC) and by 11% for another (AUROC). Further in-depth analyses of chemical scaffolding shed insights on structural alerts for AR agonists/antagonists and inactive/inconclusive compounds, which may aid in future drug discovery and improvement of toxicity prediction modeling.
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Ivanova, Natasha, Jana Tchekalarova, Dimitrinka Atanasova, Daniela Pechlivanova, and Nikolai Lazarov. Strain-dependent Effects of AT1 Receptor Antagonist Losartan on Spatial Memory Performance of Wistar and Spontaneously Hypertensive Rats in Kainate Model of Temporal Epilepsy. "Prof. Marin Drinov" Publishing House of Bulgarian Academy of Sciences, June 2018. http://dx.doi.org/10.7546/crabs.2018.06.15.
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Halker Singh, Rashmi B., Juliana H. VanderPluym, Allison S. Morrow, Meritxell Urtecho, Tarek Nayfeh, Victor D. Torres Roldan, Magdoleen H. Farah, et al. Acute Treatments for Episodic Migraine. Agency for Healthcare Research and Quality (AHRQ), December 2020. http://dx.doi.org/10.23970/ahrqepccer239.
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Objectives. To evaluate the effectiveness and comparative effectiveness of pharmacologic and nonpharmacologic therapies for the acute treatment of episodic migraine in adults. Data sources. MEDLINE®, Embase®, Cochrane Central Registrar of Controlled Trials, Cochrane Database of Systematic Reviews, PsycINFO®, Scopus, and various grey literature sources from database inception to July 24, 2020. Comparative effectiveness evidence about triptans and nonsteroidal anti-inflammatory drugs (NSAIDs) was extracted from existing systematic reviews. Review methods. We included randomized controlled trials (RCTs) and comparative observational studies that enrolled adults who received an intervention to acutely treat episodic migraine. Pairs of independent reviewers selected and appraised studies. Results. Data on triptans were derived from 186 RCTs summarized in nine systematic reviews (101,276 patients; most studied was sumatriptan, followed by zolmitriptan, eletriptan, naratriptan, almotriptan, rizatriptan, and frovatriptan). Compared with placebo, triptans resolved pain at 2 hours and 1 day, and increased the risk of mild and transient adverse events (high strength of the body of evidence [SOE]). Data on NSAIDs were derived from five systematic reviews (13,214 patients; most studied was ibuprofen, followed by diclofenac and ketorolac). Compared with placebo, NSAIDs probably resolved pain at 2 hours and 1 day, and increased the risk of mild and transient adverse events (moderate SOE). For other interventions, we included 135 RCTs and 6 comparative observational studies (37,653 patients). Compared with placebo, antiemetics (low SOE), dihydroergotamine (moderate to high SOE), ergotamine plus caffeine (moderate SOE), and acetaminophen (moderate SOE) reduced acute pain. Opioids were evaluated in 15 studies (2,208 patients).Butorphanol, meperidine, morphine, hydromorphone, and tramadol in combination with acetaminophen may reduce pain at 2 hours and 1 day, compared with placebo (low SOE). Some opioids may be less effective than some antiemetics or dexamethasone (low SOE). No studies evaluated instruments for predicting risk of opioid misuse, opioid use disorder, or overdose, or evaluated risk mitigation strategies to be used when prescribing opioids for the acute treatment of episodic migraine. Calcitonin gene-related peptide (CGRP) receptor antagonists improved headache relief at 2 hours and increased the likelihood of being headache-free at 2 hours, at 1 day, and at 1 week (low to high SOE). Lasmiditan (the first approved 5-HT1F receptor agonist) restored function at 2 hours and resolved pain at 2 hours, 1 day, and 1 week (moderate to high SOE). Sparse and low SOE suggested possible effectiveness of dexamethasone, dipyrone, magnesium sulfate, and octreotide. Compared with placebo, several nonpharmacologic treatments may improve various measures of pain, including remote electrical neuromodulation (moderate SOE), magnetic stimulation (low SOE), acupuncture (low SOE), chamomile oil (low SOE), external trigeminal nerve stimulation (low SOE), and eye movement desensitization re-processing (low SOE). However, these interventions, including the noninvasive neuromodulation devices, have been evaluated only by single or very few trials. Conclusions. A number of acute treatments for episodic migraine exist with varying degrees of evidence for effectiveness and harms. Use of triptans, NSAIDs, antiemetics, dihydroergotamine, CGRP antagonists, and lasmiditan is associated with improved pain and function. The evidence base for many other interventions for acute treatment, including opioids, remains limited.