title: Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements after hemorrhagic shock in rats.
abstract: BACKGROUND
  Recent evidence suggests that drugs targeting Kv7 channels could be used to modulate vascular function and blood pressure. Here, we studied whether Kv7 channel inhibitors can be utilized to stabilize hemodynamics and reduce resuscitation fluid requirements after hemorrhagic shock.
  
  
  METHODS
  Anesthetized male Sprague-Dawley rats were instrumented with arterial and venous catheters for blood pressure monitoring, hemorrhage and fluid resuscitation. Series 1: Linopirdine (Kv7 channel blocker, 0.1-6 mg/kg) or retigabine (Kv7 channel activator, 0.1-12 mg/kg) were administered to normal animals. Series 2: Animals were hemorrhaged to a MAP of 25 mmHg for 30 min, followed by fluid resuscitation with normal saline (NS) to a MAP of 70 mmHg until t = 75 min. Animals were treated with single bolus injections of vehicle, linopirdine (1-6 mg/kg), XE-991 (structural analogue of linopirdine with higher potency for channel blockade, 1 mg/kg) prior to fluid resuscitation. Series 3: Animals were resuscitated with NS alone or NS supplemented with linopirdine (1.25-200 μg/mL). Data were analyzed with 2-way ANOVA/Bonferroni post-hoc testing.
  
  
  RESULTS
  Series 1: Linopirdine transiently (10-15 min) and dose-dependently increased MAP by up to 15%. Retigabine dose-dependently reduced MAP by up to 60%, which could be reverted with linopirdine. Series 2: Fluid requirements to maintain MAP at 70 mmHg were 65 ± 34 mL/kg with vehicle, and 57 ± 13 mL/kg, 22 ± 8 mL/kg and 22 ± 11 mL/kg with intravenous bolus injection of 1, 3 and 6 mg/kg linopirdine, respectively. XE-991 (1 mg/kg), reduced resuscitation requirements comparable to 3 mg/kg linopirdine. Series 3: When resuscitation was performed with linopirdine-supplemented normal saline (NS), fluid requirements to stabilize MAP were 73 ± 12 mL/kg with NS alone and 72 ± 24, 61 ± 20, 36 ± 9 and 31 ± 9 mL/kg with NS supplemented with 1.25, 6.25, 12.5 and 200 μg/mL linopirdine, respectively.
  
  
  CONCLUSIONS
  Our data suggest that Kv7 channel blockers could be used to stabilize blood pressure and reduce fluid resuscitation requirements after hemorrhagic shock.
authors.affiliation: Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago, Stritch School of Medicine, 2160 S. 1st Avenue, Maywood, IL, 60153, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Nassoiy
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Stritch School of Medicine, 2160 S. 1st Avenue, Maywood, IL, 60153, USA.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Byron
authors.affiliation: Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago, Stritch School of Medicine, 2160 S. 1st Avenue, Maywood, IL, 60153, USA. mmajetschak@luc.edu.|Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Stritch School of Medicine, 2160 S. 1st Avenue, Maywood, IL, 60153, USA. mmajetschak@luc.edu.
authors.forename: Matthias
authors.initials: M
authors.lastname: Majetschak
mesh_terms: D000818:Animals; D002219:Carbamates / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors*; D008297:Male; D010655:Phenylenediamines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000628:therapy*
chemical_list: D002219:Carbamates; D007211:Indoles; D051656:KCNQ Potassium Channels; D010655:Phenylenediamines; D026902:Potassium Channel Blockers; D011725:Pyridines; C101866:ezogabine; C061017:linopirdine
keywords: Blood pressure; Hemodynamics; Hemorrhagic shock; Linopirdine; Resuscitation fluid; Retigabine