Cardiovascular effects of NA+/H+ exchanger inhibition with BIIB513 following hypovolemic circulatory shock.

Na(+)/H(+) exchange (NHE) is involved in the myocardial injury that occurs during ischemia and reperfusion. The goal of the present study was to investigate the role of NHE in hypovolemic circulatory shock by using a potent NHE-1 selective inhibitor BIIB513. Acute rapid hemorrhage was induced in 14 pigs by bleeding (30 mL/kg over 30 min). Seven pigs were used as saline control. Seven other pigs received 3 mg/kg BIIB513 at 30 min after hemorrhage. Each experiment consisted of 2 h of hypovolemia followed by 2 h of fluid resuscitation. One control animal died before the experiment was completed. Six other control animals survived the entire experiment. In contrast, all the BIIB513 treated animals survived the entire protocol. Acute rapid blood loss resulted in impaired myocardial performance as well as severe hemodynamic and metabolic alterations. NHE blockade attenuated the hypovolemic hypotension and improved myocardial performance. NHE blockade also attenuated the metabolic acidosis, improved tissue oxygen delivery, and improved cardiac function from resuscitation. The circulating levels of creatine phosphokinase (CPK) and cardiac troponin-I were significantly lower in the BIIB513 treatment group. These results suggest that NHE activation plays an important pathophysiological role in hypovolemic circulatory shock, and NHE-1 blockade is a powerful intervention to improve cardiovascular outcomes of resuscitation from prolonged hypovolemic circulatory shock.