Effects of tumor necrosis factor-a on [ca2+]i and contractility in
isolated adult ventricular rabbit myocytes.
Goldhaber, Joshua I., Kevin H. Kim, Paul D. Natterson, Tracy Lawrence,
Phil Yang, and James N. Weiss.
Division of Cardiology, Cardiovascular Research Laboratory, UCLA
School of Medicine, Los Angeles, California 90095
APStracts 3:0084H, 1996.
The mechanism of the negative inotropic effect of tumor necrosis
factor-a (TNF-a) was studied in enzymatically isolated adult rabbit
ventricular myocytes. In cells loaded with Fura-2-AM and paced
intermittently at 0.2 Hz, TNF-a at doses 10,000 U/ml caused a
significant reduction in active cell shortening at 20 minutes,
without reducing the amplitude of the accompanying [Ca2+]i transient.
Similar results were obtained in cells loaded with INDO-1-AM and
paced continuously at 0.2 Hz during exposure to TNF-a (10,000 U/ml).
The effect of TNF-a on cell shortening could be prevented by the NO
synthase blocker L-NAME, but not its inactive enantiomer D-NAME. The
NO scavenger hemoglobin also attenuated the effects of TNF-a. TNF-a
also caused a significant increase in diastolic cell length without
any change in diastolic [Ca2+]i. The effect on cell length was
prevented by L-NAME, but not D-NAME. In cells loaded with the pH
indicator SNARF-AM, TNF-a did not alter pH sufficiently to account
for the negative inotropic effect. These data suggest that high doses
of TNF-a can acutely induce NO synthesis in isolated myocytes and
reduce contractility by decreasing myofilament [Ca2+]i
responsiveness. The mechanism of this altered myofilament [Ca2+]i
response is unknown but does not to appear to be pH mediated.
Received 9 June 1995; accepted in final form 19 February 1996.
APS Manuscript Number H528-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 13 March 96