The ventilatory stimulant doxapram inhibits TASK tandem pore (K2P) potassium channel function but does not affect minimum alveolar anesthetic concentration.
TWIK-related acid-sensitive K(+)-1 (TASK-1 [KCNK3]) and TASK-3 (KCNK9) are tandem pore (K(2P)) potassium (K) channel subunits expressed in carotid bodies and the brainstem. Acidic pH values and hypoxia inhibit TASK-1 and TASK-3 channel function, and halothane enhances this function. These channels have putative roles in ventilatory regulation and volatile anesthetic mechanisms. Doxapram stimulates ventilation through an effect on carotid bodies, and we hypothesized that stimulation might result from inhibition of TASK-1 or TASK-3 K channel function. To address this, we expressed TASK-1, TASK-3, TASK-1/TASK-3 heterodimeric, and TASK-1/TASK-3 chimeric K channels in Xenopus oocytes and studied the effects of doxapram on their function. Doxapram inhibited TASK-1 (half-maximal effective concentration [EC50], 410 nM), TASK-3 (EC50, 37 microM), and TASK-1/TASK-3 heterodimeric channel function (EC50, 9 microM). Chimera studies suggested that the carboxy terminus of TASK-1 is important for doxapram inhibition. Other K2P channels required significantly larger concentrations for inhibition. To test the role of TASK-1 and TASK-3 in halothane-induced immobility, the minimum alveolar anesthetic concentration for halothane was determined and found unchanged in rats receiving doxapram by IV infusion. Our data indicate that TASK-1 and TASK-3 do not play a role in mediating the immobility produced by halothane, although they are plausible molecular targets for the ventilatory effects of doxapram.
Cotten
Joseph F
JF
Department of Anesthesia and Perioperative Care, University of California San Francisco, USA.
Keshavaprasad
Bharat
B
Laster
Michael J
MJ
Eger
Edmond I
EI
Yost
C Spencer
CS
D018685:Anesthetics, Inhalation / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004315:Doxapram / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism*; D012123:Pulmonary Ventilation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019141:Respiratory System Agents / Q000378:metabolism / Q000494:pharmacology*; D014982:Xenopus laevis
D018685:Anesthetics, Inhalation; D000697:Central Nervous System Stimulants; D024683:Potassium Channels, Tandem Pore Domain; D019141:Respiratory System Agents; D004315:Doxapram