Interactions Between Potassium Channels and Serotonin in Pulmonary Arterial Hypertension PDF Download
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Author: Alicia Murray
Publisher:
ISBN:
Category :
Languages : en
Pages : 204
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Book Description
Pulmonary arterial hypertension (PAH) is a progressive disease which results from increases in mean pulmonary artery pressure and pulmonary vascular resistance. If untreated it leads to right ventricular failure and death. 5-Hydroxytryptamine (5-HT) has been implicated in the disease process and is thought to promote both vasoconstriction and remodelling of the pulmonary vasculature. The activity of potassium ion (K) channels plays a major role in influencing pulmonary artery tone by regulating resting membrane potential, intracellular Ca2 concentration and contraction of vascular smooth muscle. This study aimed to investigate possible interactions between 5-HT and K+ channels in the development of PAH in the mouse. The actions of 5-HT and a range of K+ channel blockers were investigated on isolated intralobar pulmonary arteries (IPA) from wild type (WT) mice and mice over-expressing the serotonin transporter (5HTT), which spontaneously develop PAH. Both 5-HT and linopirdine, a KCNQ K+ channel inhibitor, were found to induce contraction of IPA, but were more potent in IPA from WT mice than 5-HTT+ mice. The 5-HT induced vasoconstriction was found to involve influx of Ca2+ from the extracellular space, Ca2+ release from the sacroplasmic reticulum and a rho kinase-dependent increase in the sensitivity of the contractile machinery of pulmonary artery smooth muscle cells (PASMC) to intracellular Ca2+. Ca2+ entered the cell via both voltage operated calcium channels (VOCC), activated by membrane depolarisation, and a separate Ca2+ entry pathway, the latter appearing to contribute more in 5-HTT+ mice. The effects of linopirdine were shown to be due entirely to the entry of Ca2+ through VOCC in both WT and 5-HTT+ mice IPA. The difference in vasoconstrictor potency between WT and 5HTT+ mice was not seen with any other K+ channel blocker, suggesting a selective loss of KCNQ channels and/or VOCC in PAH resulting from 5HTT over expression. KCNQ channel activity was further investigated using the KCNQ channel openers, flupirtine and retigabine. These agents were more potent in dilating IPA from WT mice compared to 5-HTT+ mice, consistent with the loss of expression or activity of KCNQ channels in 5-HTT+ mice. Despite this, orally administered flupirtine was shown to reverse two indices of established PAH in the 5HTT+ mice; right ventricular pressure and right ventricular hypertrophy. This action of flupirtine was also seen in chronic hypoxic mice, where it prevented the development of PAH. In conclusion, this study provides evidence of an interaction between KCNQ channels and the 5-HT system in the development of PAH. By showing that a KCNQ channel opener can attenuate PAH, both in the developing and established disease situation, this study proposes a new potential therapeutic target in the treatment of PAH.
Author: Alicia Murray
Publisher:
ISBN:
Category :
Languages : en
Pages : 204
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Book Description
Pulmonary arterial hypertension (PAH) is a progressive disease which results from increases in mean pulmonary artery pressure and pulmonary vascular resistance. If untreated it leads to right ventricular failure and death. 5-Hydroxytryptamine (5-HT) has been implicated in the disease process and is thought to promote both vasoconstriction and remodelling of the pulmonary vasculature. The activity of potassium ion (K) channels plays a major role in influencing pulmonary artery tone by regulating resting membrane potential, intracellular Ca2 concentration and contraction of vascular smooth muscle. This study aimed to investigate possible interactions between 5-HT and K+ channels in the development of PAH in the mouse. The actions of 5-HT and a range of K+ channel blockers were investigated on isolated intralobar pulmonary arteries (IPA) from wild type (WT) mice and mice over-expressing the serotonin transporter (5HTT), which spontaneously develop PAH. Both 5-HT and linopirdine, a KCNQ K+ channel inhibitor, were found to induce contraction of IPA, but were more potent in IPA from WT mice than 5-HTT+ mice. The 5-HT induced vasoconstriction was found to involve influx of Ca2+ from the extracellular space, Ca2+ release from the sacroplasmic reticulum and a rho kinase-dependent increase in the sensitivity of the contractile machinery of pulmonary artery smooth muscle cells (PASMC) to intracellular Ca2+. Ca2+ entered the cell via both voltage operated calcium channels (VOCC), activated by membrane depolarisation, and a separate Ca2+ entry pathway, the latter appearing to contribute more in 5-HTT+ mice. The effects of linopirdine were shown to be due entirely to the entry of Ca2+ through VOCC in both WT and 5-HTT+ mice IPA. The difference in vasoconstrictor potency between WT and 5HTT+ mice was not seen