It is an exciting task to be the editor of the first monograph covering a new area of the biomedical sciences. Since the first report in 1980 by Robert Furchgott and colleagues (see Chapter 1) of the evidence of endothelium-dependent relaxation in isolated arteries, there are ever increasing numbers of vascular physiologists and pharmacologists who are scraping away the endothelium to look into its role in cardiovascular con trol. And the more one looks, the more one discovers. Not only is the list of substances that can induce endothelium-dependent relaxations im pressively long, but these intriguing cells can also secrete vasoconstrictor substances. The ability of the endothelium to modulate the degree of con traction of the underlying smooth muscle is an ancestral property of the blood vessel wall, illustrating the logic of nature, since the endothelial cells are located in the best possible strategic location to continuously monitor the properties (chemical or physical) of the blood. And more and more data emerge suggesting that in several cardiovascular diseases per turbations in endothelium-dependent responses are one of the early signs of the abnormal process. Thus, the importance of endothelium-dependent responses, triggered by the intellectual curiosity of one of the pioneers of vascular physiology and pharmacology, is now recognized not only by basic scientists, but also by all concerned with the cardiovascular diseases. The purpose of this monograph is to provide them with a reference work, so that they know where to start."

JAMES L. MCGAUGH Understanding of the nature and functions of neurotransmitter systems in the brain has increased enormously in recent decades. Lack of knowledge required us, not too long ago, to use the adjective "putative" when discussing transmitters. Such caution is no longer essential (at least for a number of transmitters). Impressive progress has been achieved in understanding the pharmacology, biochemistry and anatomy of transmitter systems. There has, however, been relatively less progress in understanding the functioning of brain transmitters in regulating and mediating behavior. A simple and certainly correct explanation for this is, of course, that understanding of neurotransmitter functions requires prior detailed knowledge of basic pharmacology, biochemistry and anatomy. Beyond that, it now seems likely that progress in understanding the functions of brain neurotransmitters will proceed only as we examine the interactions of neurotransmitter systems in regulating behavioral functions. This premise is, of course, suggested by the findings of studies of the chemical neuroanatomy of the brain: Neurotransmitter systems are influenced by other neurotransmitter systems and, in tum, influence the same as well as other systems. No system works alone. The chapters in this book explicitly examine the interactions of neurotransmitter systems involved in the regulation of cognitive processes. The facts and interpretations offered provide compelling support for the premise that cognitive processes are orchestrated by interactions among neurotransmitter systems. And, they offer promise that understanding of such interactions will be of critical importance in the develop ment of treatments for brain diseases affecting cognitive functioning."

More than 70 years have elapsed since U. S. von Euler and I. H. Gaddum dis- covered an unidentified depressor substance in the brain and gut. The effects of the powdery extracts were marked as 'P' on the kymograph tracings, and the nondescript name of 'substance P' still carries the breath of this adventurous period. In the 1960s, substance P returned in another disguise, staging as a hypothalamic peptide that causes copious salivary secretion (see chapter by F. Lembeck and I. Donnerer). This time, though, the mysterious substance was tracked down by S. E. Leeman and her collaborators as an undecapeptide, after it had eluded its identification for some 40 years. Substance P turned out to be the mammalian counterpart of a family of peptides which had been extracted from amphibian and nonvertebrate species and which had been given the name 'tachykinins' by V. Erspamer. Soon novel members of this peptide family were discovered, and in mammals substance P was joined by neurokinin A and neu- rokinin B. The presence of tachykinins in frog skin as well as in venoms and toxins of microbes and arachnids raises the possibility that these peptides re- present an old system of biological weapons that have been transformed to a particular messenger system in mammals.

Electric currents and electromagnetic fields have been applied to biological systems, particularly humans, with both therapeutic and pathological results. This text discusses biological responses to electric currents and electromagnetic fields, including medical applications and shock hazards. It covers fundamental physical and engineering principles of responses to short-term electrical exposure and emphasises human reactions, although animal responses are considered as well, and the treatment covers reactions from the just-detectable to the clearly detrimental. An important new chapter discusses standards for human exposure to electromagnetic fields and electric current and demonstrates how these standards have been developed using the principles treated in earlier chapters.

