Pentoxifylline attenuates cardiac dysfunction and reduces TNF-alpha 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 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.
Zhang
Ming
M
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, 351 Tache Ave., Winnipeg, Manitoba, Canada R2H 2A6.
Xu
Yan-Jun
YJ
Saini
Harjot K
HK
Turan
Belma
B
Liu
Peter P
PP
Dhalla
Naranjan S
NS
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D066298:In Vitro Techniques; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D002316:Cardiotonic Agents; D016328:NF-kappa B; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D010431:Pentoxifylline