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P2Y 12

Patrizia Ballerini, Melania Dovizio, Annalisa Bruno, Stefania Tacconelli, Paola Patrignani
Platelets, beyond their role in hemostasis and thrombosis, may sustain tumorigenesis and metastasis. These effects may occur via direct interaction of platelets with cancer and stromal cells and by the release of several platelet products. Platelets and tumor cells release several bioactive molecules among which a great amount of adenosine triphosphate (ATP) and adenosine diphosphate (ADP). ADP is also formed extracellularly from ATP breakdown by the ecto-nucleoside-triphosphate-diphosphohydrolases. Under ATP and ADP stimulation the purinergic P2Y1 receptor (R) initiates platelet activation followed by the ADP-P2Y12 R-mediated amplification...
2018: Frontiers in Pharmacology
Prokopia T Tatsidou, Vasileios G Chantzichristos, Maria E Tsoumani, Sofia Sidiropoulou, Ioannis V Ntalas, John A Goudevenos, Konstantinos Stellos, Alexandros D Tselepis
CD34 + cells expressing KDR (CD34 + /KDR + ) represent a small proportion of circulating progenitor cells that have the capacity to interact with platelets and to differentiate into mature endothelial cells, thus contributing to vascular homeostasis and regeneration as well as to re-endothelialization. We investigated the levels of CD34 + and CD34 + /KDR + progenitor cells as well as their interaction with platelets in acute coronary syndrome (ACS) patients before the initiation (baseline) of their treatment with a P2Y 12 receptor antagonist, and at 5-days post-treatment (follow-up)...
February 16, 2018: Platelets
Matthew J Czarny, Julie M Miller, Daniel Q Naiman, Chao-Wei Hwang, Rani K Hasan, Cynthia C Lemmon, Thomas Aversano
BACKGROUND: The CPORT-E trial showed the noninferiority of nonprimary percutaneous coronary intervention (PCI) at hospitals without cardiac surgery on-site (SoS) compared with hospitals with SoS for 6-week mortality and 9-month major adverse cardiac events (MACE). However, target vessel revascularization (TVR) was increased at non-SoS hospitals. Therefore, we aimed to determine the consistency of the CPORT-E trial findings across the spectrum of enrolled patients. METHODS: Post hoc subgroup analyses of 6-week mortality and 9-month MACE, defined as the composite of death, Q-wave myocardial infarction, or TVR, were performed...
March 2018: American Heart Journal
David Kopin, W Schuyler Jones, Matthew W Sherwood, Daniel M Wojdyla, Lars Wallentin, Basil S Lewis, Freek W A Verheugt, Dragos Vinereanu, M Cecilia Bahit, Sigrun Halvorsen, Kurt Huber, Alexander Parkhomenko, Christopher B Granger, Renato D Lopes, John H Alexander
BACKGROUND: We assessed antiplatelet therapy use and outcomes in patients undergoing percutaneous coronary intervention (PCI) during the ARISTOTLE trial. METHODS: Patients were categorized based on the occurrence of PCI during follow-up (median 1.8 years); PCI details and outcomes post-PCI are reported. Of the 18,201 trial participants, 316 (1.7%) underwent PCI (152 in apixaban group, 164 in warfarin group). RESULTS: At the time of PCI, 84% (267) were on study drug (either apixaban or warfarin)...
March 2018: American Heart Journal
Mozibur Rahman, Rui Sun, Subhendu Mukherjee, Bernd Nilius, Luke J Janssen
We previously described several ionic conductances in human pulmonary fibroblasts (HPFs), including one activated by two structurally distinct TRPV4-channel agonists: 4α-phorbol-12,13-didecanoate (4αPDD) and GSK1016790A. However, the TRPV4-activated current exhibited peculiar properties: it developed slowly over many minutes, exhibited reversal potentials that could vary by tens of millivolts even within a given cell, and was not easily reversed by subsequent addition of two distinct TRPV4-selective blockers (RN-1734 or HC-067047)...
