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Objective: Sepsis leads to conditions such as inflammatory and anti-inflammatory process, circulatory abnormalities, cellular and humoral reactions. Endotoxin-induced oxidative stress causes injury in the liver. The aim of this study was to evaluate the effects of a radical scavenger Tempol in lipopolysaccharide (LPS)-induced liver injury in rats. Materials and Methods: Male Wistar rats were divided into four groups: Control, LPS (15 mg/kg), LPS + Tempol group (100 mg/kg Tempol, three hours after LPS administration) and Tempol (100 mg/kg). Blood glucose and body temperature were measured during the experiment. Superoxide dismutase (SOD), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and C-reactive protein (CRP) levels were measured in plasma or liver tissue. Furthermore, histopathological changes and myeloperoxidase-stained leukocytes infiltration were assessed in liver tissue. Results: LPS caused tissue damage and leukocytes infiltration, increased AST, ALT and CRP levels, and decreased body temperature, blood glucose and SOD levels. Tempol reduced AST and ALT levels and increased SOD levels. Tempol did not prevent tissue damage, leukocytes infiltration and increment of CRP levels. There were no changes in body temperature and blood glucose levels. Conclusion: The present study suggests that tempol may have antioxidant properties in LPS-induced liver injury. These results may contribute to a better understanding of the role of tempol and basic mechanisms of underlying oxidative stressrelated liver injury for further investigations.

PEGylated carboxyhemoglobin (PEGHbCO), which has carbon monoxide-releasing properties and plasma expansion and oxygen-carrying properties, may improve both skeletal microcirculatory flow and renal cortical microcirculatory Po2 (CµPo2) and, subsequently, limit endotoxemia-induced acute kidney injury. Anesthetized, ventilated Wistar albino rats ( n = 44) underwent endotoxemic shock. CµPo2 was measured in exposed kidneys using a phosphorescence-quenching method. Rats were randomly assigned to the following five groups: 1) unresuscitated lipopolysaccharide (LPS), 2) LPS + Ringer’s acetate (RA), 3) LPS + RA + 0.5 µg·kg·−1min−1 norepinephrine (NE), 4) LPS + RA + 320 mg/kg PEGHbCO, and 5) LPS + RA + PEGHbCO + NE. The total volume was 30 mL/kg in each group. A time control animal group was used. Skeletal muscle microcirculation was assessed by handheld intravital microscopy. Kidney immunohistochemistry and myeloperoxidase-stained leukocytes in glomerular and peritubular areas were analyzed. Endotoxemia-induced histological damage was assessed. Plasma levels of IL-6, heme oxygenase-1, malondialdehyde, and syndecan-1 were assessed by ELISA. CµPo2 was higher in the LPS + RA + PEGHbCO-resuscitated group, at 35 ± 6mmHg compared with 21 ± 12 mmHg for the LPS+RA group [mean difference: −13.53, 95% confidence interval: (−26.35; −0.7156), P = 0.035]. The number of nonflowing, intermittent, or sluggish capillaries was smaller in groups infused with PEGHbCO compared with RA alone ( P < 0.05), while the number of normally perfused vessels was greater ( P < 0.05). The addition of NE did not further improve CµPo2 or microcirculatory parameters. Endotoxemia-induced kidney immunohistochemistry and histological alterations were not mitigated by PEGHbCO 1 h after resuscitation. Renal leukocyte infiltration and plasma levels of biomarkers were similar across groups. PEGHbCO enhanced CµPo2 while restoring skeletal muscle microcirculatory flow in previously nonflowing capillaries. PEGHbCO should be further evaluated as a resuscitation fluid in mid- to long-term models of sepsis-induced acute kidney injury.

