Pentoxifylline attenuates cardiac dysfunction and reduces TNF-α level in ischemic-reperfused heart

Although pentoxifylline (PTXF), a phosphodiesterase inhibitor, has been reported to exert beneficial effects in cardiac bypass surgery, its effect and mechanisms against ischemia-reperfusion (I/R) injury in heart are poorly understood. Because I/R is known to increase the level of tumor necrosis factor (TNF)-alpha in myocardium and PTXF has been shown to depress the production of TNF-alpha in failing heart, this study examined the hypothesis that PTXF may attenuate cardiac dysfunction and reduce TNF-alpha content in I/R heart. For this purpose, isolated rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 2-30 min. Although cardiac dysfunction due to ischemia was not affected, the recovery of heart function upon reperfusion was markedly improved by PTXF treatment. This cardioprotective effect of PTXF was dose dependent; maximal effect was seen at a concentration of 125 mu M. TNF-alpha, nuclear factor-kappa B (NF-kappa B), and phosphorylated NF-kappa B contents were decreased in ischemic heart but were markedly increased within 2 min of starting reperfusion. The ratio of cytosolic-to-homogenate NF-kappa B was decreased, whereas the ratio of particulate-to-homogenate NF-kappa B was increased in I/R hearts. These changes in TNF-alpha and NF-kappa B protein contents as well as in NF-kappa B redistribution due to I/R were significantly attenuated by PTXF treatment. The results of this study indicate that the cardioprotective effects of PTXF against I/R injury may be due to reductions in the activation of NF-kappa B and the production of TNF-alpha content.