In recent years, we have witnessed a rapid expansion of our knowledge regarding the role of the endothelium in the control of vascular tone (and organ perfusion) in health and disease. Physiology, pharmacology, and molecular biology have uncovered a wealth of information on structure and function of this heretofore largely neglected "organ". Clinical medicine is now called upon to define the clinical significance of these observa tions that imply the mechanisms of blood coagulation, e.g., the interaction of throm bocytes with the endothelium, vasomotor control, and specifically, the regulation of smooth muscle tone with consequences for vascular resistance and conductance and organ blood flow. Finally, metabolism of lipids with the everlasting problem of athero sclerosis is an important aspect. In a second step, implications regarding the improvement of current therapeutic con cepts, as well as the development of new modalities of pharmacotherapy will have to be discussed. The topic addressed by the 1990 Gargellen Conference: Endothelial Mechanisms of Vasomotor Control, clearly is of interest for both basic scientists and clinicians. It has been the aim of the organizers, the Society for Cooperation in Medical Science (SCMS) with this and the previous symposia to foster and support both basic science and clinical research. Research in medicine today shows two major directions of development: on the one hand, increasing involvement of the basic sciences and their methodology. On the other hand, statistical validation of concepts and therapeutic strategies in large scale population-and multicenter-studies.

"What we call the beginning is often the end, and to make an end is to make a beginning. The end is where we start from." T. S. ELIOT, "Geroniton" The discovery of endothelin-l was both an end and a beginning. It is an end because this discovery has started a plethora of investigations as to endothe1in's sites of production, mode of action, it's normal and abnormal physiological role and its involvement in a variety of pathological conditions ranging from renal failure to myocardial infarction, cardiac hypertrophy, hyperten sion, cyclosporine induced toxicity, mental depression, renal failure, stress related illness, and even stroke and sudden death. It is a beginning because no one can foresee where the investigations will ultimately lead, or how they will end. The discovery of the endothelins was a very recent event and soon specialist books will start to appear dealing in detail with different aspects of their chemistry, physiological role and pathological importance. The present book is intended to act as a guide and primer for those who are becoming intrigued by the many endothelin related articles which are now appearing in the journals but who as yet have not had the time or opportunity to be caught up in the web of enthusiasm and excitement which is motivating those more directly involved in the field of research.

Stress, high blood pressure, smoking, pollution, fast foods, overweight, excessive travelling, surgery, less movement are common features in our modern life. These features are risky for blood clotting disorders. According to WHO, over 29% of the total mortalities worldwide are due to thrombosis. By the year, 2020 cardiovascular diseases (CVDs) may cause an estimated 25 million deaths per year, thus antithrombotic therapy is of great interest.

The available thrombolytic agents such as urokinase are highly expensive, antigenic, quite unspecific, pyretogenic and hemorrhagenic. Therefore, the production of fibrinolysing enzymes, which rapidly dissolute thrombi within the vascular tree, without the detriments by microorganisms, as described in this book, is the desirable aim of today s research. "

The scientific literature has expanded dramatically in recent years, making entry into the structure of any given area extremely difficult; concurrent with this explosion more people are required to become acquainted with information outside their main line of expertise. For this reason there is a need for review articles which give an overall review of circumscribed areas. This volume reviews the subject of respiratory control mechanisms; the authors of each chapter are active research workers engaged in the area covered by their chapter. The first four chapters are concerned with the basic physiological mechanisms which sense changes in the respiratory system, in the standard physiology textbook parlance chemical and neural sensory receptors. The peripheral arterial chemoreceptors sense changes in arterial oxygen tension, carbon dioxide and pH. The first chapter describes the basic responses in the organ produced by changes in blood chemistry. Later chapters discuss changes in activity produced by exercise, chronic hypoxia and the possible role of the chemoreceptors in initiation of respiration in the new-born. In Chapter 1, a section considers the action of drugs on the peripheral chemoreceptors, and finally there is a discussion of the possible mechanisms whereby the organs sense changes in blood chemistry. This pattern is followed in subsequent chapters wherever possible; first a discussion of the basic physiological properties, followed by any clinical application and dis cussion of the mechanism whereby the receptor might operate. The remaining chapters are of a more applied nature.

