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.

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.

Contents Introduction .......................................... . 1 The Primate Eye ...................................... . 2 Embryology of Retina and Choroid ....................... . 4 Microscopic Anatomy .................................. . 4 Retina ............................................ . 4 Choroid ........................................... . 8 Material and Methods .................................. . 10 Fine Structure of the Retina 14 RetinaI Pigment Epithelium ............................. . 16 Photoreceptor Cells ................................... . 30 Outer Plexiform Layer and Horizontal Cells .................. . 64 Bipolar, Radial Clial, and Amacrine Cells .................... . 76 Canglion Cells and InternaI Limiting Membrane ............... . 98 Spatial Density of RetinaI Cells .......................... . 112 Fine Structure of the Choroid ........................... . 116 Choroidocapillaris and Its Fiber System ..................... . 118 Arteries, Veins, and Lymphatic Spaces ...................... . 134 Choroidal Nerves .................................... . 142 Cells of Choroidal Connective Tissue ....................... . 148 References ........................................... . 153 Index ................................................ . 157 vii This volume describes the morphology of the primate re tina as seen with the electron microscope. As it is an atlas, the electron micrographs are its most In trad lietian important part. The text accompanies the figures, highlighting selected topics either to explain structures or to point out structure-function relation ships. A scholarly review of the whole spectrum of research on the re tina and choroid is not feasible in a single volume. Thus, whenever available, review artides or monographs, rather than original work, are cited for reference."

Stability of the internal environment in which neuronal elements are situated is unquestionably an important prerequisite for the effective transmission of information in the nervous system. During the past decade our knowledge on the microenvironment of nerve cells has expanded. The conception that the microenvironment of neurones comprises a fluid with a relatively simple and stable composition is no longer accepted; the microenvironment is now envisaged as a dynamic structure whose composition, shape, and volume changes, thereby significantly influencing neuronal function and the trans mission of information in the nervous system. The modern conception of the neuronal microenvironment is based on the results of research over the last 20 years. The extracellular space (ECS) is comprehended not only as a relatively stable microenvironment containing neurones and glial cells (Bernard 1878), but also as a channel for communica tion between them. The close proximity of the neuronal elements in the CNS and the narrowness of the intercellular spaces provides a basis not only for interaction between the elements themselves, but also between the elements and their microenvironment. Substances which can cross the cell membranes can easily find their way through the microenvironment to adjacent cellular elements. In this way the microenvironment can assure non-synaptic com munication between the relevant neurones. Signalization can be coded by modulation of the chemical composition of the ECS in the vicinity of the cell membrane and does not require classic connection by axones, dendrites, and synapses.

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)."

The details of the receptor mechanism are not yet fully understood for any sensory system. However, sufficient data are available (for the vestibular system and for other systems) to permit meaningful tracking of the sensory messages through the nervous system and via conscious experience. The reception, process ing, storage and output of information in man and other animals, as done by means of receptors, neurons, secretory cells and muscle fibers, are collectively referred to as mind. Sensory physiologists tend to disbelieve in extrasensory perception. Sensory physiology in general is an area upon which different sciences and methods converge. Anatomists, physiologists, psychologists, physicists, chemists, and engineers have made important contributions to sensory physiology. What is special about vestibular physiology is the fact that many research workers are clinicians, living under the constant pressure of their patient's demands. This is a disadvantage when it comes to writing handbooks, but an advantage for the pa tient, since research is guided by clinical practice and can be quickly applied. Modern methods, such as recording from single nerve units and the correlation of electrophysiological and psychophysical data, have greatly contributed to our knowledge, yet the study of lesions is still important, especially in the vestibular field."

Modern Methods of Plant Analysis When the handbook Modern Methods of Plant Analysis was first introduced in 1954 the considerations were: 1. the dependence of scientific progress in biology on the improvement of existing and the introduction of new methods; 2. the difficulty in finding many new analytical methods in specialized journals which are normally not accessible to experimental plant biologists; 3. the fact that in the methods sections of papers the description of methods is frequently so compact, or even sometimes so incomplete that it is difficult to reproduce experiments. These considerations still stand today. The series was highly successful, seven volumes appearing between 1956 and 1964. Since there is still today a demand for the old series, the publisher has decided to resume publication of Modern Methods of Plant Analysis. It is hoped that the New Series will be just as acceptable to those working in plant sciences and related fields as the early volumes undoubtedly were. It is difficult to single out the major reasons for success of any publication, but we believe that the methods published in the first series were up-to-date at the time and presented in a way that made description, as applied to plant material, complete in itself with little need to consult other publications. Contributing authors have attempted to follow these guidelines in this New Series of volumes.

