Reviews of 92 Physiolog3~ Biochemistry and Pharmacology Editors R. H. Adrian, Cambridge. H. zur Hausen, Freiburg E. Helmreich, Wiirzburg • H. Holzer, Freiburg R. Jung, Freiburg • O. Krayer, Boston R. J. Linden, Leeds. P. A. Miescher, Gen~ve J. Piiper, G6ttingen • H. Rasmussen, New Haven U. Trendelenburg, Wiirzburg • K. Ullrich, Frankfurt/M. W. Vogt, G6ttingen • A. Weber, Philadelphia With 13 Figures Springer-Verlag Berlin Heidelberg New York 1982 ISBN 3-540-11105-0 Springer-Verlag Berlin Heidelberg New York ISBN 0-387-11105-0 Springer-Verlag New York Heidelberg Berlin Library of Congress-Catalog-Card Number 74-3674 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustra- tions, broadcasting, reproduction by photocopying machine or similar means, and stor- age in data banks. Under § 54 of the German Copyright Law where copies are made for other than private use, a fee is payable to 'Verwertungsgesellschaft Wort', Munich. @ by Springer-Verlag Berlin Heidelberg 1982 Printed in Germany. The use of 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 pro- tective laws and regulations and therefore free for general use. Offsetprinting and Binding: Konrad Triltsch, Wt~rzburg 2121/3130-543210 Contents Cardioactive Substances that Prolong the Open State of Sodium Channels. By P. HONERJAGER, Mfinchen/Federal Re- public of Germany. With 12 Figures .... Factors Influencing Renal Sodium Reabsorption in Volume Expansion. By F. G. KNOX and J. A. HAAS, Rochester, MN/USA .......... 75 Hormonal Coordination of the Immune Response. By J. COMSA, H. LEONHARDT, and H. WEKERLB, Homburg/Federal Republic of Germany. With 1 Figure .... : . 115 Author Index . .............. 193 Subject Index ............... 219 Indexed in Current Contents Rev. Physiol. Biochem. Pharmacol., Vol. 92 ©by Springer-Verlag 1982 Cardioactive Substances that Prolong the Open State of Sodium Channels PETER HONERJAGER * Contents 1 Introduction ........................................... 2 Chemistry of Na Channel-Gate Toxins .......................... 4 2.1 Alkaloids ......................................... 4 2.2 Diterpenoids ....................................... 6 2.3 Polypeptides ....................................... 6 Mode of Action of Na Channel-Gate Toxins ...................... 7 3.1 Methods of Analysis.................................. 7 3.2 Ceveratrum Alkaloids ................................. 7 3.3 Batrachotoxin ...................................... 9 3.4 Aconitine ......................................... 10 3.5 Grayanotoxins ..................................... 10 3.6 Scorpion Toxins .................................... 10 3.7 Sea Anemone Toxins ................................. 11 3.8 Coral Toxin ....................................... 12 3.9 Silent Na Channels ................................... 12 3.10 Antagonists ....................................... 13 4 Cardiac Action of Na Channel-Gate Toxins ....................... 15 4.1 Role of Na Channels in the Cardiac Action Potential ............ 15 4.2 Ceveratrum Alkaloids ................................. 19 4.3 Batrachotoxin ...................................... 37 4.4 Aconitine ......................................... 39 4.5 Grayanotoxins ..................................... 42 4.6 Scorpion Toxins .................................... 44 4.7 Sea Anemone Toxins ................................. 46 4.8 Coral Toxin ....................................... 50 Sarcolemmal Na Permeability and Myocardial Force of Contraction: Na-Ca Exchange ........................................ 50 5.1 Introduction ........................................ 50 5.2 Na-Ca Exchange in the Squid Giant Axon ................... 51 5.3 Nai-Ca o Exchange in Cardiac Preparations ................... 53 Comparison of Cardiac Actions of Na Channel-Gate Toxins with Those of Other Positive Inotropic Drugs ............................. 56 6.1 Isometric Contraction Curve ............................ 57 6.2 Blockade of Sarcolemmal Na Channels by Tetrodotoxin .......... 58 * lnstitut fiir Pharmakologie und Toxikologie der Technischen Universit~it Mfinchen, Biedersteiner StratSe 29, D-8000 Mtinchen 40, Federal Republic of Germany 2 P. Honerj~iger 6.3 Contraction Frequency ................................ 60 6.4 Reduction of Extracellular Na Concentration ................. 60 6.5 Variation of Extracellular K Concentration .................. 61 6.6 Inhibition of the Na Pump by Dihydro-Ouabain ............... 61 6.7 Propranolol ....................................... 62 7 Summary and Conclusions ................................. 62 References .............................................. 