and made insignificant in practice, by selecting for study simple kinds of ex periences which are devoid of emotional content and which can be tested for reliability. A simple somatosensory ''raw feel" fulfills these characteristics (see papers nos. 2,5). In any case, if we fail to find ways to use introspective reports in convincingly acceptable studies we would give up the ability to investigate the relation between conscious experience and neural activity, something warned against by William James (Krech, 1969). Another factor in the dearth of direct experimental studies is, of course, the comparative inaccessibility of the human brain for such purposes. Meaningful investigations of the issue in question requires simultaneous study of brain events and introspective reports of experiences in an awake, cooperative human subject. Analysis by neuropsychologists of pathological lesions in the brain and the related disturbances of conscious functions have contributed much to mapping the pos sible representations of these functions. The non-invasive recording of electrical activity with electrodes on the scalp, starting from Berger's initial EEG record ings in 1929, has contributed much to the problems of states of consciousness and to various cognitive features associated with sensory inputs, but not as much to the specific issue of conscious experience."

"Provides analytical chemists and biomedical scientists with an excellent summary of progress...This is a book that can be recommended to all analytical scientists interested in fluorimetry." (Analytical Chimica Acta) "This is a useful overview and gives the nonspecialist a feeling for the advantages and limitations of the methods. Overall this book is a worthwhile read and a good source of references." (TRAC)
The book is divided into chapters on new methods, new appli- cations, fluorescence immunoassays, fluorometric analysis and fluorescence spectroscopy in biomedical sciences. Specific topics are fluorescence spectroscopy using synchrotron radiation, picosecond fluorescence spectroscopy, fluorescence microscopy, fluorescence scattering by synthetic polymers, fluorescence immunoassays, fluorescence for environmental monitoring, fluorescence in flow injection analysis, hydro-geological studies, fluorescence of proteins, lipids and membranes, cell fluorescence, calcium transients.

Though it is a pleasure to write a short foreword to this collection of excellent scientific papers covering a range of biological topics, the rather depressing feature is the small number of papers. All-electronic publishing is developing and your Editors do have great faith in it. One problem for potential authors has been the reluctance of the abstracting journals to pay any attention to electronic journals - perhaps Springer should make a rapid move in this area and start the first all-electronic journal abstracting this type of literature. However, even the paper citation journals are starting to pay attention to the medium. The particular advantages of all-electronic publishing are beginning to emerge more clearly and it is clear that publishing video material is a unique advantage of our format. Several papers took advantage of this - for example those by Riehle and others on cell behaviour in tunnels, by Bereiter-Hahn and Voss on zonation in the plasmalemma and by Pavlikova, Zicha, Chaloupkova and Vesely on cell motility of tumour cells. These papers made essential and extensive use of video material, publishing some material of great originality. The work on cell pola rity and calcium ions in Fucus embryos by Brownlee, Manison and Anning used animation to present their results in an especially clear way. The facility of use of animation is another special advantage of our type of publication that should be more widely used."

