High doses of TNF-alpha acutely induced NO synthesis in isolated rabbit myocytes and reduced contractility by decreasing myofilament [Ca2+]i responsiveness.
Does TNF-alpha reduce contractility in isolated adult rabbit ventricular myocytes?
High doses of TNF-alpha acutely reduce contractility in ventricular myocytes by decreasing myofilament calcium responsiveness through a nitric oxide-dependent mechanism.
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 < or = 10,000 U/ml caused a significant reduction in active cell shortening at 20 min, without reducing the amplitude of the accompanying intracellular Ca2+ concentration (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-alpha (10,000 U/ml). The effect of TNF-alpha on cell shortening could be prevented by the nitric oxide (NO) synthase blocker NG-nitro-L-arginine methyl ester (L-NAME) but not its inactive enantiomer NG-nitro-D-arginine methyl ester (D-NAME). The NO scavenger hemoglobin also attenuated the effects of TNF-alpha. TNF-alpha 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 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 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 appear to be pH mediated.
Goldhaber et al. (Tue,) reported a other. TNF-alpha was evaluated on Active cell shortening and intracellular Ca2+ concentration ([Ca2+]i) transient. High doses of TNF-alpha acutely induced NO synthesis in isolated rabbit myocytes and reduced contractility by decreasing myofilament [Ca2+]i responsiveness.