In this study, the role of nitric oxide (NO) in the pathogenesis of hydatidosis and the interaction with effects of anthelmintic drugs, albendazole and praziquantel, were examined in larval infection caused by protoscolices obtained from hydatid cysts of sheep liver in Albino Balb/c mice. Animals were divided into ten groups including controls and infected groups. Larval infection was established with intraperitoneal injection of protoscolices. Eight months after infection with protoscolices, the infected animals were divided into 6 groups. The infected animals were given a selective inhibitor of inducible nitric oxide synthase (iNOS) L-N6-(1-Iminoethyl) lysine-hydrochloride (L-NIL), NO donor sodium nitroprusside (SNP), albendazole and praziquantel as anthelmintic drugs for 7 days. In addition, control groups were composed of intact group, control, anthelmintic drugs + L-NIL, and anthelmintic drugs + SNP. The liver and blood samples were taken for cytological, histological, immunohistochemical and biochemical analyses 7 days after treatments at the end of experiment. The animals injected with protoscolices showed histopathological changes including inflammation areas, infiltration and accumulation of leukocytes, dilation of sinusoids, and damage in endothelial cells and hepatocytes at light microscopy. Electron microscopy were revealed severe damage in sinusoidal endothelial cells, leukocytes especially eosinophils in sinusoid lumens and disorganization in endoplasmic reticulum and nuclear membrane. Endothelial nitric oxide synthase (eNOS) and iNOS reactions were increased in the tissue. Anthelmintic drugs decreased inflammation areas and damages; however, it did not change NOS reactions in the animals given protoscolices. L-NIL and SNP diminished both iNOS and eNOS reactions. Unlike the group administered the inhibitor, SNP treated group exhibited less inflammation areas. Combination of these substances and drugs resulted in decreased inflammation areas. eNOS and iNOS reactions decreased in the drugs and SNP administered group, while only iNOS reaction was decreased in L-NIL given infection group. In addition, the infected groups which received SNP displayed expanded sinusoids and hepatocytes with vacuoles, intriguingly. While levels of serum nitrite/nitrate elevated only in the infection group given drugs and SNP, it decreased in the L-NIL administered group. Tissue level of malondialdehyde increased in infection groups with drugs and SNP. In conclusion, the results indicated that NO plays an important role in the pathogenesis of hydatidosis.

Ischaemia/reperfusion (I/R) is one of the main causes of acute kidney injury (AKI), which is characterized by sterile inflammation and oxidative stress. Immune cell activation can provoke overproduction of inflammatory mediators and reactive oxygen species (ROS), leading to perturbation of the microcirculation and tissue oxygenation associated with local and remote tissue injury. This study investigated whether the clinically employed immunosuppressant mycophenolate mofetil (MMF) was able to reduce I/R-induced renal oxygenation defects and oxidative stress by preventing sterile inflammation. Rats were divided into three groups (n=6/group): (1) a sham-operated control group; (2) a group subjected to renal I/R alone (I/R); and (3) a group subjected to I/R and MMF treatment (20 mg/kg prior to I/R) (I/R+MMF). Ischaemia was induced by a vascular occluder placed on the abdominal aorta for 30 minutes, followed by 120 minutes of reperfusion. Renal I/R deteriorated renal oxygenation (P

The expectation of fluid therapy in patients with septic shock is that it corrects hypovolemia, with the aim of restoring tissue perfusion and oxygenation and organ function. This study investigated whether different types of resuscitation fluids were effective in improving renal microcirculatory oxygenation, acidosis, oxidative stress, and renal function in a rat model of endotoxemic shock. Five groups of rats were used: a sham group, a lipopolysaccharide (LPS) group, and three LPS groups that received 30 mL/kg/h of 0.9% sodium chloride (0.9% NaCl), a new bicarbonate buffered crystalloid solution closely resembling the composition of plasma (FB-Cxt) or a hydroxyethyl starch-ringer acetate solution. Systemic hemodynamic variables, renal blood flow, microvascular oxygenation, oxidative/nitrosative stress, and renal function were measured. LPS-induced shock was only partially resolved by fluid administration. Animals became arterially hypotensive despite adequate central venous pressure. Hydroxyethyl starch-ringer acetate was more effective at improving arterial pressures and renal blood flow than 0.9% NaCl or FB-Cxt. Fluids had marginal effects on pH and HCO3 levels irrespective of the buffer, or on renal μPO2 and dysfunction. Colloids increased the markers of renal oxidative stress (P

