Gazmuri Raúl J, Ayoub Iyad M, Kolarova Julieta D, Karmazyn Morris
Section of Critical Care Medicine, North Chicago VA Medical Center, North Chicago, IL 60064, USA.
Crit Care Med. 2002 Apr;30(4 Suppl):S166-71. doi: 10.1097/00003246-200204001-00010.
Activation of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) in response to the intense intracellular acidosis that develops during ischemia has been identified as an important mechanism of myocardial cell injury. NHE-1 inhibition in the quiescent (nonfibrillating) heart ameliorates functional manifestation of ischemia and reperfusion injury. We investigated in isolated heart and intact rat models of ventricular fibrillation whether NHE-1 inhibition, by using the selective inhibitor cariporide, could ameliorate myocardial abnormalities that develop during ventricular fibrillation and limit resuscitability and survival. In the isolated rat heart, cariporide significantly reduced the magnitude of ischemic contracture during ventricular fibrillation and the accompanying increases in coronary vascular resistance. Hearts that had received cariporide during ventricular fibrillation had no diastolic dysfunction after resuscitation and recovered their systolic function earlier. In intact rats, cariporide given immediately before starting chest compression allowed generation of a coronary perfusion pressure and end-tidal Pco2 comparable with control rats but with significantly less depth of compression. Cariporide had an unprecedented effect in this rat model, prompting spontaneous defibrillation after approximately 8 mins of chest compression. After resuscitation, rats treated with cariporide had significantly less ventricular ectopic activity, better hemodynamic function, and higher survival rates (22 of 24 [94%] vs. 15 of 24 [63%] in control rats, p <.05). We conclude that NHE-1 inhibition may represent a novel and highly effective form of treatment for resuscitation from ventricular fibrillation.
缺血期间发生的强烈细胞内酸中毒会激活肌膜钠氢交换体同工型1（NHE-1），这已被确定为心肌细胞损伤的重要机制。在静息（非颤动）心脏中抑制NHE-1可改善缺血和再灌注损伤的功能表现。我们在离体心脏和完整大鼠心室颤动模型中研究了使用选择性抑制剂卡里波罗ide抑制NHE-1是否能改善心室颤动期间出现的心肌异常，并限制复苏能力和生存率。在离体大鼠心脏中，卡里波罗ide显著降低了心室颤动期间缺血性挛缩的程度以及随之而来的冠状动脉血管阻力增加。在心室颤动期间接受卡里波罗ide的心脏在复苏后没有舒张功能障碍，并且更早恢复其收缩功能。在完整大鼠中，在开始胸外按压前立即给予卡里波罗ide可产生与对照大鼠相当的冠状动脉灌注压和呼气末二氧化碳分压，但所需的按压深度明显更小。卡里波罗ide在该大鼠模型中产生了前所未有的效果，在胸外按压约8分钟后促使自发除颤。复苏后，接受卡里波罗ide治疗的大鼠室性异位活动明显减少，血流动力学功能更好，生存率更高（24只中有22只[94%]，而对照大鼠为24只中有15只[63%]，p<.05）。我们得出结论，抑制NHE-1可能代表一种用于心室颤动复苏的新型且高效的治疗形式。
