ACTIONS OF GENERAL-ANESTHETICS AND ARACHIDONIC-ACID PATHWAY INHIBITORS ON K+ CURRENTS ACTIVATED BY VOLATILE ANESTHETICS AND FMRFAMIDE IN MOLLUSCAN NEURONS
Cmb. Lopes et al., ACTIONS OF GENERAL-ANESTHETICS AND ARACHIDONIC-ACID PATHWAY INHIBITORS ON K+ CURRENTS ACTIVATED BY VOLATILE ANESTHETICS AND FMRFAMIDE IN MOLLUSCAN NEURONS, British Journal of Pharmacology, 125(2), 1998, pp. 309-318
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 sta
gnalis. 2 I-K(An) was activated by all the volatile anaesthetics studi
ed. The maximal responses varied from agent to agent, with halothane a
pproximate to sevoflurane > isoflurane > enflurane approximate to chlo
roform. 3 I-K(An) was inhibited rather than activated by the n-alcohol
s 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 substa
ntially removed by halothane. Nonetheless, both I-K(An) and I-K(FMRFa)
had similar sensitivities to the potassium channel blockers tetraethy
lammonium and 4-aminopyridine, consistent with both currents flowing t
hrough the same channels. Responses to low concentrations of halothane
and FMRFamide showed synergy. 5 The phospholipase A(2) inhibitor aris
tolochic acid inhibited I-K(An), consistent with a role for arachidoni
c acid (AA). The lipoxygenase and cyclooxygenase inhibitor nordihydrog
uaiaretic 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 in
domethacin. These findings suggest that neither lipoxygenase nor cyclo
oxygenase pathways of AA metabolism are involved in the anaesthetic ac
tivation of I-K(An). 6 Inhibitors of a third, cytochrome P450-mediated
, pathway of AA metabolism (clotrimazole and econazole) potently block
ed I-K(An), suggesting possible roles for certain cytochrome P450 isof
orms in the activation of I-K(An).