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The Action of Antiepileptic and Other Drugs On THE ACTION OF ANTIEPILEPTIC AND OTHER DRUGS ON Na- AND Ca-SPIKES IN MAMMALIAN NON-MYELINATED NERVES. Peter Elliott | A thesis submitted for the degree of Doctor of Philosophy. Department of Pharmacology, The School of Pharmacy, University of London. 1 990 ProQuest Number: U415922 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest U415922 Published by ProQuest LLC(2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 Abstract. The effects of some antiepileptic and local anaesthetic drugs on sodium- and calcium-dependent compound action potentials (Na- and Ca-spikes) in mammalian non-myelinated nerves have been compared, using the rat preganglionic cervical sympathetic trunk in vitro as the test system. To record the Ca-spike, the normal Na-spike was blocked by tetrodotoxin (TTX) and 1 mM 4-aminopyridine (4-AP) added. The spikes 2+ 2+ 2+ were maintained on substituting Sr or Ba for Ca but were blocked by inorganic Ca channel antagonists, with the following order of potency (IC ): Cd^+ (3.3 uM) > La^+ (6.9 uM) > Ni^+(44 uM) > Co^+ (0.47 2+ 50 2+ m M ) > M n (0.71 mM) > M g (16.4 m M ) • A comparison of the local anaesthetics, lidocaine and procaine with the antiepileptics phenytoin, carbamazepine and phenobarbitone on the Na-spike was made over a range of stimulation frequencies (0.2-20 Hz). There was no discernible difference in the frequency-dependence of block between these two groups of drugs. Differences were revealed in their relative effectiveness on single Na- and Ca-spikes. The antiepileptics were more potent blockers of the Ca-spike (ratio of i c ^q s °f the Na- and Ca-spikes: pentobarbitone, 21; phenobarbitone, 5.0; carbamazepine, 3.2; and phenytoin, 1.2), whereas the local anaesthetics were more potent on the Na-spike (lidocaine, 0.23; and procaine, 0.29). Catecholamines were also tested on the Ca-spike. L-noradrenaline produced an average maximal depression of the Ca-spike of 90% 1.5 uM) . Potencies (IC^) of other agonists were: clonidine (0.44 uM), L-adrenaline (1.3 uM), dopamine (46 uM), L-phenylephrine (154 uM), +/-amidephrine (>10 mM). Phentolamine was the most potent antagonist tested (Schild plot analysis giving a pA^ of 6.5). Yohimbine was at least ten times weaker; prazosin (10 uM) and +/-propranolol (1 uM) had no antagonistic action. In conclusion, it is proposed that inhibition of calcium currents may contribute to the therapeutic efficacy of some antiepileptic drugs and to the inhibitory action of catecholamines on transmitter release. Acknowledgements. I would like to express my gratidute to Prof. David Brown for giving me the chance to work in his lab. and for the help and advise (and patience) over the years. I would like to especially thank Steve Marsh for his invaluable help. Also thanks to Derek King for the photography and Chris Courtice for technical help. Also thanks to many others both at the School of Pharmacy and at Cardiff for their help and advice. 4 C o nt e n t s • Page Chapter One: Introduction. (A) Possible anatomical sites of antiepileptic drug action....... 15 (B) Possible mechanisms of antiepileptic drug action .............. 17 (1) Facilitation of inhibitory neurotransmission. (i) % -aminobutyric acid (GABA)................................ 17 (2) Inhibition of excitatory neurotransmission. (i) Excitatory amino acids ...................................... 20 (ii) Acetylcholine............................................... 20 (3) Action on the sodium pump .......................................... 21 (4) Actions on synaptic transmission and calcium currents. (i) Neuromuscular junction...................................... 25 (ii) Post-tetanic potentiation................................. 26 (iii) Synaptosomal calcium uptake ............................. 27 (iv) Transmitter r el ea se........................................ 27 (v) Calcium currents ............................................. 28 (5) Action of antiepileptics on the spontaneous activity induced by low calcium solutions............................... 29 (6) Action on sodium currents....................................... 32 (C) Objectives of this study .............. 44 Chapter Two: Methods. (A) Dissection............................................................ 47 (B) Extracellular recordings of D.C. potentials and compound action potentials• (1) Recording chamber and superfusion............................. 48 (2) Electrical stimulation and recording techniques.............. 