Hemorrhage-induced α-adrenergic signaling results in myocardial TNF-α expression and contractile dysfunction

Abstract

Hemorrhagic shock (HS), secondary to major blood loss, frequently precedes multiple organ dysfunction and is accompanied by a surge in circulating catecholamine levels. Expression of the cardiodepressant cytokine, tumor necrosis factor-α (TNF-α), has been observed in the heart after HS and resuscitation (HS/R) and α1-adrenergic blockade prevented translocation of the nuclear transcription factor, NF-κB, to the nucleus. We hypothesized that α1-adrenergic stimulation induces myocardial TNF-α expression, which results in depressed cardiac function after HS/R. The role of α1-adrenergic stimulation in myocardial TNF-α expression and depressed cardiac function after HS/R was assessed by treatment with the α1-adrenergic inhibitor, prazosin hydrochloride (1 mg/kg ip), for 1 h before the onset of hemorrhage. In addition, TNF-α was neutralized with a specific antibody (600 μl/kg iv) 5 min before hemorrhage. HS was induced by the withdrawal of blood to a mean blood pressure of 50 mmHg for 1 h. Contractile function was measured with the use of a Langendorff apparatus 2 h after the end of HS. HS/R led to significant decreases in left ventricular developed tension and in the maximal rate of pressure increase over time during both contraction and relaxation. Myocardial expression of TNF-α measured by enzyme-linked immunosorbent assay increased significantly after 30 min of hemorrhage and peaked after 60 min of HS and 45 min of resuscitation. Depression in cardiac function after HS/R was reversed by 85% in hearts from rats treated with a TNF-α neutralizing antibody and by 90% in hearts from rats treated with prazosin hydrochloride. We conclude that HS activates a α1-adrenergic pathway, resulting in TNF-α expression in the heart and depressed myocardial contractile function.