TUMOR-NECROSIS-FACTOR-ALPHA INDUCES A BIPHASIC EFFECT ON MYOCARDIAL-CONTRACTILITY IN CONSCIOUS DOGS

Tumor necrosis factor-alpha (TNF-alpha) likely plays a role in the pat hophysiology of myocardial depression observed in septic shock. To eva luate the hemodynamic effects of TNF-alpha in vivo while eliminating t he influence of altered sympathetic tone, eight conscious chronically instrumented dogs were studied after pretreatment with propranolol (2 mg/kg) and atropine (2 mg). Using three sets of piezoelectric crystals to measure left ventricular (LV) volume and LV manometers to measure pressure, we determined load-independent parameters of LV systolic per formance before, during, and after infusion of recombinant human TNF-a lpha (rhTNF-alpha, 40 mu g/kg for 1 hour). Plasma was analyzed for epi nephrine and norepinephrine. Between 1 and 7 hours of exposure, rhTNF- alpha induced significant increases in circulating catecholamines. Nor epinephrine rose from 268.6+/-47.2 to 426.2+/-87.0 pg/mL (P<.05) at 1 hour and peaked at 921.2+/-156.8 pg/mL (P<.001) at 4 hours after initi ating rhTNF-alpha treatment. Similarly, epinephrine increased from 130 .2+/-30.9 to 884.5+/-210.2 pg/mL (P<.05) at 1 hour and peaked at 3195. 3+/-476 pg/mL (P<.001) at 4 hours. Before the surge of circulating cat echolamines and despite complete beta- adrenergic blockade, rhTNF-alph a induced a 7% to 40% increase in LV contractile performance during th e 60-minute infusion. After this initial positive inotropic effect, rh TNF-alpha treatment led to precipitous systolic dysfunction between 2 and 7 hours of exposure; this myocardial depressant effect persisted a t 25 hours. LV systolic performance declined to 19% to 35% of baseline values, depending on the specific contractile parameter evaluated. We conclude that rhTNF-alpha affects LV systolic function in a time-depe ndent biphasic manner. Increases in circulating catecholamines after r hTNF-alpha infusion cannot account for the early improvement in LV sys tolic performance.