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

Abstract

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 microM. TNF-alpha, nuclear factor-kappaB (NF-kappaB), and phosphorylated NF-kappaB contents were decreased in ischemic heart but were markedly increased within 2 min of starting reperfusion. The ratio of cytosolic-to-homogenate NF-kappaB was decreased, whereas the ratio of particulate-to-homogenate NF-kappaB was increased in I/R hearts. These changes in TNF-alpha and NF-kappaB protein contents as well as in NF-kappaB 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-kappaB and the production of TNF-alpha content.

• Authors: Ming Zhang, Yan-Jun Xu, Harjot K Saini, Belma Turan, Peter P Liu, Naranjan S Dhalla
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 289 Issue 2 Pg. H832-9 (Aug 2005) ISSN: 0363-6135 [Print] United States
• PMID: 15833806 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• NF-kappa B
• Phosphodiesterase Inhibitors
• Tumor Necrosis Factor-alpha
• Pentoxifylline

Topics

• Animals
• Cardiotonic Agents (pharmacology)
• Heart (drug effects, physiopathology)
• In Vitro Techniques
• Myocardial Reperfusion Injury (metabolism, physiopathology)
• Myocardium (metabolism)
• NF-kappa B (metabolism)
• Pentoxifylline (pharmacology)
• Phosphodiesterase Inhibitors (pharmacology)
• Rats
• Tissue Distribution
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)