Actions of general anaesthetics and arachidonic acid pathway inhibitors on K+ currents activated by volatile anaesthetics and FMRFamide in molluscan neurones

1 K+ currents activated by volatile general anaesthetics (I-K(An)) and by the neuropeptide FMRFamide (I-K(FMRFn)) were studied under voltage clamp in isolated identified neurones from the pond snail Lymnaea stagnalis. 2 I-K(An) was activated by all the volatile anaesthetics studied. The maximal responses varied from agent to agent, with halothane approximate to sevoflurane > isoflurane > enflurane approximate to chloroform. 3 I-K(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 I-K(An). 4 Unlike I-K(An) which did not desensitize at reasonable halothane concentrations, I-K(FMRFa) desensitized at most FMRFamide concentrations studied. This desensitization could be substantially removed by halothane. Nonetheless, both I-K(An) and I-K(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 A(2) inhibitor aristolochic acid inhibited I-K(An), consistent with a role for arachidonic acid (AA). The lipoxygenase and cyclooxygenase inhibitor nordihydroguaiaretic acid blocked I-K(FMRFa) but did not affect I-K(An). I-K(An) and I-K(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 I-K(An). 6 Inhibitors of a third, cytochrome P450-mediated, pathway of AA metabolism (clotrimazole and econazole) potently blocked I-K(An), suggesting possible roles for certain cytochrome P450 isoforms in the activation of I-K(An).