Aminopyridines and Similarly Acting Drugs: Effects on Nerves, Muscles and Synapses: Proceedings of a IUPHAR Satellite Symposium in Conjunction with the 8th International Congress of Pharmacology, Paris, France, July 27-29, 1981

Théramex.

LIST OF PARTICIPANTS

Sandor AGOSTON,     Department of Anaesthesiology, University Hospital, Oostersingel 59, 9700 RB Groningen, The Netherlands

A. Peter BALL,     Infectious Diseases Unit, Cameron Hospital, Windygates, Fife, KY8 5RR, United Kingdom

Eric A. BARNARD,     Department of Biochemistry, Imperial College of Sciences and Technology, London SW 7, United Kingdom

Penelope J. BARNARD,     Department of Biochemistry, Imperial College of Sciences and Technology, London SW 7, U.K

Claude BERGMAN,     Laboratoire de Neurobiologie, Ecole Normale Supérieure, 46, rue d’Ulm, 75230 Paris Cedex 05, France

Félix BERGMANN,     Department of Pharmacology, The Hebrew University, Hadassah Medical School, Jerusalem 91000, Israël

Pierre-Paul van BOGAERT,     Laboratorium voor Fysiologie, Universiteit Antwerpen, RUCA, Groenenborgerlaan 171, B 2020 Antwerpen, Belgium

William C. BOWMAN,     Department of Physiology and Pharmacology, University of Strathclyde, George Street 204, Glasgow G1 1XW, Scotland, United Kingdom

Barbara W. BRANDOM,     Department of Anesthesiology, Children’s Hospital of Pittsburgh, 125 de Soto Street, Pittsburgh, PA 15213, U.S.A

Jean-Louis BRIGANT,     Laboratoire de Neurobiologie cellulaire, C.N.R.S., 91190 Gif sur Yvette, France

Jean CHANELET,     Laboratoire de Physiologie, U.E.R. de Sciences Médicales et Pharmaceutiques, 49045 Angers Cedex, France

Renato CORRADETTI,     Istituto Interfacolta di Farmacologia e Tossicologia della Universita di Firenze, Viale G.B. Morgagni 65, 50134 Firenze, Italia

René COUTEAUX,     Laboratoire de Cytologie, Université Pierre et Marie Curie, 7, Quai Saint-Bernard, 75230 Paris Cedex 05, France

Jean-Marc DUBOIS,     Laboratoire de Neurobiologie, Ecole Normale Supérieure, 46, rue d’Ulm, 75230 Paris Cedex 05, France

Yves DUNANT,     Département de Pharmacologie, Ecole de Médecine, rue de l’Ecole de Médecine 20, 1211 Genève 4, Switzerland

Nicholas DURANT,     Department of Anesthesiology, University of California, UCLA, School of Medicine, Los Angeles, CA 90024, U.S.A

K.A. Paul EDMAN,     Department of Pharmacology, University of Lund, Sölvegatan 10, S 223 62 Lund, Sweden

Dan FARINE,     Ambassade d’Israël, 3, rue Rabelais, 75008 Paris, France

Frederic Noël FASTIER,     Department of Pharmacology, Otago University, P.O. Box 913, Dunedin, New-Zealand

Rainer H.A. FINK,     Department of Zoology, La Trobe University, Bundoora, Victoria 3083, Australia

Francis F. FOLDES,     Department of Anesthesiology, Montefiore Hospital and Medical Center, 111 East 210th Street, Bronx, NY 10467, U.S.A

Martin GALVAN,     Physiologisches Institut der Universität München, Pettenkoferstrasse 12, 8000 München 2, Federal Republic of Germany

Alasdair James GIBB,     Department of Physiology and Pharmacology, University of Strathclyde, Royal College, 204 George Street, Glasgow Gl 1XW, Scotland, United Kingdom

Walter E. GLOVER,     School of Physiology and Pharmacology, University of New South Wales, P.O. Box 1, Kensington, New South Wales 2033, Australia

Gertrude GOGOLÁK,     Institut für Neuropharmakologie, Währinger Strasse 13a, 1090 Wien, Austria

Stephen GOMEZ,     Department of Neuropathology, Institute of Neurology, The National Hospital, Queen Square, London WC1 N, 3 BG, United Kingdom

Peter GRAFE,     Physiologisches Institut der Universität München, Pettenkoferstrasse 12, 8000 München 2, Federal Republic of Germany

