Download or read book Examining the Effects of Activator Compounds on HERG Cardiac Potassium Channel Protective Currents Conducted in Response to Premature Stimulations written by Jacob Kemp and published by . This book was released on 2020 with total page 118 pages. Available in PDF, EPUB and Kindle. Book excerpt: The human ether-a-go-go-related gene (hERG) encodes the rapid delayed rectifier cardiac potassium channel. Vital for repolarization of the myocardium and termination of the cardiac action potential, loss of function in hERG K+ channels can result in Long QT Syndrome Type II (LQTS2). Additionally, hERG channels have been shown to mediate robust repolarizing currents in response to premature depolarizations, reflective of channels remaining in the open state into the refractory period. Thought to be protective against afterdepolarizations, loss of function in this regard may leave individuals susceptible to arrhythmia. Recently, several small molecule activators of hERG have been discovered. The effects of these compounds on the protective currents mediated by hERG channels have yet to be studied. The work presented in this thesis examines the effects of both Type I and II hERG channel activators on protective currents mediated by hERG channels, in the context of an inherited mutation.
Download or read book Small Molecule Targeting of Cardiac HERG Channels to Protect Against Arrhythmias written by Ravichandra Venkateshappa and published by . This book was released on 2023 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The hERG potassium channel encoded by the ether-a-go-go-related gene (hERG) is essential for ventricular repolarization. These channels have a distinctive kinetic profile in that they conduct a modest current during the plateau phase, attain their maximum conductance during phase 3 of cardiac repolarization, and then close slowly. Due to acquired or hereditary conditions, dysfunction of these channels reduces hERG currents, prolongs action potential length (as shown by a prolonged QT interval), and predisposes individuals to potentially fatal ventricular arrhythmias. This-relationship between hERG dysfunction and QT prolongation (Long QT Syndrome, LQTS) has sparked interest in the role of hERG channels in phase 3 repolarization and arrhythmia generation and the possibility that small molecules hERG agonists may be utilized to restore function. A series of small molecules have been found and classified according to their mode of action. In -vitro and in -vivo investigations have shown that Type 2 activators that enhance hERG currents by decreasing channel inactivation, risk over-correction of the action potential and Short QT Syndrome. Type 1 activators, which preferentially slow the deactivation of hERG channels, on the other hand, may provide a more subtle restoration of hERG currents. A few studies have postulated that the slow deactivation of hERG channels may suppress triggered activity by allowing protective repolarizing current flow in response to premature depolarizations arriving in the refractory period. However, there are no direct experimental correlations between these protective hERG currents and ventricular arrhythmia, or the effects of manipulation of deactivation by Type 1 hERG activators. In my thesis, I examine the role of hERG protective currents and the use of a hERG Type 1 activator as a mechanism based therapy for both acquired and inherited forms of LQTS. Using a translational approach ranging in complexity from single cells to the entire organ these studies aim to provide improved understanding of the pathogenic mechanisms associated with hERG channel dysfunction and the effect of targeted slowing of hERG deactivation in suppressing arrhythmias.
Download or read book The Mechanism of Action of External Protons on HERG Potassium Channels written by Yu Shi and published by . This book was released on 2018 with total page 178 pages. Available in PDF, EPUB and Kindle. Book excerpt: Myocardial ischemia occurs when there is a reduction of blood flow to the heart due to blockage of an artery, causing inefficient delivery of oxygen and nutrients to the heart muscle. Acidosis is one of the major consequences during myocardial ischemia and affects a wide array of ion channels in the heart that may predispose individuals to cardiac arrhythmia. The human ether-à-go-go (hERG) related gene encodes the potassium channel that conducts the IKr current, which is responsible for the repolarization phase of the cardiac action potential and is particularly sensitive to external acidosis. External acidosis had been well observed to reduce hERG channel overall conductance, right-shift the voltage-dependence of activation, and accelerate deactivation rate, all of which lead to a loss-of-function effect on the hERG channels. We hypothesized that this can prolong action potential duration, increase susceptibility of individuals to long QT syndrome and reduce the protective current against premature ectopic beat. My first study aimed to determine the site and mechanism for the right-shift in the voltage-dependence of activation. I found that external protons disrupt stable interactions formed by the cation binding pocket, compose of three acidic residues: D456, D460 in S2, and D509 in S3, with positive charges in S4 to destabilize the activated voltage sensor. My second study aims to determine the site and mechanism for the acceleration of deactivation induced by external protons. Using voltage-clamp fluorimetry and gating current measurement with long duration protocols to measure voltage sensor mode-shift, we determined that external protons reduced the voltage sensor mode-shift by right shifting the voltage-dependence of deactivation suggesting that the relaxed conformation of the voltage sensor is destabilized and that D509 is a critical protonation site. In my last study, I used zebrafish heart as a translational model, with the optical mapping technique to investigate the effect of external protons on the overall cardiac action potential. We discovered that at low pH, the cardiac action potential is significantly prolonged, triangulation is increased, and the electrical restitution curve is flattened, which are all predictors for arrhythmogenicity.
