title: TASK-1 (KCNK3) and TASK-3 (KCNK9) tandem pore potassium channel antagonists stimulate breathing in isoflurane-anesthetized rats.
abstract: 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.
authors: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, GRB 444, 55 Fruit St., Boston, MA 02114, USA. jcotten@partners.or
authors: Joseph F
authors: JF
authors: Cotten
mesh_terms: D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D044482:Benzeneacetamides / Q000494:pharmacology; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D004315:Doxapram / Q000494:pharmacology; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D007530:Isoflurane; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D010991:Plethysmography; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors*; D011427:Propiophenones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects*; D019141:Respiratory System Agents / Q000494:pharmacology; D013268:Stimulation, Chemical
chemical_list: C558924:A 1899; D018685:Anesthetics, Inhalation; D001549:Benzamides; D044482:Benzeneacetamides; D007202:Indicators and Reagents; C407082:Kcnk9 protein, rat; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; D011427:Propiophenones; D019141:Respiratory System Agents; C014870:flopropione; C420132:potassium channel subfamily K member 3; D004315:Doxapram; D007530:Isoflurane