This section will consider the structure and function of muscle receptors, as well as the central nervous system mechanisms with which they are concerned. In volume I of this Handbook, receptor mechanisms are discussed in detail. Also, the crustacean stretch receptor and the frog muscle spindle have been considered. The present section will be concerned with vertebrate muscle receptors with an emphasis on mammals. Muscle receptors provide interesting examples of specialized mechanorecep tors. The muscle spindle is a striking case of a receptor which is regulated in its function by the central nervous system in efferent neurons. Muscle receptors have long been known to playa crucial role in the reflex regulation of movement. In recent years it has become apparent that these receptors are also important in sensory phenomena such as the perception of position and movement. St. Louis, July 1974 c.c. HUNT Contents Chapter I The Morphology of Muscle Receptors. By D. BARKER. With 99 Figures . . . . . . . . . . . . . . . .. 1 Chapter II The Physiology of Muscle Receptors. By C.C. HUNT. With 21 Figures . . . . . . . . . . . . . . . . . 191 Chapter III Central Actions of Impulses in Muscle Afferent Fibres. By A. K. McINTYRE. With 8 Figures 235 Author Index 289 Subject Index 299 List of Contributors BARKER, David Department of Zoology, University of Durham, Science Laboratories, South Road, Durham DH1 3LE, Great Britain HUNT, Carlton C. Department of Physiology and Biophysics, Washington University, School of Medicine, 660 South Euclid Avenue, St. Louis, Mo. 63110, USA McINTYRE, A. K."

In 1976, when Springer-Verlag commissioned Professors Giebisch, Tosteson, and Ussing to edit what was destined to become a monumental five-volume Handbuch (" Membrane Transport in Biology", 1978 [Vols I, II, III] and 1979 [Vols IV A, B]), the subject of transepithelial secretion was still in its infancy. Not surprisingly, therefore, their Handbuch concentrated mainly on trans- epithelial absorption, although substantial chapters dealing with some secre- viz. "Ion Transport Across the Choroid Plexus" tory organs were included, (by E. M. Wright), "Sweat Glands" (by J. H. Thaysen), "Lacrimal Gland" (by J. H. Thaysen) and "Transport Across Insect Excretory Epithelia" (by J. P. H. Maddrell) in Volume III and "Transport in Salivary and Salt Glands" (by J. A. Young and E. W. Van Lennep), "Gastric Secretion" (by T. E. Machen and J. G. Forte), "Transport Processes in the Exocrine Pan- creas" (by I. Schulz and K. J. Ullrich), and "Transport of Ions in Liver Cells" (by M. Claret) in Volume IVB. The publication in 1977 of the seminal paper of Silva and his colleagues on the mechanism of secretion of salt and water in the salt excreting gland of the dogfish (American Journal of Physiology 233, F298-F306, 1977) provided physiologists with their first real insight into the mechanisms underlying transepithelial fluid secretion, however, and, in the ensuing years, interest in the topic has exploded as is evidenced by the numerous international symposia on exocrine secretion held since that date.

Since the endothelium plays such an important role in the pathophysiology of the circulatory system, the readers attention is directed here towards the possible involvement of these polypeptides in the aetiology of ischaemic heart disease, cerebrovascular accidents, hypertension, atherosclerosis and renal failure.

Skeletal muscle consumes significant amounts of oxygen, and its oxygen flux increases significantly under conditions of exercise and muscle contraction. This makes the muscle vulnerable to oxidative stress since concomitantly with the increase of oxygen flow there is an increase of free oxygen radicals which are a byproduct of muscle respiration. A number of studies in the last decade have documented the involvement of free oxygen radicals in exercising muscles. The consequences of muscle oxidative stress have resulted mainly in increased muscle protein oxidation, elevation of lipid peroxidation, and depletion of muscle antioxidants. The mechanisms of this oxidative stress are under extensive investigation in laboratories around the world and are topics of the chapters in this volume. This book is intended for professionals who are interested in muscle function, physiology, pathophysiology and well-being, such as therapists, trainers and medical professionals as well as for researchers in the field of muscle physiology.

Despite major efforts by the scientific community over the years, our understanding of the pathogenesis or the mechanisms of injury of multiple sclerosis is still limited. Consequently, the current strategies for treatment and management of patients are limited in their efficacy. The mechanisms of tissue protection and repair are probably even less understood. One reason for these limitations is the enormous complexity of the disease and every facet of its pathogenesis, the mechanisms of tissue injury, the diagnostic procedures and finally the efficacy of treatments and their side effects. The aim of this book is to review the most recent advances made in this highly complex field.