Background and objectives: Acute kidney injury (AKI) is a clinical condition associated with a degree of morbidity and mortality despite supportive care, and ischemia/reperfusion injury (I/R) is one of the main causes of AKI. The pathophysiology of I/R injury is a complex cascade of events including the release of free oxygen radicals followed by damage to proteins, lipids, mitochondria, and deranged tissue oxygenation. In this study, we investigated whether the antioxidant ascorbic acid would be able to largely prevent oxidative stress and consequently, reduce I/R-related injury to the kidneys in terms of oxygenation, inflammation, and renal failure. Materials and methods: Rats were divided into three groups (n = 6/group): (1) a time control group; (2) a group subjected to renal ischemia for 60 min by high aortic occlusion followed by 2 h of reperfusion (I/R); and (3) a group subjected to I/R and treated with an i.v. 100 mg/kg bolus ascorbic acid 15 min before ischemia and continuous infusion of 50 mg/kg/hour for 2 h during reperfusion (I/R + AA). We measured renal tissue oxidative stress, microvascular oxygenation, renal oxygen delivery and consumption, and renal expression of inflammatory and injury markers. Results: We demonstrated that aortic clamping and release resulted in increased oxidative stress and inflammation that was associated with a significant fall in systemic and renal hemodynamics and oxygenation parameters. The treatment of ascorbic acid completely abrogated oxidative stress and inflammatory parameters. However, it only partly improved microcirculatory oxygenation and was without any effect on anuria. Conclusion: The ascorbic acid treatment partly improves microcirculatory oxygenation and prevents oxidative stress without restoring urine output in a severe I/R model of AKI.

Erythropoietin (EPO) suppresses epileptic seizures, but the mechanism is unclear. The search for novel targets in the therapy of epilepsy has focused recently on brain inflammation since brain inflammation and the associated blood-brain barrier (BBB) damage appears to be an integral part of epilepsy pathophysiology. We examined the effects of EPO on proinflammatory mediators in brain and serum in PTZ-induced generalized seizure model. The inflammation markers (IL-1β, TNF-α, IL-6, IL-10), BBB and neuron damage markers (S100B, Neuron specific enolase; NSE, respectively) in serum and brain of Sprague-Dawley male rats were examined with the ELISA method. Nitric oxide synthase (NOS) isoforms were investigated immunohistochemically in hippocampus. EPO treatment 4 h and 24 h before PTZ administration had diverse effects. EPO treatment 4 h before PTZ administration elongated the seizure latency, decreased the inflammation and damage markers in serum and brain significantly, whereas EPO treatment 24 h before PTZ administration lowered inflammation and damage markers to control levels and decreased the seizure stage. PTZ-induced seizures increased inducible NOS (iNOS) activity and decreased endothelial NOS (eNOS) activity in hippocampus. Both EPO pretreatments reversed these effects. These findings, i.e., decreased iNOS activity and increased eNOS activity by EPO suggest the first time that the favorable effect of EPO pretreatment on inflammatory mediators triggered by PTZ-induced seizures. This can provide further insight into epilepsy treatment and new prophylactic strategies against epilepsy risk.

Background Modulation of inflammation and oxidative stress appears to limit sepsis-induced damage in experimental models. The kidney is one of the most sensitive organs to injury during septic shock. In this study, we evaluated the effect of N-acetylcysteine (NAC) administration in conjunction with fluid resuscitation on renal oxygenation and function. We hypothesized that reducing inflammation would improve the microcirculatory oxygenation in the kidney and limit the onset of acute kidney injury (AKI). Methods Rats were randomized into five groups (n = 8 per group): (1) control group, (2) control + NAC, (3) endotoxemic shock with lipopolysaccharide (LPS) without fluids, (4) LPS + fluid resuscitation, and (5) LPS + fluid resuscitation + NAC (150 mg/kg/h). Fluid resuscitation was initiated at 120 min and maintained at fixed volume for 2 h with hydroxyethyl starch (HES 130/0.4) dissolved in acetate-balanced Ringer’s solution (Volulyte) with or without supplementation with NAC (150 mg/kg/h). Oxygen tension in the renal cortex (CμPO2), outer medulla (MμPO2), and renal vein was measured using phosphorimetry. Biomarkers of renal injury, inflammation, and oxidative stress were assessed in kidney tissues. Results Fluid resuscitation significantly improved the systemic and renal macrohemodynamic parameters after LPS. However, the addition of NAC further improved cortical renal oxygenation, oxygen delivery, and oxygen consumption (p

