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 IC50s of 42 nM (33-52), 1.6 μM (0.8-3.3), and 22 μM (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.