Advances in Compararative and Environmental Physiology helps biologists, physiologists, and biochemists keep track of the extensive literature in the field. Providing comprehensive, integrated reviews and sound, critical, and provocative summaries, this series is a "must" for all active researchers in environmental and comparative physiology. Cellular volume and osmolality in animals is a well studied topic and this specific volume in the series provides the reader with a thorough grounding in this area of physiology. Consisting of two parts, the text discusses osmolality and volume control in terms of both inorganic and organic ions which as a result gives an excellent overview to those working and interested in this field.

After the pioneering studies by Ussing and co-workers, studies of epithelial Nael transport have come a long way. The first phase of the phenomenological description of the cell as a black box has been follow ed by studies of cellular mechanisms, the interplay of the different trans port components, and the mechanisms of regulation. A broad spectrum of methods has been applied to many epithelia in a variety of species. For the individual epithelia transport schemes have been proposed, and, at this point I think it is appropriate to take a pause and search for elements common to several epithelia. This aspect triggered the publica tion of this book, and in fact the various chapters emphasize that the funetional eomponents, expressed in the various epithelia, are not in finite in number, but they occur in epithelia which are separated in evolu tion by several hundred million years. The authors come both from the field of veterinary and human physiology as weIl as from biology. In my opinion, the close contacts and eollaborations between physiologists and biologists have been essential for the progress in this field. I wish to thank all authors for their con tributions, and I hope that the reader will appreciate this collection of up to date reviews on epithelia in nonvertebrates and vertebrates."

Coronary heart disease is one of the major health problems in indus trialized nations because of its high incidence and severity. Recent innovations in medical and surgical treatment of coronary heart dis ease have increased the importance of accurate diagnostic methods for determining the severity of coronary disease, identifying potential treatment alternatives, and evaluating the results of treatment. Great advances have also been made in basic research on coronary circula tion and its interaction with myocardial contraction and relaxation and neural and humoral control. With respect to these developments, the papers included in the present monograph deal with important topics concerned with the basic mechanism of coronary circulation as well as ones of clinical relevance. It is directed toward physicians (cardiologists, cardiac surgeons, cardiac radiologists, anestheologists, and others) and basic scientists (e.g., physiologists, bioengineers). We would like to em phasize the importance of a multidisciplinary approach in which basic scientists and clinicians work closely together. This volume consists of nine chapters. Chapter 1 contains macro scopic and microscopic descriptions of coronary vascular anatomy, which is closely related to the functions of coronary circulation. In Chap. 2 two methods in current use to evaluate phasic coronary blood velocity waveforms are presented, i.e., the laser Doppler and ultrasound Doppler methods. Chapter 3 describes the mechanical properties of coronary circulation, a knowledge of which is indispens able for an understanding of coronary arterial and venous blood flow velocity waveforms in relation to cardiac contraction and relaxation."

The development of a new antiarrhythmic drug involves many people with disparate skills. The organic chemist who makes it is guided not only by the structure-action relations of previous compounds, but by anticipation of a requirement for a particular type of action. In fact several of the best-known antiarrhythmics, including lidocaine, mexiletine, amiodarone and verapamil, were originally synthesized for other purposes. Physicians have to determine whether the new drug works, and pharma cologists how it works. For some years I have believed that there was room for a work which could be understood by all these groups and which could enlighten each about the point of view of the others. Thus when I was invited by Springer-Verlag to prepare a volume in their series Handbook of Experimental Pharmacology, I already had a firm conception of what its form should be. In any multi-author work there are two objectives which cannot always readily be reconciled. The first is to select topics which would relate to each other in a coherent manner. to give a logical and orderly shape to the volume as a whole. The second is to offer authors the greatest possible freedom to express themselves as they wish. When the general design was complete, prospective contributors were invited to write specific chapters, being provided with a complete list of their coauthors and chosen topics, so that they could avoid overlap."

This volume contains the lectures presented at the NATO Advanced Study Institute (ASI) on "Trafficking of Intracellular Membranes: From Molecular Sorting to Membrane Fusion", held in Espinho, Portugal, from June 19 to June 30,1994. The objective of this Institute was to survey recent developments and to discuss future directions in the rapidly advancing field of membrane cell biology, with particular emphasis on the dynamical properties and intracellular flow of membranes. A wide range of interrelated topics around the central theme of intracellular trafficking of membranes was covered, including lipid flow, membrane fusion, dynamics of membrane components, protein folding and assembly, vesicular transport in membrane biogenesis, exocytosis and endocytosis. A large variety of experimental techniques and systems, including the application of viruses and model systems, to study these processes was also considered. Membrane cell biology is a broad discipline which encompasses many scientific areas including cell biology, biochemistry, biophysics, virology, immunonology and genetics. Indeed, recent advances in the cell biology of membranes could not have been made without this multidisciplinary approach. Significant progress achieved during the last few years in understanding how newly synthesized lipids and proteins find their way to the cell organelles, how molecular sorting and the continuous flow of membranes allow each cellular membrane to maintain its own distinct molecular composition, and, thereby, the individuality of the various intracellular compartments, was discussed in considerable detail in this Institute.