Download or read book J Wave Syndromes written by Charles Antzelevitch and published by Springer. This book was released on 2016-06-27 with total page 342 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book delineates the state of the art of the diagnosis and treatment of J wave syndromes, as well as where future research needs to be directed. It covers basic science, translational and clinical aspects of these syndromes. The authors are leading experts in their respective fields, who have contributed prominently to the literature concerning these topics. J wave syndromes are one of the hottest topics in cardiology today. Cardiac arrhythmias associated with Brugada syndrome (BrS) or an early repolarization (ER) pattern in the inferior or infero-lateral ECG leads are thought to be mechanistically linked to accentuation of transient outward current (Ito)-mediated J waves. Although BrS and ER syndrome (ERS) differ with respect to magnitude and lead location of abnormal J waves, they are thought to represent a continuous spectrum of phenotypic expression termed J wave syndromes. ERS is divided into three subtypes with the most severe, Type 3, displaying an ER pattern globally in the inferior, lateral and right precordial leads. BrS has been linked to mutations in 19 different genes, whereas ERS has been associated with mutations in 7 different genes. There is a great deal of confusion as to how to properly diagnose and treat the J wave syndromes as well as confusion about the underlying mechanisms. The demonstration of successful epicardial ablation of BrS has provided new therapeutic options for the management of this syndrome for which treatment alternatives are currently very limited, particularly in the case of electrical storms caused by otherwise uncontrollable recurrent VT/VF. An early repolarization pattern is observed in 2-5% of the US population. While it is clear that the vast majority of individuals exhibiting an ER pattern are not at risk for sudden cardiac death, the challenge moving forward is to identify those individuals who truly are at risk and to design safe and effective treatments.
Download or read book Cardiac Repolarization written by Ihor Gussak and published by Springer Science & Business Media. This book was released on 2003-03-13 with total page 549 pages. Available in PDF, EPUB and Kindle. Book excerpt: A comprehensive review of all the latest developments in cardiac electrophysiology, focusing on both the clinical and experimental aspects of ventricular repolarization, including newly discovered clinical repolarization syndromes, electrocardiographic phenomena, and their correlation with the most recent advances in basic science. The authors illuminate the basic electrophysiologic, molecular, and pharmacologic mechanisms underlying ventricular repolarization, relate them to specific disease conditions, and examine the future of antiarrhythmic drug development based on both molecular and electrophysiological properties. They also fully review the clinical presentation and management of specific cardiac repolarization conditions.
Download or read book Drug Discovery and Evaluation Pharmacological Assays written by Hans Vogel and published by Springer Science & Business Media. This book was released on 2007-10-30 with total page 2118 pages. Available in PDF, EPUB and Kindle. Book excerpt: The new edition of this successful reference offers both cutting-edge and classic pharmacological methods. Thoroughly revised and expanded to two volumes, it offers an updated selection of the most frequently used assays for reliably detecting the pharmacological effects of potential drugs. Every chapter has been updated, and numerous assays have been added. Each of the more than 1,000 assays comprises a detailed protocol outlining purpose and rationale, and a critical assessment of the results and their pharmacological and clinical relevance.
Download or read book Pharmacology of Potassium Channels written by Nikita Gamper and published by Springer Nature. This book was released on 2021-09-27 with total page 546 pages. Available in PDF, EPUB and Kindle. Book excerpt: The aim of the present book is to comprehensively review current advances in understanding of genetics, structural biology, pharmacology of potassium channels and their roles in disease as well as to identify current gaps in knowledge. The ultimate goal is to provide a scientific foundation for better understanding of modulatory mechanisms and pharmacology of potassium channels and to use this understanding to drive future drug discovery. This book will be a must-have for academic and industrial scientists interested in physiology, pharmacology, pathology and structure-functional relationships of ion channels. The book will also be helpful for lecturers and students in the college and university classrooms, as well as for anyone interested in the state-of-the art in modern cell biology, physiology and pharmacology.