Purpose To study the role of renal hypoperfusion in development of renal microcirculatory dysfunction in endotoxemic rats. Methods Rats were randomized into four groups: a sham group (n = 6), a lipopolysaccharide (LPS) group (n = 6), a group in which LPS administration was followed by immediate fluid resuscitation which prevented the drop of renal blood flow (EARLY group) (n = 6), and a group in which LPS administration was followed by delayed (i.e., a 2-h delay) fluid resuscitation (LATE group) (n = 6). Renal blood flow was measured using a transit-time ultrasound flow probe. Microvascular perfusion and oxygenation distributions in the renal cortex were assessed using laser speckle imaging and phosphorimetry, respectively. Interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α were measured as markers of systemic inflammation. Furthermore, renal tissue samples were stained for leukocyte infiltration and inducible nitric oxide synthase (iNOS) expression in the kidney. Results LPS infusion worsened both microvascular perfusion and oxygenation distributions. Fluid resuscitation improved perfusion histograms but not oxygenation histograms. Improvement of microvascular perfusion was more pronounced in the EARLY group compared with the LATE group. Serum cytokine levels decreased in the resuscitated groups, with no difference between the EARLY and LATE groups. However, iNOS expression and leukocyte infiltration in glomeruli were lower in the EARLY group compared with the LATE group. Conclusions In our model, prevention of endotoxemia-induced systemic hypotension by immediate fluid resuscitation (EARLY group) did not prevent systemic inflammatory activation (IL-6, IL-10, TNF-α) but did reduce renal inflammation (iNOS expression and glomerular leukocyte infiltration). However, it could not prevent reduced renal microvascular oxygenation. Electronic supplementary material The online version of this article (doi:10.1007/s00134-011-2267-4) contains supplementary material, which is available to authorized users.

Lung structural changes and immunoreactivity of endothelial (eNOS)- and inducible nitric oxide synthase (iNOS) were investigated by light microscopy in lungs of treated and untreated diabetic rats. Diabetes was induced by a single intraperitoneal (i.p.) injection of 65 mg kg(-1) streptozotocin (STZ) in Wistar albino male rats. Diabetic rats received daily i.p. doses of dexamethasone (2 mg kg(-1)), leptin (0.5 microg kg(-1)) and intramuscular insulin (20 U kg(-1)) or a combination of these drugs for 1 week starting 4 weeks after the STZ injections. After treatment, the blood levels of glucose, leptin, insulin and nitrate/nitrite (NO(3) (-)/NO(2) (-)) were measured. Dilatation of alveoli and alveolar ducts, partial alveolar wall thickening and increased eNOS- and iNOS characterized the diabetic rat lungs. High blood glucose and nitrate/nitrite levels as well as low insulin and leptin levels were also present. Treatment with insulin, dexamethasone and a combination of these drugs resulted in improvement of the structural and immunohistochemical abnormalities. The most effective treatment was insulin therapy. Leptin administration resulted in increased relative amounts of extracellular material, which led to noticeable respiratory efficiency in the diabetic rat lungs. All treatments except leptin lowered blood glucose levels. The combination of insulin and dexamethasone increased blood leptin and insulin, while the remaining diabetic rats had blood with low leptin and insulin concentrations. These results suggest that therapy with insulin plus dexamethasone but not therapy with leptin is beneficial for diabetics.

