Mechanism of cardioprotective action of TNF-alpha in the isolated rat heart

Abstract

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.

Animals and 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.

Keywords: Adult cardiomyocytes; Cardiac function; Intracellular calcium; Ischemia-reperfusion; Tumour necrosis factor.

Figure 1)

Effect of tumour necrosis factor alpha (TNF-α; 25 μg/mL) on the ischemia-reperfusion induced changes in left ventricular end diastolic pressure (LVEDP) and left ventricular developed pressure (LVDP) in the isolated rat hearts. Global ischemia in control and TNF-α treated hearts was induced by stopping the coronary flow for 30 min, followed by reperfusion for 10, 20 and 30 min. Each value is a mean ± SE of six separate experiments. *P<0.05 compared with respective control value

Figure 2)

Effect of tumour necrosis factor alpha (TNF-α 25 μg/mL) on the ischemia-reperfusion induced changes in +dP/dt and –dP/dt in the isolated rat hearts. The experimental conditions are the same as those in Figure 1. *P<0.05 compared with respective control value

Figure 3)

Traces showing the effect of 50 ng/mL of tumour necrosis factor alpha (TNF-α) on the KCl (30 mM) -induced increase inintracellular calcium concentration in freshly isolated cardiomyocytes from adult rat hearts