with any other K+ channel blocker, suggesting a selective loss of KCNQ channels and/or VOCC in PAH resulting from 5HTT over expression. KCNQ channel activity was further investigated using the KCNQ channel openers, flupirtine and retigabine. These agents were more potent in dilating IPA from WT mice compared to 5-HTT+ mice, consistent with the loss of expression or activity of KCNQ channels in 5-HTT+ mice. Despite this, orally administered flupirtine was shown to reverse two indices of established PAH in the 5HTT+ mice; right ventricular pressure and right ventricular hypertrophy. This action of flupirtine was also seen in chronic hypoxic mice, where it prevented the development of PAH. In conclusion, this study provides evidence of an interaction between KCNQ channels and the 5-HT system in the development of PAH. By showing that a KCNQ channel opener can attenuate PAH, both in the developing and established disease situation, this study proposes a new potential therapeutic target in the treatment of PAH.
Author: Jason X. -J. Yuan
Publisher: Springer Science & Business Media
ISBN: 1607615002
Category : Medical
Languages : en
Pages : 493
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Book Description
Membrane Receptors, Channels and Transporters in Pulmonary Circulation is a proceeding of the 2008 Grover Conference (Lost Valley Ranch and Conference Center, Sedalia, Colorado; September 3-7, 2008), which provided a forum for experts in the fields of those receptors, channels and transporters that have been identified as playing key roles in the physiology and pathophysiology of the pulmonary circulation. The book rigorously addresses: i) recent advances in our knowledge of receptors, channels and transporters and their role in regulation of pulmonary vascular function; ii) how modulation of expression and function of receptors, channels and transporters and their interrelationships contribute to the pathogenesis of pulmonary vascular disease; and iii) the therapeutic opportunities that may be revealed by enhancing our understanding of this area. The overall goal was to explore the mechanisms by which specific receptors, channels and transporters contribute to pulmonary vascular function in both health and disease, and how this knowledge may lead to novel interventions in lung dysplasia, pulmonary edema, lung injury, and pulmonary and systemic hypertension to reduce and prevent death from lung disease. Membrane Receptors, Channels and Transporters in Pulmonary Circulation is divided into six parts. Part 1 (Ion Channels in the Pulmonary Vasculature: Basics and New Findings) is designated for basic knowledge and recent findings in the research field of ion channels in pulmonary circulation. There are five chapters in Part I discussing the function, expression, distribution and regulation of various ion channels present in pulmonary vascular smooth muscle cells and how these channels are integrated to regulate intracellular Ca2+ and cell functions. Part II (TRP Channels in the Pulmonary Vasculature: Basics and New Findings) is composed of five chapters that are exclusively designed to discuss the role of a recently identified family of cation channels, transient receptor potential (TRP) channels, in the regulation of pulmonary vascular tone and arterial structure. Part III (Pathogenic Role of Ion Channels in Pulmonary Vascular Disease) includes four chapters that discuss how abnormal function and expression of various ion channels contribute to changes in cell functions and the development of pulmonary hypertension. Part IV (Receptors and Signaling Cascades in Pulmonary Arterial Hypertension) consists of five chapters devoted to the role of bone morphogenetic protein receptors, Notch receptors, serotonin receptors, Rho kinase and vascular endothelial growth factor receptors in the development of pulmonary arterial hypertension. Part V (Receptors and Transporters: Role in Cell Function and Hypoxic Pulmonary Vasoconstriction) includes four chapters designed to illustrate the potential mechanisms involved in oxygen sensing and hypoxia-induced pulmonary vasoconstriction and hypertension. Part VI (Targeting Ion Channels and Membrane Receptors in Developing Novel Therapeutic Approaches for Pulmonary Vascular Disease) consists five chapters which discuss the translational research involving on membrane receptors, channels and transporters, including their potential as novel drug targets. We hope that Membrane Receptors, Channels and Transporters in Pulmonary Circulation will allow readers to foster new concepts and new collaborations and cooperations among investigators so as to further understand the role of receptors, channels and transporters in lung pathophysiology. The ultimate goal is to identify new mechanisms of disease, as well as new therapeutic targets for pulmonary vascular diseases. An additional outcome should be enhanced understanding of the role of these entities in systemic vascular pathophysiology, since the conference will include researchers and clinicians with interests in both pulmonary and systemic circulations.
