© 1996 American Heart Association, Inc.
Articles |
Tumor Necrosis Factor-
Induces a Biphasic Effect on Myocardial Contractility in Conscious Dogs
From the Department of Medicine, University of Texas Health Science Center at San Antonio, and the Audie L. Murphy Memorial Veterans Hospital, San Antonio, Tex.
Correspondence to David R. Murray, MD, Medicine/Cardiology, 7703 Floyd Curl Dr, San Antonio, TX 78284.
Abstract Tumor necrosis factor-
(TNF-) likely plays a
role in the pathophysiology of myocardial depression observed in septic
shock. To evaluate the hemodynamic effects of TNF-
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 (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 performance before, during, and after
infusion of recombinant human TNF- (rhTNF-, 40 µg/kg for 1
hour). Plasma was analyzed for epinephrine and
norepinephrine. Between 1 and 7 hours of exposure,
rhTNF- 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- 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 ß-adrenergic blockade, rhTNF- induced a 7% to 40%
increase in LV contractile performance during the 60-minute
infusion. After this initial positive inotropic effect, rhTNF-
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- affects LV
systolic function in a time-dependent biphasic manner.
Increases in circulating catecholamines after rhTNF-
infusion cannot account for the early improvement in LV
systolic performance.
Key Words: cytokine • left ventricular function • septic shock • norepinephrine • epinephrine
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