A new presentation of physiological regulatory mechanisms and therapeutic applications is given in this book. It represents a collection of the most up-to-date information in cholecystokinin (CCK) research, especially focusing on the development and characterization of CCK antagonists. The book contains chapters on the synthesis, biochemical and pharmacological characterization of potent and selective CCK antagonists as well as physiological applications of these compounds. The last section of the book is devoted to the involvement of CCK in pathological states and potential clinical applications of CCK antagonists.

One of the prerequisites for survival is the ability of cells to maintain their volume. Thus, during the course of evolution cells have "learned" a variety of strategies to achieve volume homeostasis. This volume regulatory machinery involves regulation of both, cellular metabolism and cellular transport and is exploited by hormones and transmitters to regulate cellularfunction. This book to illustrates the complex interplay of cell volume regulatory mechanisms and cellular function in a variety of tissues. However, our knowledge is still far from being conclusive, and the present collection of reviews is thought to foster further experimental efforts to unravel the role of cell volume in the integrated function of cells.

The authors, all accomplished and world-renowned experts in their topic areas, have provided controversial and up-to-date accounts of the current status of research in calcium and bone metabolism by reviewing major areas of basic science which have an impact on the understanding of bone diseases and related disorders.

Idiopathic cardiomyopathy has been categorized for over 10 years by the World Health Organization as dilated, hypertrophic, or restrictive. These categories have somewhat vague boundaries; however, idiopathic dilated cardiomyopathy (IDC) finds its general definition from unexplained four-chamber dilatation, prominent systolic dysfunction with depressed ejection fraction, a marked increase in total myocardial mass without wall thickening, myocyte hypertrophy and nuclear polyploidy, rarity of frank myocardial scars, but increased interstitial connective tissue and myocyte atrophy, all in the setting of anatomically normal heart valves and coronary arteries. Mural thrombi within cardiac chambers and atrioventricular valve regurgitation are common secondary con- comitants. Myocardial inflammation is rare, but immunological abnormalities have been suggested. Ultrastructural features in- clude increased mitochondrial numbers, lipid deposits, and myo- fibrillar loss. Progressive pump failure with or without rhythm disturbances typically leads to ever-intensified medical therapies, and ultimately to transplantation or early death. The need for better understanding of IDC is represented by incidence rates varying from 5 to 8/100000 population across several populations, 10 000-20000 IDC deaths annually in the United States, and the generally increasing prevalence of the disease. More than 50% of heart transplant recipients have IDC as their primary myocardial disease. The half-life of patient sur- vival without transplantation is generally less than 5 years. Treat- ment with antiarrhythmics, calcium channel blockers, ~-adrenergic blockers, and angiotensin-converting enzyme inhibitors is being evaluated in clinical trials, but the role of such treatments in the pathobiology of progressive disease is unclear.

Sympathetic afferent fibers originate from a visceral organ, course in the thoracolumbar rami communicantes, have cell bodies located in dorsal root ganglia, and terminate in the gray matter of the spinal cord. Sympathetic afferent fibers from the heart transmit information about noxious stimuli associated with myocardial ischemia, i. e. angina pectoris. Previous reviews have described the characteristics of cardiovascular sympathetic afferent fibers (Bishop et al. 1983; Malliani 1982). This review summarizes that work and focuses on the neural mechanisms underlying the complexities of angina pectoris. In order to understand anginal pain, cells forming the classical pain pathway, the spinothalamic tract (STn, were chosen for study. These cells were chosen to address questions about anginal pain because they transmit nociceptive informa of pain. Antidromic tion to brain regions that are involved in the perception activation of STT cells provided a means of identifying cells involved with trans mission of nociceptive information in anesthetized animals. Other ascending pathways may also transmit nociceptive information, but many studies show that the STT plays an important role. Visceral pain is commonly referred to overlying somatic structures. The pain of angina pectoris can be sensed over a wide area of the thorax: in the retrosternal, precordial anterior thoracic, and anterior cervical regions of the chest; in the left or sometimes even the right shoulder, arm, wrist, or hand; or in the jaw and teeth (Harrison and Reeves 1968)."