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

Hemorrhagic shock was induced in male anesthetized rats by intermittently withdrawing blood from an iliac catheter until mean arterial blood pressure (MAP) fell and stabilized within the range of 20-30 mmHg. Survival rate, MAP, and serum and macrophage levels of tumor necrosis factor-alpha (TNF-alpha) were then evaluated. Furthermore, in ex vivo studies, the responsiveness to phenylephrine (PE; 1 nM to 10 mu M) was investigated in aortic rings from hemorrhagic shocked rats. Antibodies raised against TNF-alpha (anti-TNF-alpha 2 mg/kg) or vehicle (phosphate-buffered saline, 1 ml/kg) were injected intravenously 3 h before the bleeding. Vehicle-treated rats, subjected to hemorrhagic shock, exhibited 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 marked hypocontractility to PE compared with the reactivity of aortas from a group of sham shocked rats. Anti-TNF-alpha administration significantly improved survival rate and MAP in hypovolemic shocked rats. Furthermore, the hyporesponsiveness to PE was significantly restored in aortic rings. Therefore, these data suggest that TNF-alpha is an important mediator in the pathophysiology of hypovolemic hemorrhagic shock and it might be responsible, at least in part, for the vascular hyporeactivity of this experimental circulatory shock.