ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA IN ACUTE HYPOVOLEMIC HEMORRHAGIC-SHOCK IN RATS

Hemorrhagic shock was induced in male anesthetized rats by intermitten tly withdrawing blood from an iliac catheter until mean arterial blood pressure (MAP) fell and stabilized within the range of 20-30 mmHg. Su rvival rate, MAP, and serum and macrophage levels of tumor necrosis fa ctor-alpha (TNF-alpha) were then evaluated. Furthermore, in ex vivo st udies, the responsiveness to phenylephrine (PE; 1 nM to 10 mu M) was i nvestigated in aortic rings from hemorrhagic shocked rats. Antibodies raised against TNF-alpha (anti-TNF-alpha 2 mg/kg) or vehicle (phosphat e-buffered saline, 1 ml/kg) were injected intravenously 3 h before the bleeding. Vehicle-treated rats, subjected to hemorrhagic shock, exhib ited acute and serious hypotension (MAP = 20-30 mmHg) and high levels of serum (790 +/- 47 pg/ml) and macrophage (78 +/- 9 pg/ml) TNF-alpha and died within 30 min. Moreover, aortas from shocked rats showed a ma rked hypocontractility to PE compared with the reactivity of aortas fr om a group of sham shocked rats. Anti-TNF-alpha administration signifi cantly improved survival rate and MAP in hypovolemic shocked rats. Fur thermore, the hyporesponsiveness to PE was significantly restored in a ortic rings. Therefore, these data suggest that TNF-alpha is an import ant mediator in the pathophysiology of hypovolemic hemorrhagic shock a nd it might be responsible, at least in part, for the vascular hyporea ctivity of this experimental circulatory shock.