64 Abbreviations and Symbols ATXII Toxin II fromAnemoniasulcata h Inactivation variable of Iqa cAMP Cyclic adenosine 3',5'-mono- channels phosphate m Activation variable of Na D 600 o~-Isopropyt-c~-[(N-met hyl-N- channels homoveratryl)-'),-aminopropyl]- I K Transmembrane/( current 3,4,5-trimethoxyphenylaceto- INa Transmembrane Na current nitrile (gallopamil) through Na channels ScTXII Toxin II from Androctonus Isi Transmembrane slow inward australis Hector (Ca, Na) current STX Saxitoxin PNa Membrane permeability to Na TTX Tetrodotoxin ions *max Maximal rate of depolarization during the upstroke of the F c Peak force of contraction action potential AF c Change in peak force of con- [ ]a Extraeellular concentration traction [ 1; Intracellular concentration 1 Introduction It is now recognized that many toxic substances evolved by plants or ani- mals act by interfering with the excitation process of nerve and muscle cells. Specifically, these compounds alter the rapid and transient increase in membrane permeability to Na ions (PNa), that initiates the action potential. According to the general mode by which toxins modify the Na permeability mechanism, or Na channels, two groups can be distinguished. The first group of substances, including tetrodotoxin (TTX) and saxi- toxin (STX), blocks the flow of Na ions through Na channels. The second group of toxins maintains an open form of the Na channel, thereby pro- longing the time during which Na ions flow into the cell. This group com- prises alkaloids (ceveratrum alkaloids, batrachotoxin, aconitine), the diter- penoid grayanotoxins, and polypeptides from scorpions, sea anemones and coral and contains the most potent and most specific substances known to increase the Na permeability of excitable membranes. Toxins Cardioactive Substances that Prolong the Open State of Sodium Channels 3 which prolong the open state of Na channels will be referred to as Na channel-gate toxins to denote the specific function of the Na channel affected by these agents, i.e. the gating mechanism which controls the activation and inactivation of Na channels. While the general pharmacology of one subgroup of Na channel-gate toxins, the ceveratrum alkaloids, has been studied for more than a cen- tury, the basic mechanism of their action, as outlined above, has been elucidated only during the last 2 decades following the discovery of the ionic permeability changes responsible for membrane excitation (Hodgkin and Huxley 1952). For methodological reasons we possess more detailed information concerning the effect of Na channel-gate toxins on nerve fibres and nerve cells in culture than on myocardial and other excitable cells. This review, therefore, includes a brief description of effects on the type of preparation which yielded most information on the mechanism of action at the level of Na channels. For in-depth information of the effects of toxins on Na channels, the reader is referred to the reviews by Ulbricht (1969, 1974), Hille (1970), Narahashi (1974), Khodorov (1979), Ritchie (1979), Catterall (1980), and Lazdunski et al. (1980), and to the original literature cited in connection with individual toxins. This review deals with the direct cardiac effects of Na channel-gate toxins observed in isolated cardiac preparations. The main effects are a positive inotropic effect without a significant chronotropic effect and an arrhythmogenic effect. Early references to the direct cardiac effects of ceveratrum alkaloids are given in the reviews by Krayer and Acheson (1946) and Trautwein (1963). Trautwein (1963) also reviewed the litera- ture concerning the cardiac effects of aconitine. The Benforado review (1967) includes a chapter on the direct cardiac effects of ceveratrum alkaloids and concludes that "the mechanism by which the veratrum alkaloids exert their positive inotropic action on the heart is not known". The last 15 years have brought considerable progress in our understand- ing of the basic membrane action of ceveratrum alkaloids and other Na channel-gate toxins and of the relationship between ion fluxes through the sarcolemma and myocardial force of contraction. Perhaps the most impressive result is that the large group of chemically diverse Na channel- gate toxins represents a single class of inotropic agents. They possess a characteristic mode of action that differs from that of other cardioactive drugs, e.g., cardioactive steroids, catecholamines, and other agents thought to act by influencing the cellular concentration of cyclic nucleo- tides. In the intact animal organism, the direct cardiac effects of Na channel- gate toxins may not be recognized because of cardiovascular or cardio- cardiac reflexes following