Elliott, Peter; (1990) The action of antiepileptic and other drugs on Na- and Ca-spikes in mammalian non-myelinated nerves. Doctoral thesis (Ph.D), UCL (University College London).

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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 were maintained on substituting Sr2+ or Ba2+ for Ca2+ but were blocked by inorganic Ca channel antagonists, with the following order of potency (IC50): Cd2+ (3.3 uM) > La3+ (6.9 uM) > Ni2+ (44 uM) > Co2+ (0.47 mM) > Mn2+ (0.71 mM) > Mg2+ (16.4 mM). 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 (0.2-20Hz). 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 IC50s °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% (IC50 1.5 uM). Potencies (IC50) 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 pA2 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.

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