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Effects of the Kv7 voltage‐activated potassium channel inhibitor linopirdine in rat models of haemorrhagic shock
Author(s) -
Nassoiy Sean P.,
Babu Favin S.,
LaPorte Heather M.,
Byron Kenneth L.,
Majetschak Matthias
Publication year - 2018
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12958
Subject(s) - resuscitation , medicine , shock (circulatory) , anesthesia , saline , pharmacology
Summary Recently, we demonstrated that Kv7 voltage‐activated potassium channel inhibitors reduce fluid resuscitation requirements in short‐term rat models of haemorrhagic shock. The aim of the present study was to further delineate the therapeutic potential and side effect profile of the Kv7 channel blocker linopirdine in various rat models of severe haemorrhagic shock over clinically relevant time periods. Intravenous administration of linopirdine, either before (1 or 3 mg/kg) or after (3 mg/kg) a 40% blood volume haemorrhage, did not affect blood pressure and survival in lethal haemorrhage models without fluid resuscitation. A single bolus of linopirdine (3 mg/kg) at the beginning of fluid resuscitation after haemorrhagic shock transiently reduced early fluid requirements in spontaneously breathing animals that were resuscitated for 3.5 hours. When mechanically ventilated rats were resuscitated after haemorrhagic shock with normal saline ( NS ) or with linopirdine‐supplemented (10, 25 or 50 μg/ mL ) NS for 4.5 hours, linopirdine significantly and dose‐dependently reduced fluid requirements by 14%, 45% and 55%, respectively. Lung and colon wet/dry weight ratios were reduced with linopirdine (25/50 μg/ mL ). There was no evidence for toxicity or adverse effects based on measurements of routine laboratory parameters and inflammation markers in plasma and tissue homogenates. Our findings support the concept that linopirdine‐supplementation of resuscitation fluids is a safe and effective approach to reduce fluid requirements and tissue oedema formation during resuscitation from haemorrhagic shock.