Effects of the Kv7 voltage‐activated potassium channel inhibitor linopirdine in rat models of haemorrhagic shock

Abstract

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.

Natural and engineered chemokine (C-X-C motif) receptor 4 agonists prevent acute respiratory distress syndrome after lung ischemia–reperfusion injury and hemorrhage

“…There were no statistically significant differences among groups. We showed previously that in rats ventilated with FiO 2 of 1.0, the hemorrhage protocol alone does not lead to impairment of lung function during crystalloid resuscitation within the time period studied 16 . Therefore, the thoracic injury component, i.e.…”

Impact of KvLQT1 potassium channel modulation on alveolar fluid homeostasis in an animal model of thiourea-induced lung edema

“…However, direct evidence of KvLQT1 function in endothelial integrity, using specific pharmacological drugs, has, to the best of our knowledge, never been reported. Nevertheless, inhibition of vascular Kv7 channels, after intravenous administration of the broad KCNQ blocker linopirdine reduced fluid resuscitation requirements and tissue edema formation after hemorrhagic shock ( Nassoiy et al, 2018 ). On the contrary, Khimenko et al showed that K ATP activation both protected against, and reversed, the increase in endothelial permeability associated with ischemia-reperfusion injury in a model of isolated rat lungs ( Khimenko et al, 1995 ).…”

Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock

“…Male Sprague-Dawley rats (300-405 g) were purchased from Envigo (Indianapolis, IN, USA). The hemorrhagic shock models were performed as described previously [10,[12][13][14]. In brief, anesthesia induction was performed with the animal and isoflurane-soaked gauze placed in a bell jar.…”