Nassoiy Sean P, Byron Kenneth L, Majetschak Matthias
Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago, Stritch School of Medicine, 2160 S. 1st Avenue, Maywood, IL, 60153, USA.
Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Stritch School of Medicine, 2160 S. 1st Avenue, Maywood, IL, 60153, USA.
J Biomed Sci. 2017 Jan 17;24(1):8. doi: 10.1186/s12929-017-0316-1.
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.
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.
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.
Our data suggest that Kv7 channel blockers could be used to stabilize blood pressure and reduce fluid resuscitation requirements after hemorrhagic shock.
最近的证据表明，靶向Kv7通道的药物可用于调节血管功能和血压。在此，我们研究了Kv7通道抑制剂是否可用于稳定血流动力学并减少失血性休克后的复苏液体需求量。
对麻醉的雄性Sprague-Dawley大鼠植入动脉和静脉导管，用于血压监测、出血和液体复苏。系列1：将利诺吡啶（Kv7通道阻滞剂，0.1 - 6 mg/kg）或瑞替加滨（Kv7通道激活剂，0.1 - 12 mg/kg）给予正常动物。系列2：将动物出血至平均动脉压（MAP）为25 mmHg，持续30分钟，然后用生理盐水（NS）进行液体复苏，使MAP恢复至70 mmHg，直至t = 75分钟。在液体复苏前，动物接受单次推注溶媒、利诺吡啶（1 - 6 mg/kg）、XE - 991（利诺吡啶的结构类似物，对通道阻滞具有更高效力，1 mg/kg）治疗。系列3：动物单独用NS或用补充有利诺吡啶（1.25 - 200 μg/mL）的NS进行复苏。数据采用双向方差分析/Bonferroni事后检验进行分析。
系列1：利诺吡啶短暂地（10 - 15分钟）且剂量依赖性地使MAP升高高达15%。瑞替加滨剂量依赖性地使MAP降低高达60%，这可被利诺吡啶逆转。系列2：维持MAP在70 mmHg时，溶媒组的液体需求量为65 ± 34 mL/kg，静脉推注1、3和6 mg/kg利诺吡啶组分别为57 ± 13 mL/kg、22 ± 8 mL/kg和22 ± 11 mL/kg。XE - 991（1 mg/kg）降低的复苏需求量与3 mg/kg利诺吡啶相当。系列3：当用补充有利诺吡啶的生理盐水（NS）进行复苏时，单独用NS稳定MAP的液体需求量为73 ± 12 mL/kg，补充有1.25、6.25、12.5和200 μg/mL利诺吡啶的NS组分别为72 ± 24 mL/kg、61 ± 20 mL/kg、36 ± 9 mL/kg和31 ± 9 mL/kg。
我们的数据表明，Kv7通道阻滞剂可用于稳定失血性休克后的血压并减少液体复苏需求量。
