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    Endothelin Receptor Antagonism by Tezosentan Attenuates Lung Injury Induced by Aortic Ischemia-Reperfusion
    (ELSEVIER SCIENCE INC, 2009) Kiris, Ilker; Narin, Cueneyt; Gulmen, Senol; Yilmaz, Nigar; Sutcu, Recep; Kapucuoglu, Nilguen
    Tezosentan is a novel dual endothelin receptor antagonist. The purpose of this study was to examine the effect of tezosentan on lung injury induced by abdominal aortic ischemia-reperfusion (IR) in rats. Thirty-two Wistar-albino rats were randomized into four groups (eight per group) as follows: control group (sham laparotomy), aortic IR group (120 min ischemia and 120 min reperfusion), aortic IR + tezosentan group (a bolus intravenous injection of 10 mg/kg tezosentan before ischemia plus continuous intravenous infusion of 1 mg/kg/hr tezosentan during 120 min ischemia and 120 min reperfusion), and control + tezosentan. Blood and lung tissue samples were obtained for biochemical analysis. Protein concentrations in bronchoalveolar lavage fluid and lung wet/dry weight ratios were measured. A histological evaluation was also done. Aortic IR significantly increased (p < 0.05 vs. control group) and tezosentan significantly decreased (p < 0.05 vs. aortic IR group) the plasma level of tumor necrosis factor-alpha; lung tissue levels of malondialdehyde, catalase, and myleperoxidase; and protein concentration in bronchoalveolar lavage fluid and lung wet/dry weight ratio. Histological evaluation showed that tezosentan attenuated the morphological changes associated with lung injury. The results of this study indicate that tezosentan attenuates lung injury induced by aortic IR in rats. We propose that this protective effect of tezosentan is due to (1) reduced systemic inflammatory response, (2) reduced oxidative stress and lipid peroxidation in lung tissue, (3) reduced pulmonary microvascular leakage, and (4) inhibition of leukocyte infiltration into lung tissue.
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    Endothelin Receptor Blockade with Tezosentan Ameliorates Myocardial Injury Induced by Abdominal Aortic Ischemia-Reperfusion
    (TOHOKU UNIV MEDICAL PRESS, 2008) Narin, Cueneyt; Kiris, Ilker; Gulmen, Senol; Toy, Hatice; Yilmaz, Nigar; Sutcu, Recep
    Endothelin is both a potent vasoconstrictor and an important mediator of ischemia-reperfusion (IR) injury. Therefore, the role of endothelin receptor antagonism in IR-induced-tissue injury carries great interest. Here, we examined the effect of tezosentan, a nonselective antagonist for endothelin receptors, on myocardial injury induced by abdominal aortic IR, which represents a model of the IR injury in distant organs frequently occurred after vascular surgery. Thirty-two Wistar rats were randomized into four groups (17 = 8) as follows: control (sham laparotomy), aortic IR (120 min ischemia and 120 min reperfusion), aortic IR + tezosentan (10 mg/kg intravenous injection before ischemia plus continuous intravenous infusion of 1 mg/kg/hr during the IR injury), and control + tezosentan. Biochemical analysis showed that aortic IR significantly increased (p < 0.05 vs control) the plasma levels of troponin-I, interleukin-6 and tumor necrosis factor-alpha, and the myocardial tissue levels of malondialdehyde, superoxide dismutase and catalase, whereas tezosentan significantly decreased these same factors (p < 0.05 vs aortic IR). Histological evaluation also showed that aortic IR significantly increased (p < 0.05 vs control) myocardial disorganization, myofiber swelling and myofiber cosinophilia in myocardial tissue samples, whereas tezosentan significantly decreased these factors (p < 0.05 vs aortic IR). These results indicate that tezosentan has protective effects against myocardial injury induced by abdominal aortic IR in rats. We propose that the mechanisms underlying this protective effect of tezosentan involves the reduction of oxidative stress and subsequent lipid peroxidation, the inhibition of systemic inflammatory response, and acting cytoprotective on myocytes after aortic IR.
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    Tezosentan Reduces the Renal Injury Induced by Abdominal Aortic Ischemia-Reperfusion in Rats
    (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2009) Gulmen, Senol; Kiris, Ilker; Narin, Cuneyt; Ceylan, Berit Gokce; Mermi, Betul; Sutcu, Recep; Meteoglu, Ibrahim
    Background. Renal injury induced by aortic ischemia-reperfusion (IR) is an important factor in the development of postoperative acute renal failure following abdominal aortic surgery. Endothelin (ET) is involved in the development of renal injury induced by aortic IR and tezosentan (R0 61-0612) is a specific ET receptor antagonist. The aim of this study was to examine the effect of tezosentan on renal injury induced by abdominal aortic IR in rats. Material and Methods. Twenty-four Wistar-Albino rats were randomized into three groups (eight per group). Control group underwent laparotomy and dissection of the infrarenal abdominal aorta (IAA) without occlusion. The aortic IR group underwent laparotomy and clamping of the IAA for 120 min followed by 120 min of reperfusion. Aortic IR + tezosentan group underwent same aortic IR periods, and received a bolus intravenous injection of 10 mg/kg tezosentan before ischemia plus continuous intravenous infusion of 1 mg/kg/h tezosentan during 120 min ischemia and 120 min reperfusion. At the end of the experiment, blood and kidney tissue specimens were obtained for biochemical analysis. Histological evaluation of the rat kidney tissues was also done. Results. Biochemical analysis showed that aortic IR significantly increased (P<0.05 versus control) while tezosentan significantly decreased (P<0.05 versus aortic IR) the tissue levels of malondialdehyde, superoxide dismutase, catalase and myeloperoxidase. Histological analyses showed that aortic IR significantly increased (P<0.05 versus control) while tezosentan significantly decreased (P<0.05 versus aortic IR) focal glomerular necrosis, dilatation of Bowman's capsule, degeneration of tubular epithelium, necrosis in tubular epithelium and tubular dilatation in the renal tissue samples. Conclusion. The results of this study indicate that tezosentan reduces renal injury induced by aortic IR in rats. We think that tezosentan exerted this beneficial effect via reducing oxidative stress and lipid peroxidation, inhibition of leukocyte infiltration into renal tissue and acting cytoprotective on renal tubular cells after aortic IR. (C) 2009 Elsevier Inc. All rights reserved.