TASK-1 (KCNK3) and TASK-3 (KCNK9) Tandem Pore Potassium Channel Antagonists Stimulate Breathing in Isoflurane-Anesthetized Rats

BACKGROUND: TASK-1 and TASK-3 tandem pore potassium channel subunits provide a constitutive acidic pH- and hypoxia-inhibited potassium conductance. TASK channels are expressed in a number of tissues involved in regulation of breathing, and the TASK-1/TASK-3 heterodimer provides the predominant hypoxia-sensitive potassium conductance in carotid body type 1 glomus chemosensing cells. The carotid bodies have an important role in regulation of breathing. Doxapram is a potent TASK-1 and TASK-3 potassium channel antagonist and a carotid body and breathing stimulant. PK-THPP and A1899 are potent and selective TASK-1 and TASK-3 antagonists. I hypothesized PK-THPP and A1899 are, like doxapram, breathing stimulants. METHODS: I studied rat TASK-3 potassium channel function by Ussing chamber using Fischer rat thyroid monolayers. To quantify breathing effects, I studied male Sprague Dawley rats spontaneously breathing 1.5% isoflurane in room air by noninvasive plethysmography and by arterial blood gas analysis. RESULTS: PK-THPP, A1899, and doxapram inhibit rat TASK-3 potassium channel function with IC(50)s of 42 nM (33-52), 1.6 mu M (0.8-3.3), and 22 mu M (18-28) (n = 4-6; 95% confidence limits). IV PK-THPP, A1899, and doxapram stimulated breathing by plethysmography with a peak change in minute ventilation relative to baseline of 84% +/- 19% and 226% +/- 56% (for PK-THPP at 0.5 and 5 mg/kg; mean +/- SEM; n = 3-4; P < 0.05 and P < 0.001, respectively, relative to vehicle); 46% +/- 2% and 236% +/- 48% (for A1899 at 5 and 25 mg/kg; n = 3-4; P > 0.05 and P < 0.001, respectively); 103% +/- 20% (for doxapram at 25 mg/kg; n = 4), and 33% +/- 9% (for dimethylsulfoxide vehicle at 1 mL/kg; n = 4). PK-THPP and A1899, unlike doxapram, induced a profound and lasting respiratory alkalosis by arterial blood gas analysis. Thirty minutes after IV drug administration, I observed an arterial pH and carbon dioxide partial pressure of 7.62 +/- 0.02 and 23 +/- 0.8 mm Hg (for PK-THPP after 5 mg/kg; n = 4; P < 0.001 for both relative to vehicle), 7.49 +/- 0.02 and 31 +/- 2 mm Hg (for A1899 at 25 mg/kg; n = 6; P < 0.05 and 0.001, respectively), 7.43 +/- 0.03 and 39 +/- 4 mm Hg (for doxapram after 25 mg/kg; n = 4; P > 0.05 for both), and 7.38 +/- 0.03 and 48 +/- 4 mm Hg (for dimethylsulfoxide vehicle after 1 mL/kg; n = 3). CONCLUSIONS: PK-THPP and A1899 are potent rat TASK-3 antagonists and effective breathing stimulants. PK-THPP and A1899 effects on breathing were of greater magnitude and/or duration relative to that of doxapram. PK-THPP and A1899 or related compounds may have therapeutic potential for treating breathing disorders..(Anesth Analg 2013;116:810-6)