49 (C) Intracellular recordings from isolated rat superior cervical ganglia. (1) Recording bath and superfusion................................ 50 (2) Electrical stimulation and recording techniques.............. 50 (D) Drugs and solutions. (1 ) D r u g s .............................................................. 53 (2) Physiological solutions......................................... 54 Chapter Three: Results. (A) Physiology of rat preganglionic cervical sympathetic nerve compound action potentials............. 58 (B) Action of drugs on compound action potential amplitude. (1) At low rates of stimulation (0.2 Hz) .......................... 59 (2) At higher rates of stimulation (5-20 Hz) ...................... 60 (C) Intracellular studies on the action of phenytoin in isolated superior cervical ganglia ............ 76 (D) Phenytoin action on the sodium pump. (1) Post-tetanic hyperpolarizations................................ 83 (2) Carbachol-induced depolarizations............................. 84 Chapter Four; Ca-spikes in rat preganglionic cervical sympathetic nerves. (A) Introduction......................................I .................. 91 (B) Methods............................................................... 95 (C) Results. (1) Comparison of Na- and Ca-spikes................................ 95 (2) Generation of Ca-spikes in the absence of sodium ............. 96 (3) Properties of the potassium channel block required to reveal Ca-spikes................................... 96 (4) Substitution of calcium by strontium or barium ............... 98 (5) Inorganic calcium channel antagonists......................... 99 (6) Comparison of the blocking actions of drugs on Na- and Ca-spikes................................................ 99 Chapter Five: Discussion. (A) Physiology of preganglionic cervical sympathetic nerve compound action potentials.................................................... 117 (B) Ca-spikes in isolated rat preganglionic cervical sympathetic 6 nerves............................................................. 118 (C) Action of the antiepileptic and other drugs. (1) Sodium channel block. (i) Basal B l o c k ................................................... 123 (ii) Frequency-dependent b l o c k ................................. 126 (iii) Intracellular results.................................... 127 (2) Action on the sodium pump. (i) Post-tetanic hyperpolarizations..%....................... 129 (ii) Action on carbachol-induced depolarizations............ 130 (3) Action of the antiepileptic and other drugs on the Ca-spike .................................................. 132 (D) Possible mechanism of action of the antiepileptic drugs ........ 134 Chapter Six: The action of catecholamines and adenosine on ca-spikes (A) Introduction. (1) Presynaptic inhibition by catecholamines in superior cervical ganglia ................................................ 142 (2) Possible mechanisms of catecholamine action ................. 144 (3) The actions of adenosine in superior cervical ganglia 147 (4) Possible mechanisms of adenosine action .................... 148 (5) A i m s ............................................................. 149 (B) Methods. (1) Recording techniques and solutions.......................... 150 (2) Analysis of results............................................ 150 (C) Results. (1) The action of catecholamine agonists on the Ca-spike ...... 151 (2) Effects of adrenoceptor antagonists on the catecholamine resp on se s........................................................ 152 (3) Action of beta-adrenoceptor drugs on the Ca-spike ......... 153 (4) Action of adenosine on the Ca-spike .......................... 153 (5) Action of potassium channel blockers on L-noradrenaline and adenosine effects on the Ca-spike. (i) 10 mM Tetraethylammonium (TEA)........................... 154 (ii) 1 mM Ba r i u m ................................................ 155 (iii) Barium sp i k e s ............................................. 155 7 (iv) Action of C a e s i u m ......................................... 155 (6) Comparison of effects of L-noradrenaline and adenosine on the Ca-spike with their actions on the superior cervical ganglion (i) Action of adrenoceptor antagonists...................... 156 (ii) The effect of 4-AP on responses to L-noradrenaline and adenosine in the superior cervical ganglion.......... 157 (iii) Comparison of the action of catecholamines on unstimulated preparations and the effects of 4-AP... 157 (iv) Action of forskolin on responses to catecholamine and a d en osi ne..................................................
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