Handbook of Experimental Pharmacology Volume 117 Editorial Board G.V.R. Born, London P. Cuatrecasas, Ann Arbor, MI D. Ganten, Berlin H. Herken, Berlin K.L. Melmon, Stanford, CA Springer Berlin Heidelberg New York Barcelona Budapest Hong Kong London Milan Paris Tokyo Diuretics Contributors o.s. Better, A. Busch, J. D(ljrup, H. Endou, R. Greger W.G. Guder, M. Hosoyamada, M. Hropot, B. Kaissling T.R. Kleyman, H. Knauf, F. Lang, H.-J. Lang, W. Mohrke E. Mutschler, T. Netzer, L.G. Palmer, J.B. Puschett I. Rubinstein, M. Schmolke, F. Ullrich, K.J. Ullrich H. Velazquez, J. Winaver Editors R.F. Greger, H. Knauf and E. Mutschler , Springer Professor Dr. med. RAINER F. GREGER Physiologisches Institut der Albert-Ludwigs-UniversiHit Freiburg Hermann-Herder-Str. 7 D-79104 Freiburg, Germany Professor Dr. med. H. KNAUF St. Bernward Krankenhaus Hildesheim Medizinische Klinik I Gastroenterologie-Kardiologie-N ephrologie Treibestr. 9 D-31134 Hildesheim, Germany Professor Dr.rer.nat. Dr. med. E. MUTSCHLER Pharmakologisches Institut fUr Naturwissenschaftler Biozentrum Niederursel Gebiiude N 260, Marie-Curie-Str. 9 D-64271 Frankfurt, Germany With 164 Figures and 32 Tables ISBN-13:978-3-642-79567-1 e-ISBN-13:978-3-642-79565-7 DOl: 10.1007/978-3-642-79565-7 Library of Congress Cataloging·in-Publication Data. Diuretics/contributors, O.S. Better ... let al.]; editors, R.F. Greger, H. Knauf, and E. Mutschler. p. cm. - (Handbook of experimental pharmacology; v. 117) Includes bibliographical references and index. ISBN-13:978-3-642-79567-I 1. Diuretics. I. Better, O.S. II. Greger, Rainer. III. Knauf, H. IV. Mutschler, Ernst. V. Series. [DNLM: 1. Diuretics. WI HA51L v. 117 1995/QV 160 D6171 1995] QP905.H3 vol. 117 [RM377] 615'.1 s - dc20 [615'.761] DNLMIDLC for Library of Congress 95-3116 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other ways, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1995 Sof tcover reprint of the hardcover I st edition 1995 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publisher cannot guarantee the accuracy of any information about dosage and applica­ tion contained in this book. In every individual case the user must check such information by consulting the relevant literature. Typesetting: Best-set Typesetter Ltd., Hong Kong SPIN: 10478734 27/3136/SPS - 5 4 3 2 1 0 - Printed on acid-free paper Preface The first edition of this handbook appeared exactly twenty-five years ago. Due to enormous changes in the area of diuretics, the second edition has had to be completely revised. Substantial progress has been made in the functional anatomy of the kidney and in the concepts of how substances and ions are specifically transported across the various nephron segments. No one could have foreseen twenty-five years ago that the late 1980s and the early 1990s have provided us with methodologies to study transport events not only at the single cell level, but even at the level of the single transporter molecule. Many of the transporters for ions and organic substances have been cloned meanwhile by the new methods of molecular biology, and their function can be described more precisely by new transport studies such as the patch-clamp technique. These new insights have also led to a new understanding of how the currently used diuretics act. Just a few months ago, the Na+Cl- co-transporter, which is the target of thiazides, the Na+2CI-K+ co-transporter, which is the target of furosemide, and the amiloride sensitive Na+ channel were cloned. Hence, the targets of diuretics have now been identified at the molecular level. In addition, during the past twenty-five years extensive studies have been performed on the pharmacokinetics of diuretics. We have learned how changes in liver metabolism and altered renal excretion influence the pharmacology of this class of compounds. Most recent studies have also focused on the transport of diuretics in the proximal nephron and tell us more about the kidney selectivity of these substances and this specific aspect of pharmacokinetics. Enormous clinical experience, together with our new understanding of the mode of action, has had a major impact on the usage of diuretics. For instance, high dosages of thiazides, which previously were used in the treatment of hypertension, are now regarded as unacceptable