Tumor necrosis factor-alpha induces a biphasic effect on myocardial contractility in conscious dogs

Circulation Research
D R Murray, G L Freeman

Abstract

Tumor necrosis factor-alpha (TNF-alpha) likely plays a role in the pathophysiology of myocardial depression observed in septic shock. To evaluate the hemodynamic effects of TNF-alpha in vivo while eliminating the influence of altered sympathetic tone, eight conscious chronically instrumented dogs were studied after pretreatment with propranolol (2 mg/kg) and atropine (2mg). 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 performance before, during, and after infusion of recombinant human TNF-alpha (rhTNF-alpha, 40 micrograms/kg for 1 hour). Plasma was analyze for epinephrine and norepinephrine. Between 1 and 7 hours of exposure, rhTNF-alpha induced significant increases in circulating catecholamines. Norepinephrine 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 initiating 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 catecholamines and despite complete ...Continue Reading

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