A number of beneficial effects of ATP-MgCl2 administration have been demonstrated in preheparinized models of shock and ischemia. However, it is not known whether ATP-MgCl2 restores and maintains the depressed cardiac output in a nonheparinized model of trauma and severe hemorrhage in which resuscitation following shock was provided only with crystalloid. To study this, rats underwent a midline laparotomy (i.e., trauma induced) and were then bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximum shed blood volume was returned in the form of Ringer's lactate (RL). Animals were then resuscitated with 4 times the volume of shed blood with RL (4x RL) during and following which ATP-MgCl2 (50 μmol/kg body weight each or an equivalent volume of normal saline) was infused intravenously. Cardiac output was determined every 15-30 min for 4.5 hr, using an in vivo hemoreflectometer and indocyanine green dilution technique. Resuscitation with 4x RL transiently restored but did not maintain cardiac output; however, ATP-MgCl2 treatment restored and maintained cardiac output at control values. ATP-MgCl2 infusion also significantly decreased total peripheral resistance and attenuated tissue water content. Thus, ATP-MgCl2 appears to be a promising adjunct to the treatment of trauma-hemorrhage even in the absence of blood resuscitation.