Salt and Water Balance. Proceedings of The Third International Pharmacological Meeting July 24–30, 1966 PDF
Preview Salt and Water Balance. Proceedings of The Third International Pharmacological Meeting July 24–30, 1966
PROCEEDINGS OF THE FIRST INTERNATIONAL PHARMACOLOGICAL MEETING STOCKHOLM, 22-25 AUGUST, 1961 Vol. 1 Part 1: Plenary Session Part 2: Pharmacological Control of Release of Hormones Including Antidiabetic Drugs Vol. 2 Effects of Drugs on Synthesis and Mobilization ofLipids Vol. 3 New Aspects of Cardiac Glycosides Vol. 4 Drugs and Membranes Vol. 5 Methods for the Study of Pharmacological Effects at Cellular and Subcellular Levels Vol. 6 Metabolic Factors Controlling Duration of Drug Action Vol. 7 Modern Concepts in the Relationship between Structure and Pharmacological Activity Vol. 8 Pharmacological Analysis of Central Nervous A ction Vol. 9 Part 1: Bradykinin and Vaso-dilating Polypeptides Part 2: Pharmacology of the Lung Vol. 10 Abstracts PROCEEDINGS OF THE SECOND INTERNATIONAL PHARMACOLOGICAL MEETING, PRAGUE, 20-23 AUGUST, 1963 Vol. 1 Pharmacology of Conditioning, Learning and Retention Vol. 2 Biochemical and Neurophysiological Correlation of Centrally A cting Drugs Vol. 3 Pharmacology of Cholinergic and Adrenergic Transmission Vol. 4 Drugs and Enzymes Vol. 5 Pharmacology of Cardiac Function Vol. 6 Pharmacology of Smooth Muscle Vol. 7 Pharmacology of Oriental Plants Vol. 8 Evaluation of New Drugs in Man Vol. 9 Recent Advances in the Pharmacology of Toxins Vol. 10 Oxytocin, Vasopressin and their Structural Analogues Vol. 11 Drugs and Respiration PROCEEDINGS OF THE THIRD INTERNATIONAL PHARMACOLOGICAL MEETING SAO PAULO, 24-30 JULY, 1966 Vol. 1 Mode of Action of Anti-parasitic Drugs Vol. 2 Pharmacology of Reproduction Vol. 3 Clinical Evaluation of Drugs Vol. 4 Mechanisms of Drug Toxicity Vol. 5 The Control of Growth Processes by Chemical Agents Vol. 6 Drugs in Relation to Blood Coagulation, Haemostasis and Thrombosis Vol. 7 Physico-chemical Aspects of Drug Action Vol. 8 Salt and Water Balance Vol. 9 Pharmacology and Pain Vol. 10 Monoamine Oxidase Inhibitors: Relationship between Pharmacological and Clinical Effects Vol. 11 Immunopharmacology ii Salt and Water Balance Edited by K. H. BEYER Merck, Sharp & Dohme Research Laboratories, West Point, Pa. Assistant Editor V. TRCKA Research Institute of Pharmacy and Biochemistry, Prague ooo ©©[MdiMiggd^ ^eiraciracif3«7 t JlSIlQllQllÖII 1 ^ -«axiiiiiajQiuir ij-1 IFl>mi^lf»ö^g@OjS)(§[l^l PERGAMON PRESS OXFORD · LONDON · EDINBURGH · NEW YORK TORONTO · SYDNEY · PARIS · BRAUNSCHWEIG Pergamon Press Ltd., Headington Hill Hall, Oxford 4 & 5 Fitzroy Square, London W.l Pergamon Press (Scotland) Ltd., 2 & 3 Teviot Place, Edinburgh 1 Pergamon Press Inc., 44-01 21st Street, Long Island City, New York 11101 Pergamon of Canada, Ltd., 6 Adelaide Street East, Toronto, Ontario Pergamon Press (Aust.) Pty. Ltd., 20-22 Margaret Street, Sydney, New South Wales Pergamon Press S.A.R.L., 24 rue des Ecoles, Paris 5e Vieweg & Sohn GmbH, Burgplatz 1, Braunschweig Copyright © 1968 Pergamon Press Ltd. First edition 1968 Library of Congress Catalog Card No. 67-19416 (3266/67) LIST OF AUTHORS AND PARTICIPANTS BAER, J. E. Merck Institute for Therapeutic Research, West Point, Pa., U.S.A. BAYLISS, R. I. S. Westminster Hospital and Medical School (University of London), London, U.K. BELLO, A. A. Centro de Investigaciones Cardiologicas, Facultad de Ciencias Medicas, Universidad de Buenos Aires, Argentina BEYER, K. H., Jr. Merck, Sharp & Dohme Research Labora- tories, West Point, Pa., U.S.A. CAHN, J. Center of Experimental Therapeutics, Labora- tory of Neurochemistry, Hospital la Pitie, Paris, France FARAH, A. Department of Pharmacology, State Univer- sity of New York, Upstate Medical Center, Syracuse, N.Y., U.S.A. HEROLD, M. Center of Experimental Therapeutics, Labora- tory of Neurochemistry, Hospital la Pitie, Paris, France MACHADO, M. University of Säo Paulo, Sao Paulo, Brazil MCNAY, J. L. Emory University School of Medicine, At- lanta, Ga., U.S.A. MÄHER, J. F. Department of Medicine, Georgetown Uni- versity School of Medicine, Georgetown University Hospital, Washington, D. C, U.S.A. MALNIC, G. Departamento de Fisiologia, Faculdade de