Abstract 16059: Centhaquin Citrate Improves Cerebral Blood Flow and Reduces Oxidative Stress Following Hemorrhagic Shock in Rats
Introduction: Centhaquin citrate (PMZ-2010) undergoing clinical trial (NCT02408731) has been shown in animal studies to be an effective resuscitative agent, significantly improving survival of hemorrhagic shock by reducing blood lactate and increasing cardiac output and mean arterial pressure (MAP) while decreasing vascular resistance.
Specific aim: The present study was conducted in rats to determine the effects of centhaquin resuscitation on cerebral blood flow (CBF) and oxidative stress following hemorrhagic shock.
Methods: Hemorrhagic shock was induced in male Sprague Dawley rats by withdrawing blood to maintain a MAP of 35 mmHg for 30 min. Following hemorrhage, rats received a 10 min infusion of Ringer’s lactate (LR; 100% shed blood volume), LR + 0.017 mg/kg centhaquin, LR + 0.05 mg/kg centhaquin, or LR + 1 μg/kg norepinephrine (NE). Blood gases, MAP, HR, and CBF were monitored for 90 min post resuscitation, and brains were evaluated for oxidative stress parameters.
Results: Resuscitation increased MAP in all groups from 35 mmHg to 75-85 mmHg. The 0.05 mg/kg centhaquin group, however, maintained a higher MAP at both 30 min (61 ± 1.5 mmHg) and 90 min (49 ± 2.6 mmHg) post resuscitation as compared to the LR (48 ± 3.2 and 37 ± 4.7 mmHg) and NE (51 ±3.3 and 31 ±2.7) groups. Following hemorrhage, CBF was reduced by ~35% and increased in all groups returning back to baseline by the end of resuscitation. However, at 30 min post resuscitation, CBF in the LR and NE groups was decreased to -23% and -29%, respectively, from baseline. On the other hand, CBF in the 0.05 mg/kg centhaquin group decreased only -3.2% from the baseline at 30 min and remained significantly higher (P<0.05) compared to LR and NE groups for up to 90 min after resuscitation. Brain lipid peroxidation was reduced (P<0.0001) and antioxidants SOD and GSH were increased (P<0.001) in the centhaquin groups as compared to LR and NE.
Conclusions: This is the first report that centhaquin citrate resuscitation preserves CBF and reduces oxidative damage to the brain following hemorrhagic shock. These findings, combined with previous results, suggest that centhaquin citrate is a novel and effective resuscitation agent for the treatment of hemorrhagic shock.
Author Disclosures: M. Leonard: None. Z. Zhang: None. S. Briyal: None. G. Pais: None. S. Patel: None. A. Gulati: Ownership Interest; Modest; Patent issued as inventor.
- © 2016 by American Heart Association, Inc.