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Am J Physiol Heart Circ Physiol (April 15, 2005). doi:10.1152/ajpheart.00178.2005
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Submitted on February 22, 2005
Accepted on April 12, 2005

Pentoxifylline attenuates cardiac dysfunction and reduces TNF-{alpha}level in the ischemic-reperfused heart

Ming Zhang1, Yan-Jun Xu1, Harjot K Saini1, Belma Turan1, Peter P Liu2, and Naranjan S Dhalla1*

1 Department of Physiology, Faculty of Medicine, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center, University of Manitoba, Winnipeg, Manitoba, Canada
2 Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada

* To whom correspondence should be addressed. E-mail: nsdhalla{at}sbrc.ca.

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 the heart are poorly understood. Since I/R is known to increase the level of tumor necrosis factor-alpha (TNF-{alpha}) in the myocardium and PTXF has been shown to depress the production of TNF-{alpha} in the failing heart, this study examined the hypothesis that PTXF may attenuate cardiac dysfunction and reduce TNF-{alpha} content in the I/R heart. For this purpose, isolated rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 2 to 30 min. While 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 µM. TNF-{alpha}, nuclear factor kappa B (NF{kappa}B) and phosphophorylated NF{kappa}B contents, were decreased in the ischemic heart but were markedly increased within 2 min of starting reperfusion. The ratio of cytosolic to homogenate NF{kappa}B was decreased whereas that for particulate to homogenate NF{kappa}B was increased in the 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 in this study indicate that the cardioprotective effects of PTXF against I/R injury may be due to reduction in the activation of NF{kappa}B and the production of TNF-{alpha} content.




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