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    ABSTRACT: Adenosine is a ubiquitous extracellular signaling molecule with essential functions in human physiology. Due to the widespread expression of adenosine receptors, it has far-reaching effects across many different organ systems. With a prominent role in the cardiovascular system, it has been extensively studied for both its therapeutic and diagnostic abilities. One of the key areas of use is in the coronary circulation whereby adenosine produces a hyperemic response. An important target of adenosine is the coronary microcirculation whereby adenosine acts as a prominent vasodilator with many of the beneficial effects of adenosine reflected in its capacity to affect the microvessels. Adenosine also has an important role in the pre-conditioned state and also in the attenuation of ischemia-reperfusion injury. This review examines the physiology, pharmacology, and therapeutic applications of adenosine in the human cardiovascular system and provides a brief overview of important aspects of the adenosine-cardiac interaction. It also examines the role of adenosine in the coronary hyperemic response and discusses the use of adenosine for this purpose. After recent concerns about the use of adenosine, a discussion regarding safety of this drug is provided. A brief review of novel agents used to initiate coronary hyperemia is also provided.
    JACC Cardiovascular Interventions 05/2014;
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    ABSTRACT: Background and PurposeClinical deficits from stroke are diverse, prompting measurement in trials by a range of outcome scales. Statistical and clinical advantage can be gained by combining scales into a global outcome provided combinations are chosen with limited correlations. We aimed to clarify the interdependence of outcome scales by systematic review of published data and by novel analysis of data from completed acute trials.Summary of ReviewWe systematically searched ScienceDirect and PubMed to summarize published data on correlations between stroke outcome scales. We generated new data on correlations among salient scales at 90 days poststroke in patients from the Virtual International Stroke Trials Archive (VISTA). We calculated Pearson and Spearman-Rank correlation coefficients for continuous and ordinal measures, respectively. We also assessed partial correlations, adjusted for baseline National Institute of Health Stroke Scale (NIHSS), and age. Published estimates of interdependence were limited to small single-trial cohorts and gave divergent results. From the more extensive VISTA dataset, we found that the modified Rankin Scale at 90 days poststroke explained 80.8% of the National Institute of Health Stroke Scale at 90 days poststroke and 86·5% of the European Stroke Scale. National Institute of Health Stroke Scale explained 75.9% of the Barthel Index and 81·2% of the Scandinavian Stroke Scale.After adjustment, modified Rankin Scale explained 56.6% of National Institute of Health Stroke Scale, 75.2% of Barthel Index. National Institute of Health Stroke Scale explained 60.2% of Barthel Index.Conclusion Correlations and partial correlations among stroke outcome scales in trial datasets are higher than previously reported. The new estimates are more reliable for trial planning due to the sample size and diversity.
    International Journal of Stroke 04/2014; 9(3).
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    ABSTRACT: The calgranulin-like protein MTS1/S100A4 and the receptor for advanced glycation end-products (RAGE) have recently been implicated in mediating pulmonary arterial smooth muscle cell proliferation and vascular remodelling in experimental pulmonary arterial hypertension (PH). Here, the effects of RAGE antagonism upon 2 weeks of hypobaric hypoxia (10% O2)-induced PH in mice were assessed. Treatment with sRAGE was protective against hypobaric hypoxia-induced increases in right ventricular pressure but distal pulmonary vascular remodelling was unaffected. Intralobar pulmonary arteries from hypobaric hypoxic mice treated with sRAGE showed protection against a hypoxia-induced reduction in compliance. However, a combination of sRAGE and hypoxia also dramatically increased the force of contractions to KCl and 5-HT observed in these vessels. The acute addition of sRAGE to the organ bath produced a small, sustained contraction in intralobar pulmonary vessels and produced a synergistic enhancement of the maximal force of contraction in subsequent concentration-response curves to 5-HT. sRAGE had no effect on 5-HT-induced proliferation of Chinese hamster lung fibroblasts (CCL39), used since they have a similar pharmacological profile to mouse pulmonary fibroblasts but, surprisingly, produced a marked increase in hypoxia-induced proliferation. These data implicate RAGE as a modulator of both vasoreactivity and of proliferative processes in the response of the pulmonary circulation to chronic-hypoxia.
    Pulmonary Pharmacology &amp Therapeutics 01/2014;
  • The Canadian journal of cardiology 01/2014;
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    ABSTRACT: Many G-protein-coupled receptors trigger the synthesis of cAMP in order to transduce signals from the membrane into the cell cytoplasm. As stimulation of each receptor type results in a specific physiological outcome, compartmentalization of proteins that make, break, and are activated by cAMP underpin receptor-specific responses. Until 2002, it was thought that static compartmentalization of phosphodiesterase 4 (PDE4), conferred by N-terminal targeting sequences, was one way to shape intricate cAMP gradients that formed after receptor activation. Discovery of the PDE4-β-arrestin complex represented a major breakthrough in cAMP signaling, as it spurred the initial realization that PDE4s could be transported to sites of high cAMP to orchestrate destruction of the second messenger at the same time as the receptor's signal to the G-protein is silenced. This chapter charts the scientific process that led to the discovery and characterization of the PDE4-β-arrestin interaction and discusses the known functions of this signaling complex.
    Handbook of experimental pharmacology 01/2014; 219:293-307.