Author: Peter Lanzer
Publisher: Springer
ISBN: 9783642370779
Category : Medical
Languages : en
Pages : 5004
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Book Description
Vascular management and care has become a truly multidisciplinary enterprise as the number of specialists involved in the treatment of patients with vascular diseases has steadily increased. While in the past, treatments were delivered by individual specialists, in the twenty-first century a team approach is without doubt the most effective strategy. In order to promote professional excellence in this dynamic and rapidly evolving field, a shared knowledge base and interdisciplinary standards need to be established. Pan Vascular Medicine, 2nd edition has been designed to offer such an interdisciplinary platform, providing vascular specialists with state-of-the art descriptive and procedural knowledge. Basic science, diagnostics, and therapy are all comprehensively covered. In a series of succinct, clearly written chapters, renowned specialists introduce and comment on the current international guidelines and present up-to-date reviews of all aspects of vascular care.
Author: Michel Félétou
Publisher: Morgan & Claypool Publishers
ISBN: 1615041230
Category : Science
Languages : en
Pages : 309
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Book Description
The endothelium, a monolayer of endothelial cells, constitutes the inner cellular lining of the blood vessels (arteries, veins and capillaries) and the lymphatic system, and therefore is in direct contact with the blood/lymph and the circulating cells. The endothelium is a major player in the control of blood fluidity, platelet aggregation and vascular tone, a major actor in the regulation of immunology, inflammation and angiogenesis, and an important metabolizing and an endocrine organ. Endothelial cells controls vascular tone, and thereby blood flow, by synthesizing and releasing relaxing and contracting factors such as nitric oxide, metabolites of arachidonic acid via the cyclooxygenases, lipoxygenases and cytochrome P450 pathways, various peptides (endothelin, urotensin, CNP, adrenomedullin, etc.), adenosine, purines, reactive oxygen species and so on. Additionally, endothelial ectoenzymes are required steps in the generation of vasoactive hormones such as angiotensin II. An endothelial dysfunction linked to an imbalance in the synthesis and/or the release of these various endothelial factors may explain the initiation of cardiovascular pathologies (from hypertension to atherosclerosis) or their development and perpetuation. Table of Contents: Introduction / Multiple Functions of the Endothelial Cells / Calcium Signaling in Vascular Cells and Cell-to-Cell Communications / Endothelium-Dependent Regulation of Vascular Tone / Conclusion / References
Author: Toshio Nakanishi
Publisher: Springer Nature
ISBN: 9811511853
Category : Medical
Languages : en
Pages : 374
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Book Description
This open access book focuses on the molecular mechanism of congenital heart disease and pulmonary hypertension, offering new insights into the development of pulmonary circulation and the ductus arteriosus. It describes in detail the molecular mechanisms involved in the development and morphogenesis of the heart, lungs and ductus arteriosus, covering a range of topics such as gene functions, growth factors, transcription factors and cellular interactions, as well as stem cell engineering technologies. The book also presents recent advances in our understanding of the molecular mechanism of lung development, pulmonary hypertension and molecular regulation of the ductus arteriosus. As such, it is an ideal resource for physicians, scientists and investigators interested in the latest findings on the origins of congenital heart disease and potential future therapies involving pulmonary circulation/hypertension and the ductus arteriosus.
Author: Robert P. Baughman
Publisher: Springer Science & Business Media
ISBN: 1603270744
Category : Medical
Languages : en
Pages : 255
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Book Description
Interstitial lung disease (ILD) is a broad category of lung diseases that includes more than 150 disorders characterized by scarring or fibrosis of the lungs. In Pulmonary Arterial Hypertension and Interstitial Lung Disease: A Clinical Guide, renowned experts provide a state-of-the-art overview of the problems seen by physicians in the clinical management of ILDs. Divided into two sections, the first part provides and update on general issues and introduces both interstitial lung disease and associated pulmonary hypertension. A detailed analysis of the pathology of the various interstitial lung diseases is also provided. The second part addresses specific categories of disease. Bronchiolitis, hypersensitivity pneumonitis, and other conditions are covered, and the use of inspiratory and expiratory high resolution CT scan is discussed as well. This important new text is an invaluable resource for the practicing physician who must be aware of the broad and troubling manifestations of interstitial lung disease.