A. Sergio GUERRERO,     Departamento de Farmacologia, Universidad de Chile, Casilla 16387, (P.O.Box), Santiago 9, Chile

Alan L. HARVEY,     Department of Physiology and Pharmacology, University of Strathclyde, Glasgow Gl 1XW, Scotland, United Kingdom

Bernard HUE,     U.E.R. de Médecine, Département de Physiologie, rue Haute de Reculée, 49045 Angers Cedex, France

Maurice ISRAËL,     Département de Biophysique et de Neurochimie, Laboratoire de Neurobiologie Cellulaire, C.N.R.S., 91190 Gif sur Yvette, France

Elzbieta JANKOWSKA,     Göteborg Universitet, Fysiologiska Institutionen, Box 33031, S 400 33 Göteborg, Sweden

Donald H. JENKINSON,     Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom

Philippe JOURDON,     Institut de Pharmacologie, 15, rue de l’Ecole de Médecine, 75006 Paris, France

Abdur Rauf KHAN,     Department of Pharmacology, University of Lund, Sölvegatan 10, S 223 62 Lund, Sweden

Sadashiv M. KIRPEKAR,     State University of New York, Department of Pharmacology, Downstate Medical Center (Box 29), 450 Clarkson Avenue, Brooklyn, NY 11203, U.S.A

Boris Israelovitch KHODOROV,     A.V. Vishnevsky Surgery Institute of the Academy of Medical Sciences of the U.S.S.R., Moscow 113093, U.S.S.R

Ulrich KUHNT,     Max-Planck-Institut für Biophysikalische Chemie, D-3400 Göttingen-Nikolausberg, Postfach 968, Federal Republic of Germany

Ernst LAMMEL,     Physiologisches Institut der Philipps-Universität, Deutschhausstrasse 2, D 3550 Marburg/Lahn, Federal Republic of Germany

Paul LECHAT,     Institut de Pharmacologie, 15, rue de l’Ecole de Médecine, 75006 Paris, France

Gérard Le FUR,     Pharmindustrie, B.P. 158, 92231 Gennevilliers, France

Madeleine LEMEIGNAN,     Institut de Pharmacologie, 15, rue de l’Ecole de Médecine, 75006 Paris, France

George E. LEWIS,     Pathology Division, U.S. Army Medical Research, Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21701, U.S.A

Rodolfo LLINAS,     Department of Physiology and Biophysics, New York University Medical Center, 550 First Avenue, New York, NY 10016, U.S.A

Konrad LÖFFELHOLZ,     Pharmakologisches Institut der Universität Mainz, Obere Zahlbacher Strasse 67, 6500 Mainz 1, Federal Republic of Germany

Robert LOWY,     Groupe de Recherches sur la Physiopathologie de la Nutrition (U.177 INSERM), 15, rue de l’Ecole de Médecine, 75006 Paris, France

Håkan LUNDH,     Department of Neurology, University Hospital, S 221 85 Lund, Sweden

Joseph J. McARDLE,     Department of Pharmacology, New Jersey Medical School, Newark, New Jersey 07103, U.S.A

Takashi MAENO,     Department of Physiology, Shimane Medical University 89-1 Enyacho, Izumo 693, Japan

Alberto MALLART,     Laboratoire de Neurobiologie Cellulaire du C.N.R.S., 91190 Gif sur Yvette, France

Kurt MANDREK,     Institut für Physiologie der Universität Marburg/Lahn, Deutschhausstrasse 2, 3550 Marburg/Lahn, Federal Republic of Germany

Ian G. MARSHALL,     The University of Strathclyde, Department of Physiology and Pharmacology, Royal College, 204 George Street, Glasgow Gl 1XW, Scotland, United Kingdom

Dalila MARTINEZ de MUÑOS,     Instituto Nacional Politecnico, Centro de Investigacion y de estudiantos avanzados, Departamento de Neurociencias, Appartado Postal 14-740, Mexico City 14, D.F., 5 Mexico

Hans MEVES,     I. Physiologisches Institut der Universität des Saarlandes, D 6650 Homburg/Saar, Federal Republic of Germany

Hervé MILLART,     Laboratoire de Pharmacologie, C.H.R., 45, rue Cognacq Jay, 51092 Reims Cedex, France

Jordi MOLGÓ,     Institut de Pharmacologie, 15, rue de l’Ecole de Médecine, 75006 Paris, France

Gonzalo MONTOYA,     Departamento de Ciencias Fisiologicas, Facultad de Ciencias Biologicas y de Recursos Naturales, Universidad de Concepcion, Concepcion, Chile

