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Endothelin-Related Drugs Benefit Patients With Pulmonary Hypertension
September 10, 2009Recent research to block the effects of endothelin, a powerful substance that constricts blood vessels and stimulates cell growth, has led to successful treatment of pulmonary arterial hypertension and provides hope for treating other chronic diseases. The usefulness of the new drugs to treat congestive heart failure is much less clear, said Professor Matthias Barton, M.D. of the Department of Medicine at the University of Zurich School of Medicine.
Dr. Barton will give an update on endothelin research at the American Physiological Society's (APS; www.the-aps.org) 11th International Conference on Endothelin. The title of his talk is "What You Should Know About Endothelin," is part of the symposium, "Roles of Endothelin-1 on Cardiac Function and Diseases." The conference takes place Sept. 9-12 in Montreal.
What is Endothelin?
Endothelin's importance in both health and disease quickly became clear after researchers first discovered its receptors in the early 1990s, according to Dr. Barton. It is the most potent and longest lasting of the blood vessel constrictors (vasoconstrictors) and is 100 times more powerful than the vasoconstrictor norepinephrine.
The human body continuously produces endothelin and increases its production in response to disease conditions, such as inflammation, high blood pressure or high cholesterol. Nitric oxide, a substance also released from the endothelium that dilates the blood vessels (vasodilator), helps counterbalance endothelin production.
Endothelin's duties are wide ranging. In addition to being a vasoconstrictor, it also helps regulate cell growth, contributes to heart muscle contractility and helps determine heart rate. That is only a partial list, and it is all beneficial. On the negative side, endothelin can disturb heart rhythm and promote unfavorable changes in the heart muscle following congestive heart failure. Endothelin also promotes kidney disease and coronary artery disease, among other disorders.
Researchers have recently developed drugs in hopes of blocking the negative effects of the most important form of endothelin, endothelin-1. The drugs, including ambrisentan, bosentan, darusentan, enrasentan, sitaxsentan, and tezosentan are endothelin receptor antagonists. That is, they work by preventing endothelin-1 from linking with one or both of its receptors, ETA and ETB. Endothelin cannot work without at least one of these receptors.
Endothelin Receptor Antagonists and Fighting Disease
Clininal trials have begun to use endothelin receptor antagonists to treat pulmonary hypertension, resistant arterial hypertension, proteinuric renal disease, cancer and autoimmune diseases such as scleroderma. The following are some research highlights on endothelin receptor antagonists:
Pulmonary Hypertension. The FDA has approved the use of endothelin blockers to treat human pulmonary hypertension which is a disease with a poor prognosis. The first clinical trials have demonstrated benefits regarding symptoms and have improved the quality of life of the patients. These drugs targeted either the ETA receptor alone, or both receptors, ETA and ETB, together.
Clinical research so far suggests that endothelin antagonists will be a major part of pulmonary hypertension therapy in the future. Among the issues still to be resolved are whether drugs that block ETA alone will be more effective in treating pulmonary hypertension than drugs that block both ETA and ETB and whether it is best to combine the drugs with other drugs, such as vasodilators.
Proteinuric Renal Disease. Protein excretion in the urine is a reliable predictor of cardiovascular risk. According to the first clinical studies treatment with drugs that block ETA alone, and treatment with drugs that blocks both receptors, reduced protein excretion in the urine in patients with renal failure, even in patients already treated with other anti-proteinuric drugs. Clinical research in this area is ongoing.
Coronary Artery Disease. Research on mice with atherosclerosis (hardening of the arteries from plaque buildup) has found that inhibiting endothelin inhibits the development of atherosclerotic plaque. Also in mice, blocking the ETA receptor alleviates some of the causes leading to angina and can reduce damage to the heart tissue following a heart attack. Finally, chronic treatment with an ETA receptor improves the ability of blood vessels to dilate. This improved vasodilation has also been found in human studies.