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    ABSTRACT: Systems biology has gained a tremendous amount of interest in the last few years. This is partly due to the realization that traditional approaches focusing only on a few molecules at a time cannot describe the impact of aberrant or modulated molecular environments across a whole system. Furthermore, a hypothesis-driven study aims to prove or disprove its postulations, whereas a hypothesis-free systems approach can yield an unbiased and novel testable hypothesis as an end-result. This latter approach foregoes assumptions which predict how a biological system should react to an altered microenvironment within a cellular context, across a tissue or impacting on distant organs. Additionally, re-use of existing data by systematic data mining and re-stratification, one of the cornerstones of integrative systems biology, is also gaining attention. While tremendous efforts using a systems methodology have already yielded excellent results, it is apparent that a lack of suitable analytic tools and purpose-built databases poses a major bottleneck in applying a systematic workflow. This review addresses the current approaches used in systems analysis and obstacles often encountered in large-scale data analysis and integration which tend to go unnoticed, but have a direct impact on the final outcome of a systems approach. Its wide applicability, ranging from basic research, disease descriptors, pharmacological studies, to personalized medicine, makes this emerging approach well suited to address biological and medical questions where conventional methods are not ideal.
    Computational and Structural Biotechnology Journal. 01/2014;
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    ABSTRACT: The ability of a cell to transform an extracellular stimulus into a downstream event that directs specific physiological outcomes, requires the orchestrated, spatial and temporal response of many signalling proteins. The notion of compartmentalised signalling pathways was popularised in the 1980s by Brunton and colleagues, with their discovery that spatially segregated cAMP directs a variety of signalling responses in cardiomyocytes. It is now understood that compartmentalisation is a common mechanism used by all cells to ensure the interaction of signalling ‘second messenger’ molecules with localised ‘pools’ of appropriate effector proteins. In this way, the cell can elicit differential cellular responses by using a single, freely diffusible, molecular species. Recently, the compartmentalisation schemes employed by signalling systems involving cyclic nucleotides, calcium and nitric oxide have been elucidated and as a result, the varied range of functional consequences underpinned by such strategies can be better appreciated.
    Current Opinion in Genetics & Development. 01/2014; 27:20–25.
  • Cytokine 01/2014;
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    ABSTRACT: The regulation of small GTPases by arrestins is a relatively new way by which arrestin can exert influence over cell signalling cascades, hence, molecular interactions and specific binding partners are still being discovered. A pathway showcasing the regulation of GTPase activity by β-arrestin was first elucidated in 2001. Since this original study, growing evidence has emerged for arrestin modulation of GTPase activity through direct interactions and also via the scaffolding of GTPase regulatory proteins. Given the importance of small GTPases in a variety of essential cellular functions, pharmacological manipulation of this pathway may represent an area with therapeutic potential, particularly with respect to cancer pathology and cardiac hypertrophy.The regulation of small GTPases by arrestins is a relatively new way by which arrestin can exert influence over cell signalling cascades, hence, molecular interactions and specific binding partners are still being discovered. A pathway showcasing the regulation of GTPase activity by β-arrestin was first elucidated in 2001. Since this original study, growing evidence has emerged for arrestin modulation of GTPase activity through direct interactions and also via the scaffolding of GTPase regulatory proteins. Given the importance of small GTPases in a variety of essential cellular functions, pharmacological manipulation of this pathway may represent an area with therapeutic potential, particularly with respect to cancer pathology and cardiac hypertrophy.
    Handbook of experimental pharmacology 01/2014; 219:375-85.
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    ABSTRACT: We investigated 3 hypotheses: (1) N-terminal pro-B-type natriuretic peptide (NT-proBNP) predicts cardiovascular disease events in patients with hypertension, (2) NT-proBNP is associated with blood pressure variability, and (3) NT-proBNP predicts benefit from antihypertensive regimens. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized a subset of 6549 patients at risk with no history of coronary heart disease to either atenolol-based or amlodipine-based blood pressure-lowering treatment. During 5.5 years of follow-up, 485 cardiovascular disease cases accrued and were matched with 1367 controls. Baseline and 6-month in-trial NT-proBNP were measured. The results show that NT-proBNP improves cardiovascular disease risk prediction beyond established predictors, continuous net reclassification improvement of 22.3% (P<0.0001). Furthermore, a 1-mm Hg increase in the SD of systolic blood pressure was associated with 2% higher baseline NT-proBNP in a multivariable regression analysis (P<0.0001). However, NT-proBNP predicted cardiovascular disease risk independently of blood pressure variation (odds ratio per SD increase in log NT-proBNP 1.24; 95% confidence interval, 1.06-1.45; P=0.007). Atenolol-based treatment led to a 69.6% increase in NT-proBNP at 6 months (P<0.0001). In contrast, amlodipine-based treatment reduced NT-proBNP by 36.5% (P<0.0001). Amlodipine recipients who achieved a 6-month NT-proBNP below the median (61 pg/mL) were at lower risk of cardiovascular disease when compared with those who did not (odds ratio, 0.58; 95% confidence interval, 0.37-0.91) after adjustment for confounders inclusive of baseline NT-proBNP and achieved blood pressure. If confirmed, these novel results suggest that NT-proBNP, as well as aiding cardiovascular disease risk assessment, may also help assess the efficacy of specific antihypertensive regimens. Further relevant studies seem warranted.
    Hypertension 12/2013;
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