TUMOR-NECROSIS-FACTOR-ALPHA CAUSES MYOCARDIAL DEPRESSION IN GUINEA-PIGS

Background and Methods: Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of metabolic and cardiovascular derangements in sepsis and endotoxicosis. We tested the hypothesis that TNF-alpha causes myocardial depression and alters the cardiac responsiveness to administered norepinephrine. Albino Hartley guinea pigs (n = 32) of either sex were injected iv with saline (1.5 mL) or recombinant human TNF-alpha (1 mg/kg). At 6, 24, or 72 hrs after injection, atria were harvested, split, connected to force displacement x transducer-amplifier-recorder systems and maintained in vitro in oxygenated 37.5-degrees-C Krebs-Henseleit buffer. Results: Maximal left atrial force of contraction and maximal left atrial velocity of contraction were decreased in the TNF-alpha treated animals compared with controls (p < .05), irrespective of time after TNF-alpha injection. There were no differences between groups for left atrial maximal velocity of relaxation and right atrial rate. The norepinephrine concentration that elicited a 50% maximal left atrial contractile response (ED50) was higher in TNF-alpha treated animals compared with controls (p < .05). Maximal left atrial force of contraction, maximal right atrial rate, and right atrial ED50 were similar in the two groups. Conclusions: These results indicate that TNF-alpha injected in vivo causes in vitro myocardial depression and alters cardiac responsiveness to norepinephrine.