Download or read book Anesthetic Pharmacology written by Alex S. Evers and published by Cambridge University Press. This book was released on 2011-03-10 with total page 2902 pages. Available in PDF, EPUB and Kindle. Book excerpt: In recent years our understanding of molecular mechanisms of drug action and interindividual variability in drug response has grown enormously. Meanwhile, the practice of anesthesiology has expanded to the preoperative environment and numerous locations outside the OR. Anesthetic Pharmacology: Basic Principles and Clinical Practice, 2nd edition, is an outstanding therapeutic resource in anesthesia and critical care: Section 1 introduces the principles of drug action, Section 2 presents the molecular, cellular and integrated physiology of the target organ/functional system and Section 3 reviews the pharmacology and toxicology of anesthetic drugs. The new Section 4, Therapeutics of Clinical Practice, provides integrated and comparative pharmacology and the practical application of drugs in daily clinical practice. Edited by three highly acclaimed academic anesthetic pharmacologists, with contributions from an international team of experts, and illustrated in full colour, this is a sophisticated, user-friendly resource for all practitioners providing care in the perioperative period.
Download or read book Ion Channels written by James N. C. Kew and published by . This book was released on 2010 with total page 586 pages. Available in PDF, EPUB and Kindle. Book excerpt: Ion channels are intimately involved in the everyday physiological functions that enable us to live a full and varied life. When disease strikes, malfunction of ion channels or their dependent is often involved, either as the cause or the effect of the illness. Thus, billions of dollars have been, and still are being, invested in research to understand the physiological and pathophysiological functions of ion channels in an attempt to develop novel therapeutic treatments for a wide range of diseases. This book provides a comprehensive overview of ion channel structure and function. It comprises two major parts. Part one is an introductory overview of the ion channel superfamily and the generic aspects of ion channel function. This part also reviews the methodologies by which ion channel function can be studied from the perspective of performing detailed biophysical characterization through to the deployment of high throughput approaches for identifying novel ion channel ligands. Part two of the book provides an in-depth review of the individual ion channel subfamilies and, as such, is subdivided into four broad sections: Voltage-Gated Ion Channels, Extracellular Ligand-Gated Ion Channels, Intracellular Ligand-Gated Ion Channels, and Polymodal-Gated Ion Channels, with each chapter focused on specific family members. These chapters have been written by world leading experts and provide a detailed overview of the structure, biophysics, localization, pharmacology, physiology, and disease relevance of each particular ion channel subfamily. Reviewing both the basic principles of ion channel function and providing a detailed up-to-date review of the phsyiological and pharmacological aspects of individual ion channel sub-families, this book constitutes both an excellent introduction to the field for non-specialists, as well as a highly valuable reference text for experienced researchers already working in the ion channel area.
Download or read book WHO Global Report on Traditional and Complementary Medicine 2019 written by World Health Organization and published by World Health Organization. This book was released on 2019-05-16 with total page 228 pages. Available in PDF, EPUB and Kindle. Book excerpt: This report is structured in five parts: national framework for traditional and complementary medicine (T&CM); product regulation; practices and practitioners; the challenges faced by countries; and finally the country profiles. Apart from the section on practices and practitioners the report is consistent with the format of the report of the first global survey in order to provide a useful comparison. The section on practices and practitioners which covers providers education and health insurance is a new section incorporated to reflect the emerging trends in T&CM and to gather new information regarding these topics at a national level. All new information received has been incorporated into individual country profiles and data graphs. The report captures the three phases of progress made by Member States; that is before and after the first WHO Traditional Medicine Strategy (1999?2005) from the first global survey to the second global survey (2005?2012) and from the second survey to the most recent timeline (2012?2018).