This book attempts to present new aspects on electrophysiologi- cal mechanisms and catecholaminergic contributions in the set- ting of acute and chronic myocardial ischemia. Special emphasis is placed on the full scope from basic molecular and cellular mechanisms to experimental models of close clinical proximity. A number of internationally distinguished scientists present their latest findings in this significant research area within the peri- meter of cardiovascular disease which continues to lead mortality statistics in most industrialized countries. Contents of this book cover in addition to other subjects re- lease and uptake of catecholamines in ischemia, regulation of re- ceptors, adrenergic contribution to ventricular arrhythmias and mechanisms of ischemic malignant arrhythmias as well as un- derlying changes in membrane currents and the electrophysiolog- ical response to beta-adrenergic blocking drugs. In addition to original contributions, a number of editorial chapters are in- cluded for conclusions and future development in these areas. The main purpose of this book is to provide further inside in two traditionally separated research topics that are gravitating to more collaborative work and inspire more joint research ventures in the future. It provides a comprehensive view on clinically sig- nificant problems where basic research may stimulate further studies in man. Therefore this book may prove to be valuable to both cardiologists and interested clinicians as well as basic scien- tists.

A qualitative leap in the understanding of cardiovascular and n- ral regulation by the renin-angiotensin system, and of the role of this s- tem in tissue damage, has occurred as a result of the many recent advances in molecular genetic techniques. The cloning of the genes for the components of the renin-angiotensin system, the design of specific angiotensin receptor ligands, and the use of embryonic gene targeting te- niques for the creation of mutant strains have established that the renin- angiotensin system is important in blood pressure regulation, ion and fluid homeostasis, and tissue growth and remodeling Further investigation of the mechanisms by which this system p- ticipates in cardiovascular regulation may shed some light on the pat- genesis of several cardiovascular diseases, e. g. , hypertension, congestive heart failure, and chronic renal failure. Despite the promise of this system as a target for therapeutic interventions for these diseases, there are great challenges in the integration of the attempts to close the gap between the traditional literature of medicine and the explosion of information from the new technologies. This book's title, Angiotensin Protocols, reflects the authors' strong efforts to translate expert knowledge into easy-to-follow practice. The book opens with introductory chapters, and each specialty section provides detailed methods covering a wide variety of techniques, ranging from genetic manipulation of targeted genes to functional studies of the renin- angiotensin system.

The Editorial Board and the Publishers of the Handbook of Experimental Pharmacology wish to express their profound grief at the untimely death of Professor Peter Baker. Aware of his international recognition as an expert on the ubiquitous role of calcium in physiological processes and their pharma cological control, the Board was gratified when Professor Baker accepted its invitation to edit a new Handbook volume on "Calcium in Drug Actions". He went about this task with his usual energy and effectiveness so that, in the few months before his unexpected death, Professor Baker had mustered his distinguished contributors, got them to provide their manuscripts, and seen almost the entire material into the press. This achievement is all the more remarkable when one bears in mind the extraordinary number of his other commitments during the same time; they are mentioned in Sir Alan Hodgkin's preface to this volume. With so many other professional and personal responsibilities upon him, the Board of the Handbook wishes to record its grateful appreciation for the admirable way in which Professor Baker took on and carried out the additional work of bringing this fine book into existence; and the Board wishes it to be dedicated to the memory of Professor Peter Frederick Baker. The Editorial Board: G. V. R. BORN, P. CUATRECASAS, H. HERKEN, A.

The need for greater international collaboration is becoming increas. ingly clear. Practically every nation or people has, in addition to its own characteristics and history, its own medical tradition. Methods and ways of thinking that are successfully established in one place may not be accepted in another for some time. The medical tradition and training in different countries can take quite different forms. What would our present knowledge be - Without the creative, spontaneous ideas and contributions from the romance countries? - Without the opportunity of research, as it is practised on a large scale in the USA, where so many young Europeans took their first steps in experimental science? - Without the conscientious clinical work done in Central Europe and the valuable experience gained there? - Without, finally, the sober and critical scientific approach, as fostered in the cool heads of Northern Europe for generations? None of these qualities is sufficient without the others, but together they are a source of strength. Ultimately, we hope, through sensible con centration of efforts (while maintaining variety), to overcome the lack of an integrated approach in experimental science and to prevent repetition of painful mistakes. In this regard, the first two ESKA congresses have brought us great advances."