Resistant Arterial hypertension. Treatment with a drug that blocks ETA alone, and treatment with a drug that blocks both receptors, substantially reduced arterial blood pressure in human patients with essential or resistant essential hypertension. Further research is necessary to determine whether the drugs can reduce hypertension-related organ damage such as failure of the heart or kidneys or the number of deaths associated with hypertension.
Heart Failure. In several long-term clinical studies with human patients with acute or chronic congestive heart failure, none has shown that the receptor blockers can provide any benefit. Dr. Barton noted that not all of the data from the human trials was available to scientists so that they could further analyze these results. In addition, patients in the trials received the endothelin blockers along with standard treatments for heart failure, perhaps masking the possible benefits of the new drugs, he said. He recommends further research in the area of heart failure, which could possibly include lower drug dosages and close monitoring and treatment of edema in this very ill patient population.
American Physiological Society (APS)
Endothelin's importance in both health and disease quickly became clear after researchers first discovered its receptors in the early 1990s, according to Dr. Barton. It is the most potent and longest lasting of the blood vessel constrictors (vasoconstrictors) and is 100 times more powerful than the vasoconstrictor norepinephrine.
The human body continuously produces endothelin and increases its production in response to disease conditions, such as inflammation, high blood pressure or high cholesterol. Nitric oxide, a substance also released from the endothelium that dilates the blood vessels (vasodilator), helps counterbalance endothelin production.
Endothelin's duties are wide ranging. In addition to being a vasoconstrictor, it also helps regulate cell growth, contributes to heart muscle contractility and helps determine heart rate. That is only a partial list, and it is all beneficial. On the negative side, endothelin can disturb heart rhythm and promote unfavorable changes in the heart muscle following congestive heart failure. Endothelin also promotes kidney disease and coronary artery disease, among other disorders.
Researchers have recently developed drugs in hopes of blocking the negative effects of the most important form of endothelin, endothelin-1. The drugs, including ambrisentan, bosentan, darusentan, enrasentan, sitaxsentan, and tezosentan are endothelin receptor antagonists. That is, they work by preventing endothelin-1 from linking with one or both of its receptors, ETA and ETB. Endothelin cannot work without at least one of these receptors.
Endothelin Receptor Antagonists and Fighting Disease
Clininal trials have begun to use endothelin receptor antagonists to treat pulmonary hypertension, resistant arterial hypertension, proteinuric renal disease, cancer and autoimmune diseases such as scleroderma. The following are some research highlights on endothelin receptor antagonists:
Pulmonary Hypertension. The FDA has approved the use of endothelin blockers to treat human pulmonary hypertension which is a disease with a poor prognosis. The first clinical trials have demonstrated benefits regarding symptoms and have improved the quality of life of the patients. These drugs targeted either the ETA receptor alone, or both receptors, ETA and ETB, together.
Clinical research so far suggests that endothelin antagonists will be a major part of pulmonary hypertension therapy in the future. Among the issues still to be resolved are whether drugs that block ETA alone will be more effective in treating pulmonary hypertension than drugs that block both ETA and ETB and whether it is best to combine the drugs with other drugs, such as vasodilators.
Proteinuric Renal Disease. Protein excretion in the urine is a reliable predictor of cardiovascular risk. According to the first clinical studies treatment with drugs that block ETA alone, and treatment with drugs that blocks both receptors, reduced protein excretion in the urine in patients with renal failure, even in patients already treated with other anti-proteinuric drugs. Clinical research in this area is ongoing.
Coronary Artery Disease. Research on mice with atherosclerosis (hardening of the arteries from plaque buildup) has found that inhibiting endothelin inhibits the development of atherosclerotic plaque. Also in mice, blocking the ETA receptor alleviates some of the causes leading to angina and can reduce damage to the heart tissue following a heart attack. Finally, chronic treatment with an ETA receptor improves the ability of blood vessels to dilate. This improved vasodilation has also been found in human studies.
Resistant Arterial hypertension. Treatment with a drug that blocks ETA alone, and treatment with a drug that blocks both receptors, substantially reduced arterial blood pressure in human patients with essential or resistant essential hypertension. Further research is necessary to determine whether the drugs can reduce hypertension-related organ damage such as failure of the heart or kidneys or the number of deaths associated with hypertension.