Medicina, Universidade de Säo Paulo, Säo Paulo, Brasil O'CONNELL, J. M. BRIAN Department of Medicine, Georgetown Uni- versity School of Medicine, Georgetown Uni- versity Hospital, Washington, D.C., U.S.A. vii Vlll LIST OF AUTHORS AND PARTICIPANTS PEKKARINEN, A. Department of Pharmacology, Turku Uni- versity, Turku, Finland PETERS, W. Department of Pharmacology, University of Lausanne, Lausanne, Switzerland SCHREINER, G. E. Department of Medicine, Georgetown Uni- versity School of Medicine, Georgetown Uni- versity Hospital, Washington, D.C., U.S.A. SENFT, G. Department of Pharmacology, Freie Univer- sität Berlin, West Berlin TAQUINI, A. C. Centro de Investigaciones Cardiologicas, Fa- cultad de Ciencias Medicas, Universidad de Buenos Aires, Argentina WEINER, I. Department of Pharmacology, State Univer- sity of New York, Upstate Medical Center, Syracuse, N.Y., U.S.A. WIRZ, H. University of Basle and J. R. Geigy S.A., Basle, Switzerland YEYATI, N. Centro de Investigaciones Cardiologicas, Fa- cultad de Ciencias Medicas, Universidad de Buenos Aires, Argentina INTRODUCTORY REMARKS K. H. BEYER, JR. Merck, Sharp & Dohme Research Laboratories West Point, Pennsylvania, U.S.A. AT THE outset of this Symposium on Salt and Water Balance, I should like to introduce a few comments regarding its title and composition that need to be made and which, I hope, do not anticipate the primary assign- ments of the speakers. To any of you who have reflected on the title of the Symposium and the subject titles and speakers who make up the program, it should be clear that the subject of the Symposium is by no means covered by the titles of the papers. Indeed, to cover the subject of salt and water balance reasonably adequately we would need to design a series of symposia to run the course of this Third International Congress of Pharmacology. Moreover, we would need to invite our friends who are prominent in various phases of cardiac, vascular and extravascular physiology as well as nephrology at both a preclinical and a clinical level to lend perspective to this subject. Thus, for practical reasons, we are confined to a consideration of the modulation of renal functions by drugs that influences particularly salt and water excretion by the kidney, and to select an international group of speakers for this general subject. It is abundantly evident that with the advent of the thiazides almost 10 years ago the management of salt and water retention has been substantially improved from the point of view of both physician and patient alike. This is because the kidney, unlike any other organ, influences most profoundly the several electrolytes and water in the over-all maintenance of this fundamental aspect of homeostasis. It is also because these agents combined convenience of oral administration with a very practical order of potency, reliability and safety that was not available previously. The advantages and the shortcomings of these agents are so well known to the physician that we have elected to emphasize the preclinical attributes of other diuretics, some newer, some older. This is not to imply that there is unanimity among pharmacologists regarding the fundamental aspects of the thiazides, their mode and site of action in the nephron, their antihypertensive action, whether their effect on glucose 1 2 Κ. Η. BEYER, JR. tolerance in man is direct, or indirect, and whether some of the preclinical research along these lines has relevance to the clinical situation. I'm sure some of these matters will be treated in the discussions. The order of activity of the thiazides and the intermittent use of organo- mercurials, even when combined in therapy, did not suffice to impress on other than the most thoughtful physician what was going on in the main- tenance of the patient's homeostasis despite therapy. If the fluid retention were mild, or if the patient were hypertensive with little evidence of electrolyte retention, the homeostasis of the patient adjusted adequately to vagaries of dosage or frequency of administration. If the clinical condition were critical, and these drugs were inadequate to the need for therapy, they posed no great problem beyond the fear of toxicity from excessive use of the