Author: Marc Humbert
Publisher: Springer Science & Business Media
ISBN: 3642386644
Category : Medical
Languages : en
Pages : 569
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Book Description
This volume focuses on current evidence-based pharmacological treatments of various forms of pulmonary hypertension and provides a comprehensive review of the latest developments in this area. The first part of the book covers the definition, classification, pathophysiology, pathology, biomarkers and animal models of the disease, thus laying the conceptual basis for what follows. The middle section provides an overview of the established therapies, such as calcium channel blockers, prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors and inhaled nitric oxide. The last section explores novel pathways and emerging therapeutic approaches including soluble guanylate cyclase stimulators, Rho-kinase inhibitors, inhibitors of serotonin receptors and transporters, peptide growth factors, vasoactive peptides, modulators of redox equilibrium and cyclic nucleotide homeostasis, as well as immunosuppressive and anti-proliferative agents. Particular attention is given to the clinical applications of these experimental therapies, that are on the horizon. The book thus spans the continuum from basic science to clinical applications.
Author: Thomas F. DeRosa
Publisher: Elsevier
ISBN: 0080480918
Category : Science
Languages : en
Pages : 701
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Book Description
Significant Pharmaceuticals Reported in US Patents identifies the next generation of pharmaceuticals reported in US Patents. This "hands-on" title provides explicit laboratory methods for preparing the most recent and effective medications. Each entry documents the biological testing protocols used to evaluate a drug and the significance of the current treatment agent over previous methods. Pharmaceuticals are included in this review only if at least two of the following criteria were met: Effectiveness in treating an illness, Innovative, ease of preparation, synergy with existing Medications. Pharmaceuticals are reported for 27 separate classes of illness, including: AIDS, Alzheimer's Disease, Cardiovascular Disorders, Diabetes, Epilepsy, Hepatitis C, Osteoporosis, Obesity and Sleep Disorders. Significant Pharmaceuticals Reported in US Patents has been designed to be used as both a reference and synthetic guide for pharmaceutical, medicinal and organic chemists and graduate students. Researchers working in other areas will also find the information valuable as in many instances intermediates or the next generation pharmaceutical are readily convertible into other industrial products including: anti-oxidants, chemical additives, herbicides, polymer precursors, water purification agents. Clear structural depictions of reagents and chemical transformations have been supplied to permit the identification of other future applications. Identifies next generation pharmaceuticals Provides practical preparation methods for each active agent and derivatives Documents the analytical characterization and biological testing results of active agents
Author: Fatima Shad Kaneez
Publisher: BoD – Books on Demand
ISBN: 9535133616
Category : Medical
Languages : en
Pages : 318
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Book Description
Serotonin - A Chemical Messenger Between All Types of Living Cells is a very interesting book on the most ancient neurotransmitter, hormone and trophic factor serotonin or 5-hydroxytryptamine (5-HT). This unique chemical is present in all living cells including plants and animals. This book will take us through a serene journey of the evolutionary history of serotonin and its role from man to mollusk. There are many interesting chapters incorporated in this book, including novel approaches for detecting minor metabolites of serotonin in human plasma, production and function of serotonin in cardiac cells, immuno-thrombotic effects of serotonin in platelets to the identification and localization of serotonin in the nervous system and gonad of bivalve mollusks.
Author: Theodoros Aslanidis
Publisher: BoD – Books on Demand
ISBN: 1789840414
Category : Medical
Languages : en
Pages : 116
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Book Description
This book, published by IntechOpen, focuses on interesting aspects of pulmonary medicine. The first section of the book is dedicated to interventional pulmonology, and includes updates on bronchial thermoplasty, virtual bronchoscopy, and endobronchial ultrasound. The second section highlights special aspects of pulmonary circulation and pulmonary hypertension. Throughout the book, the authors offer us not only a "vigorous" review of the current literature but also a research path to further advancement.