Heart Failure. In several long-term clinical studies with human patients with acute or chronic congestive heart failure, none has shown that the receptor blockers can provide any benefit. Dr. Barton noted that not all of the data from the human trials was available to scientists so that they could further analyze these results. In addition, patients in the trials received the endothelin blockers along with standard treatments for heart failure, perhaps masking the possible benefits of the new drugs, he said. He recommends further research in the area of heart failure, which could possibly include lower drug dosages and close monitoring and treatment of edema in this very ill patient population.
American Physiological Society (APS)
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Endothelin-1 inhibitors in chronic pancreatitis
Fibrosis is a key feature of chronic pancreatitis and pancreatic cancer. The extensive deposition of extracellular matrix proteins fosters the development of an exocrine and endocrine organ insufficiency, and accelerates progression of the tumour.
Males May Experience Greater Physical Pain Due To Lower Levels Of A Key Protein, Endothelin
Agonizing physical pain, known as vaso-occlusive pain, can afflict children who have sickle cell disease (SCD).
International conference on endothelin
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It is known that I/R induces an inflammatory response deleterious to the organ involved but also to the system as a whole.
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Will IVF work for a particular patient? The answer may be found in her blood
For the first time, researchers have been able to identify genetic predictors of the potential success or failure of IVF treatment in blood.
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A new study published in the May 2008 (volume 8, issue 25) edition of the journal of Nutrition Research shows Pycnogenol (pic-noj-en-all), an antioxidant plant extract from the bark of the French maritime pine tree, reduces blood sugar in type II diabetes patients, allows people to lower their antihypertensive medication and improves cardiovascular disease (CVD) risk factors.
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Endothelin Protocols (Methods in Molecular Biology, 206) (Methods in Molecular Biology) by Janet J. Maguire (Editor), Anthony P. Davenport (Editor) A panel of multidisciplinary experts describes in detail readily reproducible methods to investigate all aspects of the endothelin system from its synthesis and metabolism, to its function in health and disease. Theses methods use state-of-the-art molecular techniques to quantify the expression of mRNA for both endothelin receptors and the endothelin converting enzymes. They show how peptides, precursors, receptors, and synthetic enzymes can be localized and quantified in plasma, culture supernatants, tissue homogenate, and tissue sections using antibodies. Several in vivo protocols illustrate the role of the endothelin peptides in healthy human individuals and describe animal models that can be used to predict the therapeutic potential of cardiovascular drugs that manipulate... |
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Endothelin Receptors: From the Gene to the Human (Pharmacology and Toxicology) by Robert R. Ruffolo (Editor) Since the discovery of endothelin, major advances have been made in understanding the molecular structure and function of the endothelin receptors. At least two subtypes of receptors, designated ETA and ETB, have been identified through biochemical and pharmacological techniques. These subtypes are cloned and expressed and additional subtypes appear to exist. The biochemical events involved in the signal transduction processes that ultimately activate the cellular machinery involved in the end-organ responses are presented, as are the mechanisms by which the receptors recognize specific and different G-proteins. Functions mediated by the receptors at the cellular, tissue and, organ level are reviewed in detail, as well as the roles that they may play a part in the physiologic and... |
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Endothelin: Tole in Health & by GULATI (Author) Endothelin summarizes the progress made in the field of endothelin research since its discovery. Initially it was believed to have vasoactive properties, however it is now known that endothelin, as well as vasculature, is involved in many other systems. Care has been taken to include almost all major systems into the text. The book focuses on the role of endothelin in the pathophysiology of several diseases, both cardiovascular and non-cardiovascular, and its role in inflammation. Endothelin interaction with a variety of other regulatory agents is discussed, providing a text which will be of great value to scientists engaged in studies on this multifunctional polypeptide. |