and much lower doses have been shown to be equally effective but do not induce comparable side effects. Intentionally, a major focus of the second editon is on basic mech­ anisms: functional anatomy, the physiological and biochemical processes involved in kidney function, metabolism, and the transport of diuretics. Furthermore, the specific chapters dealing with the most frequently used VI Preface groups of diuretics provide a comprehensive update, and the final chapter discusses the clinical use of diuretics as from this year's prospective. We would like to thank Prof. H. Herken, the editor of the first edition, who helped us with the concept of this second edition, and we are very grateful to all the authors for their expert contributions. Finally, we would also like to thank the publisher for its most competent co-operation. Freiburg R. GREGER Hildesheim H. KNAUF Frankfurt E. MUTSCHLER March 1995 List of Contributors BEITER, O.S., Dr. Rebecca Chutick Crush Syndrome Center and Depart­ ment of Physiology and Biophysics, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, POB 9649, Haifa 31096, Israel BUSCH, A., Physiologisches Institut, UniversiHit Tiibingen, GmelinstraBe 5, 0-72076 Tiibingen, Germany D0RUP, J., Department of Cell Biology, Institute of Anatomy, University of Aarhus, DK-8000 Aarhus, Denmark ENDou, H., Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181, Japan GREGER, R., Physiologisches Institut der Albert-Ludwigs-Universitat, Hermann-Herder-Str. 7,0-79104 Freiburg, Germany GUDER, W.G., Institut fUr Klinische Chemie, Stadtisches Krankenhaus Miinchen-Bogenhausen, Englschalkinger StraBe 77, 0-81925 Miinchen, Germany HOSOYAMADA, M., Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181, Japan HROPOT, M., Hoechst AG, Herz/KreislaufTherapeutika, FB Pharmakologie, H 821, 0-65926 Frankfurt, Germany KAISSLING, B., Anatomisches Institut der Universitat, Winterthurerstr. 190, CH-8057 Ziirich, Switzerland KLEYMAN, T.R., Department of Medicine, Renal-Electrolyte Division, University of Pennsylvania School of Medicine, 700 Clinical Research Building, 422 Curie Boulevard, Philadelphia, PA 19104, USA KNAUF, H., St. Bernward Krankenhaus Hildesheim, Medizinische Klinik I, Gastroenterologie-Kardiologie-Nephrologie, Treibestr. 9, 0-31134 Hildesheim, Germany VIII List of Contributors LANG, F., Physiologisches Institut, UniversiHit Tiibingen, GmelinstraBe 5, D-72076 Tiibingen, Germany LANG, H.-J., Hoechst AG, Herz/Kreislauf Therapeutika, FB Pharmakologie, H 821, D-65926 Frankfurt, Germany MOHRKE, W., Procter & Gamble Pharmaceuticals, Dr. Otto-Rohm-Str. 2-4, D-64331 Weiterstadt, Germany MUTSCHLER, E., Pharmakologisches Institut fUr Naturwissenschaftler, Biozentrum Niederursel, Gebaude N260, Marie-Curie-Str. 9, D-60439 Frankfurt, Germany NETZER, T., E. Merck, Klinische Forschung und Entwicklung Deutschland 1, D-64271 Darmstadt, Germany PALMER, L.G., Department of Physiology and Biophysics, Cornell University Medical College, 1300 York Avenue, New York, NY 10021, USA PUSCHETT, J.B., Department of Medicine SL 12, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112-2699, USA RUBINSTEIN, I., Dr. Rebecca Chutick Crush Syndrome Center and Depart­ ment of Physiology and Biophysics, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, POB 9649, Haifa 31096, Israel SCHMOLKE, M. Institut fUr Klinische Chemie, Stadtisches Krankenhaus Miinchen-Bogenhausen, Englschalkinger StraBe 77, D-81925 Miinchen, Germany ULLRICH, F., Du Pont Pharma GmbH, Du Pont StraBe 1, D-61352 Bad Homburg, Germany ULLRICH, K.J., Max-Planck-Institut fUr Biophysik, Kennedyallee 70, D-60596 Frankfurt, Germany VELAZQUEZ, H., Research Office (151), Department of Veterans Affairs Medical Center, 950 Campbell Avenue, West Haven, CT 06516, USA WINAVER, J., Dr. Rebecca Chutick Crush Syndrome Center and Department of Physiology and Biophysics, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, POB 9649, Haifa 31096, Israel Contents CHAPTER 1 Functional Anatomy of the Kidney B. KAISSLING and J. D0RUP. With 20 Figures. 1 A. Structural Organization ofthe Kidney. 1 I. Microanatomy of the Kidney . 1 1. Nephron........................................... 1 2. Cortex............................................. 4 3. Medulla ........................................... 4 4. Kidney Size ..