Yoshio OHTA,     Montefiore Hospital and Medical Center, Anesthesiology Research Laboratory, 111 East 120th Street, Bronx, NY 10467, U.S.A

Dimitri PASKOV,     5, rue Razlatitza, 1463 Sofia, Bulgaria

Monique PECOT-DECHAVASSINE,     Laboratoire de Cytologie, Université Pierre et Marie Curie, 4, place Jussieu, 75230 Paris cedex 05, France

Marcel PELHATE,     U.E.R. de Médecine, Laboratoire de Physiologie, rue Haute de Reculée, 49045 Angers Cedex, France

Federico PERADEJORDI,     Centre de Mécanique Ondulatoire du C.N.R.S., 23, rue du Maroc, 75019 Paris, France

Yves PICHON,     Département de Biophysique, Laboratoire de Neurobiologie Cellulaire du C.N.R.S., 91190 Gif sur Yvette

Robert POLAK,     Medical Biological Laboratory, T.N.O., Postbox 45, 2280 AA Rijswijk, The Netherlands

Joaquim RIBEIRO,     Centro de Biologia, Instituto Gulbenkian de Ciencia, Oeiras, Portugal

Michael J. ROWAN,     Department of Pharmacology, University of Dublin, Trinity College, Dublin 2, Eire

Nayef Emile SAADE,     Departement de Sciences Naturelles, Faculté des Sciences, Université Libanaise, Hadeth-Beyrouth, Liban

Olav SAND,     Department of Physiology, Veterinary College of Norway, P.O. Box 8146, Oslo 1, Norway

Jean-Pierre SAVINEAU,     Université de Bordeaux II, Institut de Biochimie Cellulaire et de Neurochimie du C.N.R.S., 1, rue Camille Saint-Saens, 33000 Bordeaux, France

Marc SCHIAVONE,     State University of New-York, Downstate Medical Center, Department of Pharmacology, Box 29, 450 Clarkson Avenue, Brooklyn, NY 11203, U.S.A

Andreas SCHMITT,     Rudolf-Buchheim Institut fuer Pharmakologie der Justus-Liebig Universitaet, Frankfurter Str. 107, D 6300 Giessen, Federal Republic of Germany

Madeleine SEBALD,     Département des Anaérobies, Institut Pasteur, 25, rue du Docteur Roux, 75015 Paris, France

Lawrence C. SELLIN,     Pathology Division, Department of the Army, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21701, U.S.A

M. SHAHID,     Department of Physiology and Pharmacology, University of Strathclyde, George Street 204, Glasgow Gl 1XW, Scotland, United Kingdom

Norman Nathan SHARE,     Laboratoire Merck, Sharp & Dohme-Chibret, Route de Marsat, B.P. 127, 63203 Riom Cedex, France

Takeshi SHIMAHARA,     Département de Biophysique, Laboratoire de Neurobiologie Cellulaire du C.N.R.S., 91190 Gif sur Yvette, France

Vojtech SOBEK,     Laboratory for the Research of Infectious Diseases, Faculty of Pediatrics, Charles University, 180 81 Prague 8, Bulovka, Czechoslovakia

Emil STOYANOV,     Department of Anaesthesiology and Resuscitation, Medical Academy, Bul. Patriarch Evitmi 59, 1463 Sofia, Bulgaria

Magdolna SZENTE,     Alsókikötö sor 5. VIII. 48, 6726 Szeged, Hungaria

France TAZIEFF-DEPIERRE,     Institut de Pharmacologie, 15, rue de l’Ecole de Médecine, 75006 Paris, France

Stephen THESLEFF,     Department of Pharmacology, University of Lund, Sölvegatan 10, S 223 62 Lund, Sweden

Toshimitsu UCHIYAMA,     Department of Pharmacology, Toho University School of Medicine, 21-16 Omori-Nishi 5 chome, Ota-Ku, Tokyo 143, Japan

Werner ULBRICHT,     Christian-Albrechts Universität zu Kiel, Physiologisches Institut, Olshausenstrasse 40/60, 2300 Kiel 1, Federal Republic of Germany

Oswaldo VITAL-BRAZIL,     Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, C.P. 1170, Campinas, Sao Paulo, Brazil

Wolfgang WEIDE,     Pharmakologisches Institut der Universität Mainz, Obere Zahlbacher Strasse 67, 6500 Mainz 1, Federal Republic of Germany

Pieter WESTRA,     Institute of Anaesthesiology, Oostersingel 59, 9713 EZ Groningen, The Netherlands