organomercurial or the excessive kaliuresis induced by the thiazides, especially in cirrhotic patients. Today, we have drugs such as ethacrynic acid (EDECRIN) and furosemide (LASEX) which extend useful diuretic therapy beyond what had been available until their introduction. When employed in mild cases of cardiac edema they are effective and their manifestations of overdosage are quali- tatively similar to those of the thiazides; attributable to dehydration and salt loss. When these same compounds are employed to their full advantage as lifesaving measures in critically ill patients, the physician must assume a greater responsibility for the clinical situation, for if the patient's ability to sustain his homeostasis were more than marginal he would not be so critically ill. His electrolyte and water balance deserve especial conside- ration. Most clinical conditions that indicate a need for diuretic therapy, even desperate ones, require only effective, not desperate, measures. The availa- bility of these agents has reaffirmed the fact that it is unwise to institute massive diuresis (except in pulmonary edema) to handle a situation where time and a less vigorous approach to the problem is adequate. To induce a definite hypovolemia briskly, with or without abnormal electrolyte balance, in a patient whose extravascular space and tissues are distended with fluid submits him to risks beyond his clinical disease and to which he may, or may not, accommodate. To submit a cirrhotic patient to massive diuresis is to invite consequences as dire as can be induced by a severe paracentesis. These examples could be multiplied and expanded, but they all lead to a few generalizations which bring me back to the opening comments in these introductory remarks. The modulation of renal control of electrolyte and water balance is INTRODUCTORY REMARKS 3 our most effective way of handling most clinical problems wherein fluid retention needs to be reduced. We have excellent agents with which to do this today. Some of these are even basic to hypertensive therapy; other recent ones extend the arm of therapy to salvage patients who could other- wise not be handled until the advent of these newer drugs. If the physician confines his care to patients who are in moderate need of therapy any of the more potent compounds, used as recommended, will suffice and the homeostasis of the patient will be adequate to handle the agents. If the physician elects to treat patients who will respond only to the more impres- sive agents, he should employ the drug carefully and should allow time for the internal milieu of the subject to adjust even haltingly to his control of the situation. If the remarkable utility of these agents is used to advance therapy rather than simply to hasten diuresis, they will be a godsend to the physician and to the patient. I had intended to point out that the diuretic agents are frequently adjuncts to therapy. The introduction of the thiazides did not supplant the need for digitalis or potent antihypertensive therapy, although the diuretics may have moderated the early need for these agents. I had intend- ed to point out that many functions, both renal and extra-renal, are important to the efficient use of diuretics, but I am sure these will be alluded to by the other speakers. Thus, it is my privilege to introduce to you the participants in this Sympo- sium on Salt and Water Balance with the assurance that, while we do have effective diuretic therapy, the situation at a research level is extremely fluid. THE PHYSIOLOGICAL ASPECTS OF ELECTROLYTE TRANSPORT H. WIRZ University of Basle and J. R. Geigy S.A., Basle, Switzerland OF THE 130 ml of plasma which are filtered each minute by the normal human kidneys, the main constituents are water, sodium ions, and chloride ions. The bulk of these are reabsorbed in the tubular system including the collecting ducts, and it is unquestionable that some transport activity must be involved in this process. Active transport, often referred to as "uphill" transport, is one which proceeds at the expense of energy against the combined chemical and (in the case of electrolytes) electrical gradients. Theoretically, in the case of our three main