Mitochondrial transport systems are essential to mitochondrial function and therefore to energy homeostasis within the cell.
The book contains studies utilizing the techniques of biochemistry, physiology, molecular biology and genetics to reveal the structure and function of mitochondrial transport systems.
It is divided into the following six sections:
- Proton Translocation: The Uncoupling Protein and the ATPase; - Carriers and Transporters; - Mitochondrial Ion Channels; Structure of the Outer Mitochondrial Membrane Channel, VDAC; - VDAC, Peripheral Kinases and Energy Utilization; - Mitochondrial Channels in Humans and Relationship to Disease.

Together with the two previous volumes of the Handbook of Experimental Pharmacology on histamine and antihistamines the present publication yields a picture of a still rapidly developing field of research. New techniques and new experimental approaches have brought us new knowledge and deeper insight into the biomedical significance of histamine, even if many questions remain to be answered about the functional and medical implications of this old biogenic amine. The present volume covers the progress in histamine research during the past two decades. A significant chapter concerns techniques for histamine determination. As the result of a consensus meeting in Munich in December 1988, a panel of eminent specialists arrived at common recommendations as to the usefulness of the available histamine assays for the most common experimental biomedical conditions. The heterogeneity of mast cells, with great differences in their reactivity to various stimuli, has become apparent, not only among species but also among the tissues of a species. New informa tion is presented about the mechanism of exocytosis. The old questions about the role of histamine in the mechanism of gastric secretion and in cardio vascular and respiratory functions have been studied with new techniques, and the role of HI and H2 receptors discussed. New observations have been made on the occurrence and possible functions of histaminergic neurons and histamine receptors in CNS where a new type of receptor, the H, seems to 3 be widely represented."

Rhythms are a basic phenomenon in all physiological systems. They cover an enormous range of frequencies with periods from the order of milliseconds up to some years. They are described by many disciplines and are investigated usually in the context of the physiology of the respective function or organ. The importance given to the research on rhythmicity is quite different in different systems. In some cases where the functional significance is obvious rhythms are at the center of interest, as in the case of respiration or locomotion. In other fields they are considered more or less as interesting epiphenomena or at best as indicators without essential functional significance, as in the case of cardiovascular or EEG rhythms. Recently the study of physiological rhythms has attracted growing interest in several fields, especially with respect to rhythm research in humans and its rapidly spreading applications in basic behavioral research, and as a diagnostic tool in clinical medicine. This development was favored by two methodological and conceptual ad vances: on the one hand, the availability of non-invasive methods of continu ous recording of physiological parameters and their computer-assisted evaluation, and on the other, the rapid development of theoretical analyses, for example, the understanding of dynamic systems, the generation of coordinated macroscopic pro cesses in systems comprising many single elements, and the mathematical tools for treating nonlinear oscillators and their mutual coupling.

Understanding the mechanisms involved in intracellular movement and localization of proteins is a central issue in cell biology. This volume is concerned with the events involved in the transport of membrane proteins, and the contents of vesicular compartments, to their ultimate destinations. In several chapters, particular attention is given to studies with viruses that are assembled by budding at specific membrane sites within the cell or at the cell surface; studies with such viral systems have provided significant insights into membrane biogenesis.

This book is dedicated to the memory of Walter Brendel, late Professor of Experimental Surgery and Chairman of the Institute for Surgical Research at the University of Munich, Germany. For 20 years Walter Brendel organized the renowned Round Table Symposium on Applied Immunology, first in Kitzbiihel and later in Axams, Austria. On the occasion of the 20th symposium in January 1989 he gathered together a number of scientists who have been leaders in the field of transplantation immunology and clinical transplantation for the past two decades. All of them had participated at previous meetings, some on a regular basis. Many of the new discoveries in applied immunology and transplantation medicine were first presented and vividly dis cussed at the Round Table Symposia. The annual Kitzbiihel! Axams meetings became well-known and invitations much sought after, not only for this reason but also because of the uniquely intimate atmosphere that promoted the free exchange of research findings and theoretical cut and thrust.

Catecholamines are important transmitter substances in the autonomic and central nervous systems. These two volumes provide a comprehensive presentation of the state-of-the-art of catecholamine research and development in the past 15 years. The volumes present in-depth reviews of topical areas of catecholamine research in which substantial progress has been made and which are of current interest to various theoretical and clinical disciplines. Each topic has been dealt with by an established expert. Clinical subjects of relevant importance are included. Catecholamines are of interest in pharmacology, physiology, biochemistry, as well as in neurology, psychiatry, internal medicine (cardiology, hypertension, asthma), ophthalmology and anesthesiology.