Teruyuki YANAGISAWA,     Department of Pharmacology, Tohoku University, School of Medicine, Seiryo-machi 2-1, Sendai 980, Japan

SCIENTIFIC SESSIONS

Outline

Chapter 1: Historical Review

Historical Review

P. Lechat,     Institut de Pharmacologie, 15 rue de l’Ecole de Médecine, 75006 Paris, France

Publisher Summary

This chapter discusses a historical review of pharmacological studies carried out on aminopyridines (AP) and related compounds. The first pharmacological investigation using pyridine concerned its action on neuromuscular transmission. The results were presented in 1883 to the Société de Biologie by Bochefontaine, who worked in Vulpian’s laboratory in the Paris School of Medicine. At that time, Bochefontaine reported the depressive action of pyridine on neuromuscular transmission, just the opposite to what is known to be the effect of aminopyridines at present. The three isomeric aminopyridines were obtained in 1894 by Meyer, who used the Hofmann procedure (the treatment of the amides of pyridine monocarboxylic acids by alkaline hypobromites). In 1915, Tchitchibabine obtained 2-AP by heating pyridine with sodamide. The six possible diaminopyridines were synthesized later. Clonic convulsions, the major sign of acute intoxication by AP, were mentioned by all workers who administered drugs to animals\. The first quantitative assays were made by von Haxthausen (1955) who determined LD50 of 4-AP in mice and found it somewhat low (5 mg/kg s.c).

The aim of this historical review is to recall briefly the main steps of the pharmacological studies carried out on aminopyridines (AP) and related compounds. Initial works describing a given effect or proposing a mechanism of action or a therapeutic application are cited here as important milestones in our story.

Pyridine was isolated from coaltar by Anderson in 1846, and picoline (methyl pyridine) appeared to be the first heterocyclic compound obtained by synthesis through the work of Klaus in 1862.

It is interesting to note that the first pharmacological investigation using pyridine concerned its action on neuromuscular transmission. The results were presented in 1883 to the Société de Biologie by Bochefontaine, who worked in Vulpian’s laboratory in the Paris School of Medicine, where my own laboratory is now located. At that time Bochefontaine reported the depressive action of pyridine on neuromuscular transmission, just the opposite to what we know to be the effect of aminopyridines today.

The three isomeric aminopyridines were obtained in 1894 by Meyer, who used the Hofmann procedure (treatment of the amides of pyridine monocarboxylic acids by alcaline hypobromites). In 1915 Tchitchibabine obtained 2-AP by heating pyridine with sodamide. The six possible diaminopyridines were synthetised later.

In 1925 Mr. Dohrn from Charlottenburg wrote a short paper entitled Pharmakologie einiger Pyridinderivate in the famous German Journal Naunyn Schmiedeberg’s Archiv für experimentelle Pathologie und Pharmakologie. In a few lines, the author described the following effects of amino-2 pyridine:

• convulsions in frogs, mice and rabbits, which were not suppressed by decapitation, disappeared immediately after the spinal cord was destroyed, although fascicular tremors continued to persist. These tremors did not cease after cutting of the innervating nerves, but disappeared after their degeneration.

• stimulation of isolated gastrocnemius, as with guanidine.

• strong rise in blood pressure.

• strong elevation of isolated gut tonus.

The introduction of a second amino group leading to 2,6-diaminopyridine did not modify the activity, but an acetyl group reduced the toxicity.

This was indeed a remarkable achievement to which there is little to add today.

Our present knowledge of the mechanism of AP action is much deeper, but it was Dr. Dohrn who described concisely and with great precision the main pharmacological properties of 2-AP, and that was 56 years ago.

In order to be more clear, I wish to go through the sequence of discoveries by examining one after the other the different actions of AP on the organism.

Aminopyridines and central nervous system.

Clonic convulsions, the major sign of acute intoxication by AP, were mentioned by all workers who administered drugs to animals: Dingemanse and Wibaut (1928) with 3-AP in the frog, then many others in mammals. The first quantitative assays were made by von Haxthausen (1955) who determined LD50 of 4-AP in mice and found it somewhat low (5 mg/kg s.c.). Local applications of 4-AP to the spinal cord of cats threw some light on the mechanism of its convulsant effects since spontaneous repetitive discharges were registered on both the dorsal and the ventral roots by Chanelet and Lemeignan (1969). Furthermore an increase in evoked monosynaptic and polysynaptic activity under the influence of 4-AP was observed in the same material again by Lemeignan (1972). The central synapses of Invertebrates were also shown to be sensitive to AP, when Hue and co-workers (1975, 1976) observed in cockroach abdominal ganglions that 4-AP increased the amplitude of both excitatory and inhibitory synaptic potentials, an effect attributed by the authors to a presynaptic action. Only very recently, man too was discovered to be sensitive in this regard when Ball and co-workers (1979) reported epileptic seizures in patients receiving 4-AP. A special mention should be made of Goodhue who discovered that birds ingesting 4-AP became desoriented and emitted distress calls that caused other, non-intoxicated birds, to leave the area (1964). This frightning effect has subsequently been used to reduce damage caused by urban and rural populations of many bird species.

