Mechanism of cardioprotective action of TNF-alpha in the isolated rat heart.
BACKGROUND
Tumour necrosis factor alphs (TNF-alpha), a proinflammatory cytokine, is synthesized in the heart under pathologic conditions; however, it is not clear whether this cytokine results in heart dysfunction or serves as a cardioprotective agent.


OBJECTIVE
To examine whether TNF-alpha in low concentrations exerts a cardioprotective effect on the heart and prevents the occurrence of intracellular calcium overload.


METHODS
The effect of TNF-alpha was studied in vivo on hemodynamic parameters in anesthetized rats. The cardioprotective action of TNF-alpha was tested against ischemia-reperfusion-induced changes in cardiac performance in the isolated perfused rat hearts. The effect of TNF-alpha on intracellular free calcium was evaluated in freshly isolated adult rat cardiomyocytes by Fura 2 technique.


RESULTS
An intravenous injection of TNF-alpha (200 mug/kg) in rats produced a transient but significant depressant effect on cardiac function and an increase in heart rate. TNF-alpha (25 mug/mL) did not affect cardiac function in the isolated heart; however, it attenuated the ischemia-reperfusion-induced changes in the left ventricular pressures (developed pressure, end diastolic pressure, +dP/dt and -dP/dt). In the isolated cardiomyocytes, TNF-alpha did not produce any change in the level of intracellular free calcium, but this agent (10 to 100 ng/mL) significantly decreased the potassium chloride (30 mM) -induced increase in free calcium.


CONCLUSIONS
The inhibitory effect of low concentrations of TNF-alpha on calcium influx may reduce the occurrence of intracellular calcium overload, and this may be responsible for improving left ventricular dysfunction due to ischemia-reperfusion injury in the heart.
Rathi
Satyajeet S
SS
Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, and Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba.
Xu
Yan-Jun
YJ
Dhalla
Naranjan S
NS