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Endothelins in Biology and Medicine by John P. Huggins (Author), John T. Pelton (Author) Endothelin-1 (ET-1), a peptide discovered in 1988, is one of the most potent contractors of vascular smooth muscle. Since their discovery, ETs have generated enormous interest in the scientific and pharmaceutical communities, prompting extensive research. This book addresses the latest findings regarding ETs-how they function, their effects, and characteristics. Divided into five sections, the book covers: endothelin receptors, endothelin synthesis and degradation, endothelin pathophysiology, ligand structure and activity relationships, and clinical studies. Pharmacologists, toxicologists, and pharmaceutical researchers will all benefit from this thorough review of current findings and future directions in ET research. |
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Endothelin Receptors and Signaling Mechanisms (Biotechnology Intelligence Unit) by David M. Pollock (Editor), Robert F. Highsmith (Editor) This book focuses on the wide variety of intracellular events that occur as a result of endothelin receptor activation. This includes a discussion of the various pathways by which endothelin activates Ca2+ signals from several intra- and extracellular sources and the effects of endothelin on ion channels and membrane function. In addition, the mechanisms by which endothelin influences the ion transport within the renal epithelium are covered, as well as the signal transduction pathways activated by endothelin in both cardiac tissue and vascular smooth muscle. |
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Endothelin (Clinical Physiology Series) by Gabor M. Rubanyi (Editor) Merely three years after the discovery of endothelin, a large amount of information has been generated about the molecular biology, biosynthesis, biological actions and potential physiological and pathological importance of this unique peptide and its isoforms. This first book on endothelins summarizes the early events which lead to the discovery of endothelin, the progress made in understanding the peptide's physiological role, and the current state-of-the-art in contemporary endothelin research. The book also discusses the potential significance of endothelins in health and disease, covers the potential role of the peptides in the integrated control of the cardiovascular system, and outlines future research directions. This comprehensive monograph is an indispensable reference for basic... | |
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Endothelin: Webster's Timeline History, 1988 - 2007 by Icon Group International (Author) Webster's bibliographic and event-based timelines are comprehensive in scope, covering virtually all topics, geographic locations and people. They do so from a linguistic point of view, and in the case of this book, the focus is on "Endothelin," including when used in literature (e.g. all authors that might have Endothelin in their name). As such, this book represents the largest compilation of timeline events associated with Endothelin when it is used in proper noun form. Webster's timelines cover bibliographic citations, patented inventions, as well as non-conventional and alternative meanings which capture ambiguities in usage. These furthermore cover all parts of speech (possessive, institutional usage, geographic usage) and contexts, including pop culture, the arts, social sciences... |
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Endothelins: Webster's Facts and Phrases by Icon Group International (Author) Ever need a fact or quotation on "endothelins"? Designed for speechwriters, journalists, writers, researchers, students, professors, teachers, historians, academics, scrapbookers, trivia buffs and word lovers, this is the largest book ever created for this word. It represents a compilation of "single sentences" and/or "short paragraphs" from a variety of sources with a linguistic emphasis on anything relating to the term "endothelins," including non-conventional usage and alternative meanings which capture ambiguities. This is not an encyclopedic book, but rather a collage of statements made using the word "endothelins," or related words (e.g. inflections, synonyms or antonyms). This title is one of a series of books that considers all major vocabulary words. The entries in each book... |
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Einfluß von Endothelin-1 auf Kontraktionskraftentwicklung und intrazelluläre Calcium-Homöostase des Myokards by Matthias Zirnig (Author) |
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Pulmonary Actions of the Endothelins (Respiratory Pharmacology and Pharmacotherapy) by Goldie (Editor), Hay (Editor) This book addresses the subject of the biology of the endothelin peptides in the lung, with particular reference to the respiratory tract and the possible mediator roles of these peptides in lung disease. The book provides an up-to-date analysis of the current literature concerning the actions of the endothelins in the lung. Specific chapters are devoted to our current understanding of endothelin synthesis, receptor subtype activation, distribution and density in the airways, its actions in vascular and airway smooth muscle and nerves and its role in tissue development, differentiation and disease. This volume will be of interest to both nonclinical and clinical researchers in pulmonary biology, as well as to teachers in academic disciplines targetting aspects of lung function and... |
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