February 2, 2018: American Journal of Respiratory Cell and Molecular Biology
Yotesawee Srisomboon, Nathan A Zaidman, Peter J Maniak, Chatsri Deachapunya, Scott M O'Grady
The objective of this study was to determine the molecular identity of ion channels involved in K+ secretion by the mammary epithelium and to examine their regulation by purinoceptor agonists. Apical membrane voltage clamp experiments were performed on human mammary epithelial cells where the basolateral membrane was exposed to the pore-forming antibiotic amphotericin B dissolved in a solution with intracellular-like ionic composition. Addition of the Na+ channel inhibitor benzamil reduced the basal current, consistent with inhibition of Na+ uptake across the apical membrane whereas the KCa 3...
January 24, 2018: American Journal of Physiology. Cell Physiology
Brian R Branchford, Timothy J Stalker, Luke Law, Gilbert Acevedo, Susan Sather, Christine Brzezinski, Katina M Wilson, Katherine Minson, Alisa B Lee-Sherick, Pavel Davizon-Castillo, Christopher Ng, Weihe Zhang, Keith B Neeves, Steven R Lentz, Xiaodong Wang, Stephen V Frye, H Shelton Earp, Deborah DeRyckere, Lawrence F Brass, Douglas K Graham, Jorge A Di Paola
BACKGROUND: Gas6 signals through the TAM (TYRO-3, AXL, MERTK) receptor family mediating platelet activation and thrombus formation via activation of the aggregate-stabilizing αIIb β3 integrin. OBJECTIVE: Here we describe anti-thrombotic effects mediated by UNC2025, a small molecule MERTK tyrosine kinase inhibitor. METHODS: MERTK phosphorylation and downstream signaling were assessed by immunoblot. Light transmission aggregometry, flow cytometry, and microfluidic analysis were used to evaluate the impact of MERTK inhibition on platelet activation and stability of aggregate formation in vitro...
October 17, 2017: Journal of Thrombosis and Haemostasis: JTH
Kuan Ken Lee, Nicky Welton, Anoop S Shah, Philip D Adamson, Sofia Dias, Atul Anand, David E Newby, Nicholas L Mills, David A McAllister
OBJECTIVE: To estimate the absolute treatment effects of newer P2Y12 inhibitors (ticagrelor and prasugrel) compared with clopidogrel in men and women with acute coronary syndrome (ACS). METHODS: We searched Ovid MEDLINE, Embase and the Cochrane Central Register of Controlled Trials for randomised controlled trials of oral P2Y12 inhibitors for acute stroke or ACS. Age-specific and sex-specific mortality was obtained for all patients admitted to hospital with myocardial infarction in Scotland from 2006 to 2010 (prior to introduction of prasugrel or ticagrelor)...
October 5, 2017: Heart: Official Journal of the British Cardiac Society
Phillip A Choi, Phillip V Parry, Joshua S Bauer, Benjamin E Zusman, David M Panczykowski, Ava M Puccio, David O Okonkwo
BACKGROUND: At present, guidelines are lacking on platelet transfusion in patients with a traumatic intracranial bleed and history of antiplatelet therapy. The aspirin and P2Y 12 response unit (ARU and PRU, respectively) assays detect the effect of aspirin and P2Y 12 inhibitors in the cardiac population. OBJECTIVE: To describe the reversal of platelet inhibition after platelet transfusion using the ARU and PRU assays in patients with traumatic brain injury. METHODS: Between 2010 and 2015, we conducted a prospective comparative cohort study of patients presenting with a positive head computed tomography and a history of antiplatelet therapy...
January 1, 2017: Neurosurgery
J Todd Belcik, Brian P Davidson, Aris Xie, Melinda D Wu, Mrinal Yadava, Yue Qi, Sherry Liang, Chae Ryung Chon, Azzdine Y Ammi, Joshua Field, Leanne Harmann, William M Chilian, Joel Linden, Jonathan R Lindner
BACKGROUND: Augmentation of tissue blood flow by therapeutic ultrasound is thought to rely on convective shear. Microbubble contrast agents that undergo ultrasound-mediated cavitation markedly amplify these effects. We hypothesized that purinergic signaling is responsible for shear-dependent increases in muscle perfusion during therapeutic cavitation. METHODS: Unilateral exposure of the proximal hindlimb of mice (with or without ischemia produced by iliac ligation) to therapeutic ultrasound (1...
