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Title: Veterinary pharmacology, ion-channels and anthelmintics
Author: Martin, Richard John
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1997
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In this collection of papers modes of action of anthelmintic and anaesthetic drugs used in Veterinary Practice are investigated using electrophysiological techniques. New preparations and analytical techniques for investigation are described along with properties of ion-channel target sites. The pharmacology of piperazine, levamisole, pyrantel, morantel, oxtantel, avermectins, cyclic depsipeptides, ketamine, metomidate, alphaxalone and xylazine are studied. This information is reviewed in formats suitable for graduate and undergraduate study. Two-micropipette current-clamp and voltage-clamp techniques for recording effects of GABA agonists and antagonists on nematode muscle are developed using Ascaris suum. Piperazine, an anthelmintic, is shown to act as a GABA agonist of low potency and, like GABA, to mediate an increase in Cl conductance by an action on extrasynaptic receptors. Diethylcarbamazine, a piperazine derivative, did not act as a GABA agonist but blocked a voltage-activated K current. The agonist profile of the Ascaris GABA receptor was similar to vertebrate GABAA receptors but the antagonist profile was very different, indicating the presence of a distinctive type of receptor (GABAN). Novel arylaminopyridazine derivatives were synthesised and tested as competitive antagonists on the GABAN receptor. The KB for NCS 281-93, was 4.7 μM. A preparation suitable for patch-clamp studies was developed and GABA receptors activated by GABA and piperazine. Both agonists activated channels with a mean single-channel conductance of 22 pS but GABA mean open-times were longer (32ms) than those of piperazine (14 ms). The effects of ivermectin on muscle GABA receptors in Ascaris and on 19 pS Cl channels were observed using cell-attached and isolated inside-out patches. Ivermectin locked open the small Cl channels when applied to the outside membrane. A novel fluorescent and active bodily ivermectin analogue was synthesised and the movement of the probe followed in vesicle membranes using the FRAP (fluorescence recovery after photobleaching) technique. Quenching experiments showed that the ivermectin probe did not move through the cell membrane in the time scale of the experiment (30 min). A novel two-microelectrode current-clamp preparation of the Ascaris pharynx was used to show that an ivermectin analogue potentiated a glutamate gated Cl channel at low concentrations and produced an increase in the Cl conductance at a higher concentration. The actions of potent and novel potential anthelmintic cyclic depsipeptides were investigated using conventional parasitological techniques and the mode of action investigated in Ascaris muscle using current-clamp. It was found that these compounds did not act directly as a GABA agonist or acetylcholine antagonist. The actions of the anthelmintic praziquantel are reviewed and a tegumental preparation of Schistosoma mansoni developed for single-channel recording.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (D.Sc.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available