title: Kv7 (KCNQ) channel openers induce hypothermia in the mouse.
abstract: Kv7 channels, encoded by corresponding kcnq genes, are expressed both centrally and peripherally where they serve to dampen neuronal activity. While Kv7 channel openers have shown efficacy in neurological and neuropsychiatric disease models, the impact of Kv7 channel activation on physiological endpoint markers have not been addressed in detail. In this study we assessed the effect of a range of Kv7 channel openers with different affinity for neuronal Kv7.2-5 channel subunits on body temperature regulation in mice. Female NMRI mice were acutely exposed to vehicle (10% Tween-80, i.p.), retigabine (3-30 mg/kg, i.p., pan-Kv7 channel opener), (S)BMS-204352 (60-240 mg/kg, i.p., Kv7.4/5 channel-preferring opener), ICA-27243 (1-10mg/kg, i.p., Kv7.2/3 channel-preferring opener), or S-(1) (10-60 mg/kg, i.p., Kv7.2/3 channel-preferring opener), and rectal body temperature was measured 15-120 min post-injection. Retigabine (>10mg/kg), ICA-27243 (≥ 10 mg/kg), and S-(1) (≥ 30 mg/kg) dose-dependently lowered rectal body temperature with maximal doses of each Kv7 channel opener inducing a marked drop (>4°C) in rectal temperature. The Kv7 channel openers showed differential temporal pharmacodynamics, which likely reflects their different pharmacokinetic profiles. Pretreatment with the pan-Kv7 channel blocker XE-991 (1.0mg/kg, i.p.) completely reversed the hypothermic effect of the pan-Kv7 opener, retigabine (15 mg/kg), whereas ICA-27243-induced hypothermia (10mg/kg) could only be partially prevented by XE-991. Because ICA-27743 and S-(1) are Kv7.2/3 channel subunit-preferring compounds, this suggests that the Kv7.2/3 channel isoform is the predominant substrate for Kv7 channel opener-evoked hypothermia. These data indicate the physiological relevance of Kv7 channel function on body temperature regulation which may potentially reside from central inhibitory Kv7 channel activity.
authors.affiliation: CNS Pharmacology - Psychiatry, Neurosearch A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark.
authors.forename: Line V
authors.initials: LV
authors.lastname: Kristensen
authors.forename: Karin
authors.initials: K
authors.lastname: Sandager-Nielsen
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Hansen
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001833:Body Temperature Regulation / Q000187:drug effects / Q000502:physiology*; D002219:Carbamates / Q000494:pharmacology; D005260:Female; D007035:Hypothermia; D007211:Indoles / Q000494:pharmacology; D051656:KCNQ Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D010655:Phenylenediamines / Q000494:pharmacology; D020033:Protein Isoforms / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D000927:Anticonvulsants; C424388:BMS204352; D001549:Benzamides; D002219:Carbamates; D007211:Indoles; D051656:KCNQ Potassium Channels; C527835:N-(6-Chloropyridin-3-yl)-3,4-difluorobenzamide; D010655:Phenylenediamines; D020033:Protein Isoforms; D011725:Pyridines; C101866:ezogabine