March 28, 2017: Circulation
Marta Kuczeriszka, Leszek Dobrowolski, Agnieszka Walkowska, Janusz Sadowski
BACKGROUND: Purine P2X and P2Y receptors (P2-R) are involved in control of renal circulation, especially in the medulla, wherein they appear to interact with angiotensin II (Ang II). Our experimental approach enabled examination of interaction with Ang II per se, in the absence of blood pressure elevation. In this whole-kidney functional study we focused on the influence of P2X1-R on perfusion of the renal medulla. METHODS: Acute experiments were conducted with normal rats, untreated or subjected to two weeks' infusion of Ang II (osmotic minipumps)...
December 2016: Pharmacological Reports: PR
Wen-Mei Zhang, Yan Liu, Tao-Tao Li, Chun-Mei Piao, Ou Liu, Jun-Ling Liu, Yong-Fen Qi, Li-Xin Jia, Jie Du
Thoracic aortic aneurysm/dissection (TAAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. However, the mechanism whereby signaling leads to SMC loss is unclear. We used senescence-associated (SA)-β-gal staining and analysis of expression of senescence-related proteins (p53, p21, p19) to show that excessive mechanical stretch (20% elongation, 3600cycles/h, 48h) induced SMC senescence. SMC senescence was also detected in TAAD specimens from both mice and humans...
October 2016: Journal of Molecular and Cellular Cardiology
Chang-Chieh Wu, Fu-Ming Tsai, Mao-Liang Chen, Semon Wu, Ming-Cheng Lee, Tzung-Chieh Tsai, Lu-Kai Wang, Chun-Hua Wang
Antipsychotic drugs (APDs) used to treat clinical psychotic syndromes cause a variety of blood dyscrasias. APDs suppress the aggregation of platelets; however, the underlying mechanism remains unknown. We first analyzed platelet aggregation and clot formation in platelets treated with APDs, risperidone, clozapine, or haloperidol, using an aggregometer and rotational thromboelastometry (ROTEM). Our data indicated that platelet aggregation was inhibited, that clot formation time was increased, and that clot firmness was decreased in platelets pretreated with APDs...
2016: BioMed Research International
Kasumi Moriguchi-Mori, Hironori Higashio, Kanako Isobe, Miho Kumagai, Kana Sasaki, Yoh-ichi Satoh, Akiyoshi Kuji, Tomoyuki Saino
Adenosine 5'-triphosphate (ATP) can act as an extracellular signal that regulates various cellular functions. The present study aimed to determine which purinoceptors play a role in ATP-induced changes in intracellular Ca(2+) ([Ca(2+)]i) and amylase secretion in mouse parotid glands. ATP induced a steep increase in [Ca(2+)]i in acinar cells. The removal of extracellular Ca(2+) or the use of Ca(2+) channel blockers slightly inhibited this increase. Inhibition of PLCγ by U73122 and of IP3 by xestospongin C did not completely block this increase...
2016: Biomedical Research
T Horváth, G Polony, Á Fekete, M Aller, G Halmos, B Lendvai, A Heinrich, B Sperlágh, E S Vizi, T Zelles
Hearing and its protection is regulated by ATP-evoked Ca(2+) signaling in the supporting cells of the organ of Corti, however, the unique anatomy of the cochlea hampers observing these mechanisms. For the first time, we have performed functional ratiometric Ca(2+) imaging (fura-2) in three different supporting cell types in the hemicochlea preparation of hearing mice to measure purinergic receptor-mediated Ca(2+) signaling in pillar, Deiters' and Hensen's cells. Their resting [Ca(2+)]i was determined and compared in the same type of preparation...
