Background-Both ␣ 1 -and -adrenergic agonists increase the severity of global myocardial ischemic injury. We hypothesized that combined -and ␣ 1 -adrenergic blockade would improve initial resuscitation and postresuscitation myocardial and neurological functions. We further hypothesized that the resulting ␣ 2 -actions of relatively brief duration would favor improved functions compared with the more prolonged effect of nonadrenergic vasopressin. Methods and Results-Three groups of 5 male domestic pigs weighing 37Ϯ3 kg were investigated. Ventricular fibrillation was untreated for 7 minutes before the start of precordial compression, mechanical ventilation, and attempted defibrillation. Animals were randomized to receive central venous injections of equipressor doses of (1) epinephrine, (2) epinephrine in which both ␣ 1 -and -adrenergic effects were blocked by previous administration of prazosin and propranolol, and (3) vasopressin during CPR. All but 1 animal were successfully resuscitated. After injection of epinephrine, significantly better cardiac output and fractional area change, together with lesser increases in troponin I, were observed after ␣ 1 -and -adrenergic blockade. Postresuscitation neurological function was also improved after ␣ 1 -and -block in comparison with unblocked epinephrine and after vasopressin. Conclusions-Equipressor doses of epinephrine, epinephrine after ␣ 1 -and -adrenergic blockade, and vasopressin were equally effective in restoring spontaneous circulation after prolonged ventricular fibrillation. However, combined ␣ 1 -and -adrenergic blockade, which represented a predominantly selective ␣ 2 -vasopressor effect, resulted in improved postresuscitation cardiac and neurological recovery.