A number of other aminopyridines were tested later, but it must be emphasized that till now 4-AP remains the most toxic of them. Cytotoxicity of aminopyridines has been found to run parallel to their convulsant potency by Lechat and co-workers (1968). Von Haxthausen (1955) was also the first to notice the stimulating respiratory effect of 4-AP. Much more recently See and co-workers (1978) showed that atropine blocked it, indicating an involvement of central muscarinic cholinoceptors. A therapeutic application of this data occurred when Sia and co-workers (1979) used 4-AP to restore normal breathing in fentanyl respiratory depressed patients.

A consequence of the central stimulating action of AP is the reduction of sleeping time following the administration of hypnotic agents, observed in mice by Abernethy and Fastier (1958).

Another manifestation of a central action of 4-AP is the analgesic activity, which von Haxthausen demonstrated in mice in 1955. Many related compounds were found later to share this action the mechanism of which is not yet fully understood. The local anesthetic property of 4-AP described by Dingemanse and Wibaut (1928) is similarly not clearly understood either.

Aminopyridines and cardiovascular system.

The pioneer here was Fastier (1948) who studied a series of amidine derivatives in dogs and rats; with Reid (1948) he noticed the similar effects of methyl isothiourea, 2-AP and iminoazole, i.e. hypertension in dogs, vasoconstriction in rats with sensitization to the vasoconstrictor action of adrenaline. The cardiac inotropic effect of AP was subsequently observed by von Haxthausen (1955) and 4-methyl-2-AP (or 2-amino 4-picoline) was marketed in Germany under the trade-name AscensilR, as an analgesic drug.

Aminopyridines and neuromuscular junction.

In 1953, at the instigation of Charonnat, I was studying the mechanisms by which injection of thiamine induced shocks in some patients. Hypothesising there was some relationship between the chemical structure of aminopyrimidine moiety of thiamine and of 4-aminopyridine, we injected animals with the latter. As Dohrn had previously found in frog with 2-AP, we observed a strong convulsant effect of 4-AP in mice and rabbits (Charonnat et al., 1953). We were however more interested then in the thiazole moiety of thiamine, which led us to discover the anticonvulsant properties of clomethiazole, but that is another story … 14 years later Mrs. Lemeignan and I (1967) again turned our attention to 4-AP and we observed that it antagonized d-tubocurarine but not suxicurarium.

We were in fact unaware at the time of two earlier works, the first one of Tsobkallo (1942) in which he described the anticurare action of 2-aminopyridine and the second one of Vohra and Pradhan (1964) reporting very briefly that 3,4-diaminopyridine antagonized d-tubocurarine. In our laboratory a pharmacological analysis of this antagonism was performed on the isolated rat phrenic-diaphragm preparation by Sobek and co-workers (1968). On the basis of our experiments on anesthetized cats and rabbits, we proposed that 4-aminopyridine enhances the release of acetylcholine evoked by nerve impulses at the neuromuscular junction. This view was confirmed when it was demonstrated that 4-AP raised EPP amplitude by increasing the EPP mean quantal content (Lundh and co-workers, 1977a; Molgo and co-workers, 1975, 1977). Such a mechanism accords with the lack of anticholinesterase activity of AP at concentrations where they increase neurotransmitter release. This was shown by Shaw and Bentley (1953) and by Lemeignan and Lechat (1967). Therapeutic applications based on this mechanism concern anesthesia (hastening the return of spontaneous movements after the blocking of d-tubocurarine (Paskov and co-workers, 1973), and some neuromuscular diseases: Eaton-Lambert syndrome (Lundh and co-workers, 1977b), myasthenia gravis (Lundh and co-workers, 1979) and botulism (Ball and co-workers, 1979). In addition to their presynaptic actions at the neuromuscular juuction, a direct action of AP on skeletal muscle contractility was first described by Fastier and McDowall (1958) and was confirmed by Bowman and co-workers (1976) and Harvey and Marshall (1977). An increased release of calcium ions from intracellular stores was proposed by Khan and Edman (1979) to account for this enhanced contractility.