Download or read book Cardiac Regeneration written by Masaki Ieda and published by Springer. This book was released on 2017-10-27 with total page 274 pages. Available in PDF, EPUB and Kindle. Book excerpt: This Volume of the series Cardiac and Vascular Biology offers a comprehensive and exciting, state-of-the-art work on the current options and potentials of cardiac regeneration and repair. Several techniques and approaches have been developed for heart failure repair: direct injection of cells, programming of scar tissue into functional myocardium, and tissue-engineered heart muscle support. The book introduces the rationale for these different approaches in cell-based heart regeneration and discusses the most important considerations for clinical translation. Expert authors discuss when, why, and how heart muscle can be salvaged. The book represents a valuable resource for stem cell researchers, cardiologists, bioengineers, and biomedical scientists studying cardiac function and regeneration.
Download or read book Low voltage activated T type Calcium Channels written by Richard W. Tsien and published by . This book was released on 1998 with total page 420 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Modeling and Simulating Cardiac Electrical Activity written by David J. Christini and published by . This book was released on 2020 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides a thorough introduction to the topic of mathematical modeling of electrical activity in the heart, from molecular details of ionic channel dynamics to clinically derived patient-specific models. It discusses how cellular ionic models are formulated, introduces commonly used models and explains why there are so many different models available. The chapters cover modeling of the intracellular calcium handling that underlies cellular contraction as well as modeling molecular-level details of cardiac ion channels, and also focus on specialized topics such as cardiomyocyte energetics and signalling pathways. It is an excellent resource for experienced and specialised researchers in the field, but also biological scientists with a limited background in mathematical modelling and computational methods. Part of Biophysical Society-IOP series.
Download or read book Protein Blood Group Antigens of the Human Red Cell written by Peter Agre and published by . This book was released on 1992 with total page 296 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Atlas of Epilepsies written by S.R. Benbadis and published by Springer Science & Business Media. This book was released on 2010-09-20 with total page 1966 pages. Available in PDF, EPUB and Kindle. Book excerpt: Atlas of Epilepsies is a landmark, all-encompassing, illustrated reference work and hands-on guide to the diagnosis, management and treatment of epilepsy in all its forms and across all age groups. The premier text in the field with over one thousand images, the Atlas’s highly illustrative approach tackles the difficult subject of epileptic seizures and epileptic syndromes, accompanied by sequential photographs of each management step. Intraoperative photographs are accompanied by detailed figure legends describing nuances, subtleties, and the thought processes involved in each step, providing a fuller understanding of each procedure. The Atlas draws on the expertise of over 300 internationally-renowned experts, and is liberally interspersed with clinical insights and personal vignettes that offer helpful tips, technical advice and critical knowledge to the clinician and scholar. The thorough and complete table of contents includes dedicated sections or chapters on important topics such as neonatal and pediatric seizures; imitators of epilepsy; EEG and neuroimaging; psychiatric and quality of life aspects of epilepsy; and a complete guide to treatment options including current and up-to-date chapters on pharmaceuticals, surgical procedures, and additional and alternative treatments. No other publication addresses epilepsies as thoroughly and completely as the Atlas of Epilepsies. Exhaustive and illustrative, convenient and current, this reference is sure to be the premier text on epilepsy for many years to come.
Download or read book Molecular Basis of Cardiovascular Disease written by Kenneth R. Chien and published by . This book was released on 2004 with total page 760 pages. Available in PDF, EPUB and Kindle. Book excerpt: The 2nd Edition of this heralded companion to Braunwald's Heart Disease explores the molecular mechanisms of cardiology and the scientific advances that are changing the practice of cardiology today. International experts discuss the role of genetics in cardiovascular disease the molecular basis of ischemic disease, thrombosis and hypertension genetic mapping approaches to inherited disorders biologically targeted agents for hypertension and heart failure and much more. Abundant figures and tables illustrate key concepts. Addresses most common cardiovascular problems from a molecular standpoint. Explores developing treatments for cardiovascular problems based on genetics. Provides references to Braunwald's Heart Disease, 6th Edition Examines today's cutting edge advances in molecular cardiology and the future of gene therapy, Examines the implications of cellular cholesterol metabolism in health and disease. . Delivers up-to-date information on understanding the origin of inherited disease.
Download or read book Drug Discovery and Evaluation Safety and Pharmacokinetic Assays written by H. Gerhard Vogel and published by Springer. This book was released on 2013-02-27 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: -A landmark in the continuously changing world of drugs -Essential reading for scientists and managers in the pharmaceutical industry involved in drug finding, drug development and decision making in the development process -Of use for government institutions and committees working on official guidelines for drug evaluation worldwide
