Hemorrhage-induced alpha-adrenergic signaling results in myocardial TNF-alpha expression and contractile dysfunction.
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-alpha (TNF-alpha), has been observed in the heart after HS and resuscitation (HS/R) and alpha(1)-adrenergic blockade prevented translocation of the nuclear transcription factor, NF-kappa B, to the nucleus. We hypothesized that alpha(1)-adrenergic stimulation induces myocardial TNF-alpha expression, which results in depressed cardiac function after HS/R. The role of alpha(1)-adrenergic stimulation in myocardial TNF-alpha expression and depressed cardiac function after HS/R was assessed by treatment with the alpha(1)-adrenergic inhibitor, prazosin hydrochloride (1 mg/kg ip), for 1 h before the onset of hemorrhage. In addition, TNF-alpha was neutralized with a specific antibody (600 microl/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-alpha 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-alpha neutralizing antibody and by 90% in hearts from rats treated with prazosin hydrochloride. We conclude that HS activates a alpha(1)-adrenergic pathway, resulting in TNF-alpha expression in the heart and depressed myocardial contractile function.
Shahani
R
R
Division of Vascular Surgery, University Health Network and Department of Surgery, University of Toronto, Toronto, Ontario, Canada M5G 2C4.
Klein
L V
LV
Marshall
J G
JG
Nicholson
S
S
Rubin
B B
BB
Walker
P M
PM
Lindsay
T F
TF
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D006470:Hemorrhage / Q000503:physiopathology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011942:Receptors, Adrenergic, alpha; D014409:Tumor Necrosis Factor-alpha; D010656:Phenylephrine; D011224:Prazosin