Aminopyridines and nervous autonomic system.

The initial observation of Dohrn in 1925 demonstrating that AP increased the tone of isolated ileum preparations was confirmed by Fastier and McDowall (1958). Subsequent studies by Vizi and co-workers (1977) demonstrated that AP enhanced the release of acetylcholine from nerve terminals of ileum Auerbach plexus.

AP have also been shown to enhance nerve impulse evoked release of other neurotransmitters:

• noradrenaline in the cat spleen by Kirpekar and co-workers (1975) and in the rabbit vas deferens by Johns and co-workers (1976).

• and glutamate and GABA at the lobster neuromuscular junction by Schauf and coworkers (1976).

Aminopyridines and excitable membranes.

In many excitable membranes, 4-AP specifically blocks the voltage-dependent potassium channels. The first voltage-clamp studies in this field were made on the cockroach giant axon by Pelhate and co-workers (1974). Two years later Llinas and coworkers (1976) demonstrated the blocking of potassium channels by 4-AP in the presynaptic terminals of the squid giant synapse. A similar action of 4-AP on potassium conductance was described in skeletal muscle membranes by Gillespie and Hutter (1975) and in cardiac muscle membranes by Kenyon and Gibbons (1979).

The ability of 4-AP to block potassium channels seems to contribute substantially to its action in facilitating the influx of calcium ions through the voltage-sensitive calcium channels in the nerve terminals that are opened by the action potential (Molgo and co-workers, 1977; Illes and Thesleff, 1978). However there might well be another mechanism underlying 4-AP’s facilitating on transmitter release. Lundh and Thesleff (1977) put forward the possibility that AP may facilitate calcium influx by direct action on voltage-sensitive calcium channels, although this hypothesis needs further investigation.

I have tried in a few minutes to indicate the development of our knowledge of aminopyridines and their related compounds. I have no doubt that the new data presented in this Symposium will advance our understanding of compounds the importance of which has grown and continues to grow so rapidly at this time.

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AMINOPYRIDINES AND IONIC CURRENTS IN EXCITABLE MEMBRANES

Outline

Chapter 2: General Review on Potassium Currents in Excitable Membranes of Nerve and Muscle

Chapter 3: Effects of Aminopyridines on Potassium Currents of the Nodal Membrane

Chapter 4: Properties and Physiological Roles of K + Currents in Frog Myelinated Nerve Fibres as Revealed by 4-Amino Pyridine

Chapter 5: Effects of Aminopyridines on Ionic Currents and Ionic Channel Noise in Unmyelinated Axons

Chapter 6: 3- and 4-Aminopyridine in Synaptic Transmission at the Squid Giant Synapse

Chapter 7: DISCUSSION OF THE FIRST SESSION

General Review on Potassium Currents in Excitable Membranes of Nerve and Muscle

H. Meves,     I. Physiologisches Institut der Universität des Saarlandes, D-6650 Homburg/Saar, Federal Republic of Germany

ABSTRACT

The paper describes the physiological and pharmacological properties of the delayed potassium outward current in nerve and muscle.

KEYWORDS

Potassium current

nerve

muscle

single channel conductance

4-aminopyridine

tetraethylammonium

barium

TIME COURSE OF POTASSIUM CURRENTS

In nerve and muscle fibres, depolarization produces a delayed K outward current IK which rises to a maximum and then declines slowly. Fig. 1 shows examples of IK from frog muscle fibres and from a mouse neuroblastoma cell recorded with the voltage-clamp method. The currents are displayed on fast and slow time scale. The time course of the rising phase is approximately fitted by an activation variable n (which increases exponentially with time) raised to the second or a higher power (Hodgkin and Huxley, 1952; Cole and Moore, 1960; Frankenhaeuser, 1963). A hyperpolarizing prepulse delays the onset of IK (Cole and Moore, 1960; Goldman and Schauf, 1973; Palti, Ganot and Stämpfli, 1976; Begenisich, 1979; Keynes and Kimura, 1980). To describe the delay mathematically, a larger exponent of n or a time shift Δt is required. The secondary decline of IK in Fig. 1B and D has been attributed to the slow inactivation of the K conductance, a process which occurs also in squid giant axons (Ehrenstein and Gilbert, 1966) and myelinated nerve fibres (Schwarz and Vogel, 1971). With the inactivation variable k and the driving force (V-VK) the equation for the delayed K current