title: Tumor necrosis factor-alpha induces a biphasic effect on myocardial contractility in conscious dogs.
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 beta adrenergic blockade, rhTNF-alpha induced a 7% to 40% increase in LV contractile performance during the 60-minute infusion. After this initial positive inotropic effect, rhTNF-alpha treatment led to precipitous systolic dysfunction between 2 and 7 hours of exposure; this myocardial depressant effect persisted at 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-dependent biphasic manner. Increases in circulating catecholamines after rhTNF-alpha infusion cannot account for the early improvement in LV systolic performance.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Murray
authors.forename: G L
authors.initials: GL
authors.lastname: Freeman
mesh_terms: D000818:Animals; D002395:Catecholamines / Q000097:blood; D004285:Dogs; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
chemical_list: D002395:Catecholamines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha