Fenofibrate Treatment Enhances Antioxidant Status and Attenuates Endothelial Dysfunction in Streptozotocin-Induced Diabetic Rats

Diabetic endothelial dysfunction is accompanied by increased oxidative stress and upregulated proinflammatory and inflammatory mediators in the vasculature. Activation of peroxisome proliferator-activated receptor-alpha (PPAR-α) results in antioxidant and anti-inflammatory effects. This study was designed to investigate the effect of fenofibrate, a PPAR-α activator, on the endothelial dysfunction, oxidative stress, and inflammation in streptozotocin diabetic rats. Diabetic rats received fenofibrate (150 mg kg−1 day−1) for 4 weeks. Fenofibrate treatment restored the impaired endothelium-dependent relaxation and increased basal nitric oxide availability in diabetic aorta, enhanced erythrocyte/liver superoxide dismutase and catalase levels, ameliorated the abnormal serum/aortic thiobarbituric acid reactive substances, and prevented the increased aortic myeloperoxidase without a significant change in serum total cholesterol and triglyceride levels. It did not affect the decreased total homocysteine level and the increased tumor necrosis factor-α level in the serum of diabetic rats. Fenofibrate-induced prevention of the endothelial function seems to be related to its potential antioxidant and antiinflammatory activity

Endotoksemik sıçan torasik aortasındaki damar yanıtları üzerine pentoksifilin'in etkileri

Aim: Tumor necrosis factor alpha (TNF-;amp;#945;) and nitric oxide (NO) are important mediators playing key roles in septic shock, a situation which is trigerred by endotoxin and other bacterial products. In this study we investigated the effects of a phosphodiesterase inhibitor, pentoxifylline on the impaired vascular responses in septic shock, since the agent is known to inhibit TNF- ;amp;#945; gene expression by increasing intracellular cAMP levels. Material and Methods: Rats were injected intraperitoneally with 5 mg/kg LPS (E.Coli, serotype 055:B5) to induce endotoxic shock. 1 hour after LPS administration pentoxifylline (12.5, 25 mg/kg) was given by the same route. Contractile responses to phenylephrine, potassium chloride-KCl) and relaxant responses to acetylcholine-ACh and sodium nitroprusside- SNP were studied in the thoracic aortas 18 hours after LPS injection. Results: The contractile responses were decreased in septic shock as well as the endothelium-dependent, receptor-mediated vasorelaxant responses. These results show that excessive NO production via iNOS induction caused by LPS and cytokines such as TNF-;amp;#945; play a key role in the vascular responsiveness seen in septic shock. Pentoxifylline (12.5 mg/kg) reversed the contractile responses (p;lt;0.05) in the sepsis group, whereas it increased the ACh responses in both doses (12.5, 25 mg/kg)(p;lt;0.05), which were decreased in the endotoxaemic animals. No differences were found between the groups in terms of the responses to the direct smooth muscle relaxant, sodium nitroprussid. Conclusion: These data obtained from the study consider that pentoxifylline administration might be a useful maneuver in the therapy of septic shock, which is a common cause of mortality.Amaç: Endotoksin ve benzeri diğer bakteri ürünleri, mantar ve viruslar tarafından başlatılan olaylar dizisi olan septik şokta TNF-? ve NO başlıca rol oynayan medyatörlerdir. Çalışmada deneysel endotoksik şok modelinde, hücre içi gen transkripsiyonunu inhibe eden, fosfodiesteraz cAMP düzeyini artırarak TNF-? inhibitörü olan pentoksifilin'in sepsiste bozulmuş olan damar yanıtları üzerine olan etkileri araştırıldı. Yöntem ve Gereç: Sıçanlarda endotoksik şok oluşturmak üzere 5 mg/kg LPS (E.coli, serotip 055:B5) intraperitoneal yolla verildi. LPS injeksiyonundan 1 saat sonra pentoksifilin (12.5 ve 25 mg/kg) intraperitoneal yolla uygulandı. LPS injeksiyonundan 18 saat sonra izole edilen torasik aort halkalarında kasılma (fenilefrin, KCl) ve gevşeme (asetilkolin ve sodyum nitroprussid) yanıtları değerlendirildi. Bulgular: Sepsiste hem kasıcı yanıtların hem de endotel bağımlı, reseptör aracılı gevşeme yanıtlarının bozulduğunu göstermektedir. Sepsisteki damar yanıtlarındaki bu olumsuz değişikliklerde LPS'nin ve TNF-? gibi sitokinlerin neden olduğu iNOS indüksiyonu sonucu aşırı NO yapımının başlıca rol oynadığını göstermektedir. Pentoksifilin 12.5 mg/kg verilen sepsisli gruptaki bozulmuş fenilefrin kontraktil yanıtlarını düzeltti (p0.05). Sepsis grubunda azalmış olan asetilkolin yanıtları pentoksifilin (12.5, 25 mg/kg) verilmesiyle düzeldi (p0.05). Direkt düz kas gevşetici ajan olan sodyum nitroprussid yanıtlarında gruplar arasında farklılık gözlenmedi. Sonuç: Pentoksifilin ile elde ettiğimiz sonuçlar, bu ajanın önemli bir mortalite nedeni olan septik şokun tedavisinde umut verici olduğunu düşündürmektedir