Interleukin (IL)-6 related cytokines may be involved in the pathophysiology of heart failure. Leukemia inhibitory factor (LIF) is an IL-6 related cytokine, and elevated levels of LIF have been found in failing hearts. The aim of our study was to investigate how LIF may influence isolated cardiomyocytes. Adult cardiomyocytes were isolated from male Wistar rat hearts and treated with 1 nM LIF for 48 h. Contractile function was measured using a video-edge detection system. Fractional shortening was reduced at 0.25 Hz in LIF treated cells (7.4% +/- 0.5%) compared to control cells (9.0% +/- 0.7%). Gene expression analysis showed that expression of the mitochondrial ATP-synthase F, a subunit was reduced in cells exposed to LIE The activity of the enzyme was also reduced in these cells (0.10 +/- 0.05 mumol/min per mg protein) compared to controls (1.23 +/- 0.40 mumol/min per in- protein). The levels of ATP and creatine phosphate were reduced by 15.0% +/- 3.0% and 11.2% +/- 2.7% in LIF treated cells. LIF increased both 3 H-deoxyglucose uptake and lactate levels, suggesting an increase in anaerobic energy metabolism. Beta-oxidation of C-14-oleic acid was increased by 51.2% +/- 14.1% following LIF treatment, but no changes were found in cellular uptake or oxidation of C-14-oleic acid to CO2. In conclusion, LIF induces contractile dysfunction and changes in energy metabolism in isolated cardiomocytes. (C) 2004 Elsevier Ltd. All rights reserved.

Excitation-contraction (E-C) coupling was investigated in rat hearts 6 wk after induction of myocardial infarction (MI) by ligation of the left coronary artery. Heart weight was increased by 74% and left ventricular end-diastolic pressure was 23 +/- 2 mmHg in MI compared with 8 +/- 2 mmHg in sham-operated controls (Sham, P < 0.001). Cell shortening was measured in voltage-clamped myocytes at 36 degrees C. In solutions where Cs(+) had been replaced by K(+), the voltage dependence of contraction was sigmoidal between -20 and +100 mV in Sham and MI cells. Verapamil (20 microM) blocked L-type Ca(2+) current and reduced contraction in Sham cells by approximately 50% (P < 0.01) but did not decrease contraction significantly in MI cells at test potentials above +10 mV. Verapamil-insensitive contractions were blocked by Ni(2+) (5 mM). Na(+)/Ca(2+) exchange current was doubled in MI compared with Sham cells at test potentials between -20 and +80 mV (P < 0.05), whereas mRNA and protein expression increased by 30-40%. Finally, voltage dependence of contraction was bell shaped in Na(+)-free solutions, but contraction was significantly increased in MI cells over a wider voltage range (P < 0.05). The insensitivity to Ca(2+) channel block in MI cells may result from an increased contribution of the Na(+)/Ca(+) exchanger to triggering of E-C coupling. These results suggest significant changes in E-C coupling in the hypertrophy and failure that develop in response to extensive MI.