Cardiovascular effects of H3 histamine receptor inverse agonist/ H4 histamine receptor agonist, clobenpropit, in hemorrhage-shocked rats

Hemorrhagic shock has a potential to be life-threatening when it is not treated. The main causes of hemorrhagic shock involve: (1) forces causing injury; and (2) diseases that can cause hemorrhage., Therefore, due to the causes of hemorrhagic shock and the life-threatening potential, the search for new methods of shock treatment is extremely valuable to the modern medicine. The aim of this study was to investigate the influence of clobenpropit in the model of hemorrhagic shock. The experiments were conducted in 110 adult male Wistar rats weighing between 205 and 470g. 1, 2 and 5 μmol/kg of intravenous H3 receptors reverse agonists, clobentropit, and/or 1, 5 and 10 μmol/kg H3 receptor agonist, imetit, were used as general anesthetics. Irreversible hemorrhagic shock was induced by the paused bleeding until the mean arterial pressure (MAP) lowered to the level of 20–25 mmHg. It was proved that, in cases of critical hypotension, clobenpropit triggered a dose-dependent increase of: systolic blood pressure (SBP), diastolic blood pressure (DBP), MPA and heart rate (HR) of rats with critical hypotension. The most significant changes in hemodynamic parameters were achieved by administrating dosages of 2 mmol/kg. This resulted in the survival rate increase to up to 100%. However, imetit did not trigger any hemodynamic changes nor an increase in SBP, DBP, MAP or HR. Furthermore, it was found that the premedication with prazosin, yohimbine, 6-hydroxydopamine and the vasopressin V1a receptor antagonist blocked the effects of clobenpropit. Additionally, premedication with propranolol, captopril and ZD 7155 did not cause any significant changes in the measured hemodynamic parameters. In conclusion, after an intravenous injection clobenpropit, the inverse agonist of H3 histamine receptors/agonist of histamine receptors H4, causes a resuscitating effect on rats in hemorrhagic shock. Moreover, such effect is based on the effector mechanisms of sympathetic nervous system and vasopressin.

失血性休克若未得到及时救治，可危及生命。该病症的主要致病因素包括：(1) 致伤外力；(2) 可引发出血的疾病。鉴于失血性休克的致病机制与致死风险，探寻新型休克治疗方法对现代医学具有极高的研究价值。
本研究旨在探究氯苯丙哌啶（clobenpropit）对失血性休克模型的干预效应。实验选用110只体重介于205~470g的成年雄性Wistar大鼠，通过静脉给予1、2及5 μmol/kg的H3受体反向激动剂氯苯丙哌啶（clobenpropit），以及1、5及10 μmol/kg的H3受体激动剂伊美替特（imetit）作为全身麻醉剂。
通过控制性放血直至平均动脉压（mean arterial pressure, MAP）降至20~25 mmHg，以此构建不可逆失血性休克模型。实验结果显示，在严重低血压状态下，氯苯丙哌啶可呈剂量依赖性提升重度低血压大鼠的收缩压（systolic blood pressure, SBP）、舒张压（diastolic blood pressure, DBP）、平均动脉压及心率（heart rate, HR）。其中，以2 mmol/kg给药剂量的血流动力学改善效果最为显著，可使大鼠存活率提升至100%。
然而，伊美替特未引发任何血流动力学变化，亦未对收缩压、舒张压、平均动脉压及心率产生提升作用。进一步研究发现，预先给予哌唑嗪、育亨宾、6-羟基多巴胺及血管加压素V1a受体拮抗剂，可阻断氯苯丙哌啶的上述效应；而预先给予普萘洛尔、卡托普利及ZD 7155，则未对检测的血流动力学参数造成显著影响。
综上，静脉注射H3组胺受体反向激动剂/ H4组胺受体激动剂氯苯丙哌啶后，可对失血性休克大鼠产生明确的复苏效应，且该效应依赖于交感神经系统与血管加压素的信号传导通路。