filtrate constituents, the active reabsorption of any one of them would create the appropriate chemical and/or electrical gradients along which the other two would move passively — downhill — in the same direction. Evidence has accumulated, however, that the sodium ion is the one constituent that is actively reab- sorbed throughout the entire length of the nephron including the collecting duct, with the possible exception of the thin descending limb of the loop of Henle. In the proximal tubule the active nature of sodium reabsorption is not apparent at first sight; the fluid to plasma concentration ratio being close to unity under normal conditions. A sodium concentration gradient is not established. The early experiments of Walker et al.1 have been confirmed by many authors and with a variety of assay procedures. But it is quite easy to artificially produce such conditions under which sodium ions are reabsorbed against concentration differences of up to 50 m-equiv./l. Such conditions include the induction of an osmotic diuresis, e.g. with mannitol or the perfusion of single proximal convoluted tubules with solutions con- taining an unreabsorbable solute. So, the proximal convoluted tubule is able to set up a sodium ion gradient even though this is not the case ordinarily. It also produces an electrical potential difference of such direction as to oppose rather than promote the 5 6 H. WIRZ reabsorption of sodium ions. Proximal tubular potential differences seem to be the consequence of rather than the reason for the sodium reabsorption. The tubule cell is electronegative by some 60 to 80 mV as compared with peritubular fluid and by 40 to 60 mV versus the tubular lumen. The trans- tubular potential difference — across all membranes from peritubular to tubular fluid — amounts to some 20 mV (lumen negative).* Intracellular sodium concentration conceivably being very low, both the electrical and chemical potentials favour the passive intrusion of sodium ions at the luminal membrane. The transport activity — as far as sodium is concern- ed—could therefore be confined to the peritubular cell border.2 In the ascending limb of the loop and in the distal convoluted tubule the sodium pump has to overcome even steeper electrochemical gradients. Transtubular electrical potentials of 60 mV and more are readily observed, and considerable sodium concentration gradients are the rule. Also in the collecting ducts active sodium reabsorption is well established. Chloride reabsorption, on the other hand, proceeds downhill. No higher degree of order is achieved if a chloride ion passes from the tubular lumen to peritubular fluid. The transtubular electrical potential is in the proper direction and so is usually the concentration gradient. This does not neces- sarily signify that the transport process is entirely passive. Even a downhill transport may be carrier mediated and would proceed at a different pace if not facilitated by some cellular activity. In the case of chloride reabsorption, however, this is highly improbable, at least in the proximal convoluted tubule. Tracer studies reveal the net chloride flux to be a fraction only of the total chloride movement. The permeability of both the luminal and the peritubular cell membrane to chloride ions is not likely to present a serious barrier. In the Necturus the short circuit current in the proximal tubule is not altered significantly if chloride ions are substituted by sulfate. Since it is improbable that a hypothetic carrier mechanism would handle sulfate ions with the same efficiency as chloride ions, this finding is highly indicative for the absence of any activity.3 The situation is not quite so clear in the ascending limb and the structures downstream of it. Here the fluid to plasma concentration ratio is consider- ably below unity in most instances. The high transtubular potential difference may suffice to explain this concentration gradient except under extreme conditions. * For the sake of completeness it must be stated that Ullrich and his colleagues at Berlin hold that this transtubular potential is an artefact and that its true value is in the vic- inity of zero.
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