February 2016: Neurochemical Research
U Banderali, E Brochiero, S Lindenthal, C Raschi, S Bogliolo, J Ehrenfeld
1 The effect of extracellular nucleotides applied on the apical side of polarised A6 cells grown on permeant filters was investigated by measuring the changes in (i) the (36) Cl efflux through the apical membranes, (ii) the intracellular chloride concentrations (aCli , measured with N-(6-methoxyquinolyl) acetoethyl ester, MQAE), (iii) ICl , the short-circuit current in the absence of Na(+) transport and (iv) the characteristics of the apical chloride channels using a patch-clamp approach. 2 ATP or UTP (0.1-500 μm) transiently stimulated ICl ...
September 1999: Journal of Physiology
Peter Clemmensen, Matthew T Roe, Judith S Hochman, Derek D Cyr, Megan L Neely, Darren K McGuire, Jan H Cornel, Kurt Huber, Dmitry Zamoryakhin, Harvey D White, Paul W Armstrong, Keith A A Fox, Dorairaj Prabhakaran, Erik Magnus Ohman
BACKGROUND: Women with acute coronary syndromes (ACS) are less likely to undergo invasive revascularization than men, but sex-specific differences in long-term outcomes and platelet reactivity among medically managed ACS patients remain uncertain. We examined sex-specific differences in long-term ischemic and bleeding outcomes and platelet reactivity for medically managed ACS patients randomized to prasugrel versus clopidogrel plus aspirin. METHODS: Data from 9,326 patients enrolled in TRILOGY ACS were analyzed to determine differences in long-term ischemic and bleeding outcomes between women (n = 3,650 [39%]) and men (n = 5,676 [61%]) randomized to prasugrel 10 mg/d (5 mg/d for patients ≥75 years and/or <60 kg) versus clopidogrel 75 mg/d...
October 2015: American Heart Journal
Gilles Montalescot, David Brieger, Anthony J Dalby, Seung-Jung Park, Roxana Mehran
The duration of dual antiplatelet therapy (DAPT) after coronary stenting has been evaluated in randomized studies with apparently conflicting results. Although longer exposure associates with more bleeding complications, late stent thrombosis (ST) and myocardial infarction are reduced. In addition, as new drug-eluting stents carry a lower risk of ST compared with the first-generation drug-eluting stents and possibly even bare-metal stents, a shift toward better protection from ST may have an effect on the duration and intensity of DAPT...
August 18, 2015: Journal of the American College of Cardiology
Connie N Hess, Stefan James, Renato D Lopes, Daniel M Wojdyla, Megan L Neely, Danny Liaw, Emil Hagstrom, Deepak L Bhatt, Steen Husted, Shaun G Goodman, Basil S Lewis, Freek W A Verheugt, Raffaele De Caterina, Hisao Ogawa, Lars Wallentin, John H Alexander
BACKGROUND: Bleeding limits anticoagulant treatment in patients with acute coronary syndromes (ACS). OBJECTIVES: We investigated whether background concomitant antiplatelet therapy influences the effects of apixaban after ACS. METHODS: This study examined high-risk ACS patients who were treated with aspirin or aspirin plus clopidogrel and who were randomized to apixaban 5 mg twice daily or placebo. In a post-hoc analysis, we assessed whether the effect of apixaban on efficacy and safety outcomes varied by the concomitant antiplatelet regimen by using simple Cox modeling and marginal structural models with propensity scores and antiplatelet therapy as a time-dependent covariate...
August 18, 2015: Journal of the American College of Cardiology
Sophia L B Oliveira, Cleber A Trujillo, Priscilla D Negraes, Henning Ulrich
Purinergic receptors belong to the most ancient neurotransmitter system. While their relevance in neurotransmission is well characterized, it has become clear that they have many other cellular functions. During development, they participate in regulation of proliferation and differentiation of stem cells. Here, we used rat embryonic telencephalon neurosphere cultures to detect purinergic P2 receptor subtype expression and possible synergistic actions of these receptors with NGF. Neurospheres proliferate in the presence of EGF and FGF-2; however, upon depletion of these growth factors, they migrate and differentiate into neurons and glial phenotypes...
September 2015: Neurochemical Research
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