Ji. Goldhaber et al., EFFECTS OF TNF-ALPHA ON [CA2-RABBIT VENTRICULAR MYOCYTES(](I) AND CONTRACTILITY IN ISOLATED ADULT), American journal of physiology. Heart and circulatory physiology, 40(4), 1996, pp. 1449-1455
The mechanism of the acute negative inotropic effect of tumor necrosis
factor-alpha (TNF-alpha) was studied in enzymatically isolated adult
rabbit ventricular myocytes. In cells loaded with fura 2 acetoxymethyl
ester (AM) and paced intermittently at 0.2 Hz, TNF-alpha at doses gre
ater than or equal to 10,000 U/ml caused a significant reduction in ac
tive cell shortening at 20 min, without reducing the amplitude of the
accompanying intracellular Ca2+ concentration ([Ca2+](i)) transient. S
imilar results were obtained in cells loaded with indo 1-AM and paced
continuously at 0.2 Hz during exposure to TNF-alpha (10,000 U/ml). The
effect of TNF-alpha on cell shortening could be prevented by the nitr
ic oxide (NO) synthase blocker N-G-nitro-L-arginine methyl ester (L-NA
ME) but not its inactive enantiomer N-G-nitro-D-arginine methyl ester
(D-NAME). The NO scavenger hemoglobin also attenuated the effects of T
NF-alpha. TNF-alpha also caused a significant increase in diastolic ce
ll length without any change in diastolic [Ca2+](i). The effect on cel
l length was prevented by L-NAME but not D-NAME. In cells loaded with
the pH indicator seminaphthorhodafluor-AM, TNF-alpha did not alter pH
sufficiently to account for the negative inotropic effect. These data
suggest that high doses of TNF-alpha can acutely induce NO synthesis i
n 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 appear to be pH mediated.