Jones, Alan Glyn; (1995) A study of the pharmacology of G protein-coupled potassium channels in rat atrial myocytes and guinea-pig submucous plexus neurones. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This study has sought to expand the rather limited pharmacological knowledge of the Gmail.com protein-coupled potassium channel of the rat atrial myocyte and guinea-pig submucous plexus neurone. These tissues were enzymatically dissociated and the cells kept in short term culture. Initially they were studied with microelectrodes using agonists to induce G protein-coupled conductances; noradrenaline and somatostatin in the case of the neurone, adenosine in the myocyte. A number of agents known to block other K+ channels were tested, of which the three most studied were cetiedil, which was developed as an antisickling agent, clotrimazole, an antifungal drug and propafenone, an antidysrhythmic. Using these and other drugs, the pharmacological profiles of the two tissues were found to be similar, but not identical. In the submucous plexus the order of potency was clotrimazole>propafenone>cetiedil, in the atrial myocyte clotrimazole>cetiedil>propafenone. The three drugs also depolarised the two tissues and reduced the resting membrane conductance, suggesting that they also blocked a tonically-active potassium conductance. There was also some suggestion from intracellular experiments that clotrimazole may have been use-dependent in its mode of action; the level of block seemed to increase after the application of agonist. Active drugs were also tested on voltage-clamped cells in whole cell configuration in which the potassium conductance had been permanently activated with GTP-γ-S to confirm that the drugs were not simply acting as receptor antagonists, and to rule out the possibility of membrane rectification distorting the results obtained from voltage recording experiments. Other currents of the submucous plexus neurone were studied; the delayed rectifier was sensitive to all three blockers (clotrimazole>cetiedil>propafenone), whereas the A-current was insensitive to clotrimazole and cetiedil. The tetrodotoxin-sensitive sodium current of these neurones was blocked by all three compounds at very similar concentrations. Cetiedil, clotrimazole and propafenone turned out to be fairly non-selective in their actions; their relative activities did, however, suggest that there may be a difference between the G protein-linked channels of rat atrial myocyte and guinea-pig submucous plexus neurones.

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