Actions of general anaesthetics and arachidonic pathway inhibitors on K+ currents activated by volatile anaesthetics and FMRFamide in molluscan neurones.
1. K+ currents activated by volatile general anaesthetics (IK(An)) and by the neuropeptide FMRFamide (IK(FMRFa)) were studied under voltage clamp in isolated identified neurones from the pond snail Lymnaea stagnalis. 2. IK(An) was activated by all the volatile anaesthetics studied. The maximal responses varied from agent to agent, with halothane sevoflurane > isoflurane > enflurane approximately chloroform. 3. IK(An) was inhibited rather than activated by the n-alcohols from hexanol to dodecanol and by the 6- and 8-carbon cycloalcohols. The n-alcohols exhibited a cutoff effect, with dodecanol being unable to half-inhibit IK(An). 4. Unlike IK(An) which did not desensitize at reasonable halothane concentrations, IK(FMRFa) desensitized at most FMRFamide concentrations studied. This desensitization could be substantially removed by halothane. Nonetheless, both IK(An) and IK(FMRFa) had similar sensitivities to the potassium channel blockers tetraethylammonium and 4-aminopyridine, consistent with both currents flowing through the same channels. Responses to low concentrations of halothane and FMRFamide showed synergy. 5. The phospholipase A2 inhibitor aristolochic acid inhibited IK(An), consistent with a role for arachidonic acid (AA). The lipoxygenase and cyclooxygenase inhibitor nordihydroguaiaretic acid blocked IK(FMRFa) but did not affect IK(An). IK(An) and IK(FMRFa) were little affected by the cyclooxygenase inhibitor indomethacin. These findings suggest that neither lipoxygenase nor cyclooxygenase pathways of AA metabolism are involved in the anaesthetic activation of IK(An. 6. Inhibitors of a third, cytochrome P450-mediated, pathway of AA metabolism (clotrimazole and econazole) potently blocked IK(An), suggesting possible roles for certain cytochrome P450 isoforms in the activation of IK(An).
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Biophysics Section, The Blackett Laboratory, Imperial College of Science, Technology and Medicine, South Kensington, London.
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Lieb
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D000438:Alcohols / Q000494:pharmacology; D018681:Anesthetics, General / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019835:FMRFamide / Q000494:pharmacology*; D006221:Halothane / Q000494:pharmacology; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008974:Mollusca; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism
D000438:Alcohols; D018681:Anesthetics, General; D018685:Anesthetics, Inhalation; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D015221:Potassium Channels; D019835:FMRFamide; D006221:Halothane