Background Renal ischemia/reperfusion (I/R) injury is commonly seen in kidney transplantation and affects the allograft survival rates. We aimed to test our hypothesis that scavenging reactive oxygen species (ROS) with tempol would protect renal oxygenation and nitric oxide (NO) levels in the acute phase of renal I/R. Methods Rats were randomly divided: (1) no I/R, no tempol; (2) no I/R, but with tempol; (3) I/R without tempol; and (4) I/R with tempol. I/R was induced by 30-min clamping of the renal artery. Tempol (200 μmol/kg/h/i.v) was administered 15 min prior to I/R. Results I/R without tempol led to a significant decrease in renal oxygen delivery and microvascular oxygenation. Tempol, however, protected renal oxygenation after I/R. At R90, the creatinine clearance rate was lower in the I/R-subjected group that did not receive tempol compared to that in the other groups. I/R injury without tempol treatment led to a significant increase in tissue malondialdehyde levels and a significant decrease in tissue NO levels. Tempol administration before I/R could prevent oxidative stress and altered tissue NO levels. Conclusions This underscores that unbalance between oxygen, NO, and ROS forms an important component of the pathogenesis of I/R-induced AKI and should therefore be taken into account when designing a prevention/treatment strategy for renal I/R injury in transplantation.

It is known that the systemic response during sepsis is caused by proinflammatory mediators such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα). The inflammatory response in sepsis causes disorders in the brain in addition to multiorgan dysfunctions including the kidneys and liver [1]. Inducible nitric oxide synthase (iNOS) is induced in hepatocytes by sepsis and mediates hepatic injury [2]. Matrix metalloproteinases (MMPs) play an important role in the formation of sepsis and mediate inflammatory response and tissue damage [3]. On the other hand, there are some cases in which systemic inflammatory response occurs without the presence of infection such as epilepsy. Cytokines are well-known inflammatory mediators in the brain, and they increase following seizures. We previously demonstrated that pentyleneterazol (PTZ)-induced generalized epileptic seizures significantly increased inflammatory markers (TNFα, IL-1β, IL-6) in the brain and S100B in serum [4]. In this preliminary study, we aimed to investigate the MMP2, MMP9, NOS, and myeloperoxidase activity in the liver and kidney and levels of serum proinflammatory cytokines following PTZ-induced generalized clonic-tonic seizures.

Background The aim of the present study was to test the potential protective effects of the organic vanadium salt bis (maltolato) oxovanadium (BMOV; 15 mg/kg) in the context of renal ischemia/reperfusion (30 min of ischemia) and its effects on renal oxygenation and renal function in the acute phase of reperfusion (up to 90 min post-ischemia). Methods Ischemia was established in anesthetized and mechanically ventilated male Wistar rats by renal artery clamping. Renal microvascular and venous oxygenation were measured using phosphorimetry. Creatinine clearance rate, sodium reabsorption, and renal oxygen handling efficiency were considered markers for renal function. Results The main findings were that BMOV did not affect the systemic and renal hemodynamic and oxygenation variables and partially protected renal sodium reabsorption. Conclusions Pretreatment with the organic vanadium compound BMOV did not protect the kidney from I/R injury.

Background: The aim of the present study was to test the hypothesis that balanced crystalloid resuscitation would be better for the kidney than unbalanced crystalloid resuscitation in a rat hemorrhagic shock model. Methods: Male Wistar rats were randomly assigned to four groups (n = 6/group): (1) time control; (2) hemorrhagic shock control; (3) hemorrhagic shock followed by unbalanced crystalloid resuscitation (0.9% NaCl); and (4) hemorrhagic shock followed by acetate and gluconate-balanced crystalloid resuscitation (Plasma Lyte). We tested the solutions for their effects on renal hemodynamics and microvascular oxygenation, strong-ion difference, systemic and renal markers of inflammation and oxidative stress including glycocalyx degradation as well as their effects on renal function. Results: The main findings of our study were that: (1) both the balanced and unbalanced crystalloid solutions successfully restored the blood pressure, but renal blood flow was only recovered by the balanced solution although this did not lead to improved renal microvascular oxygenation; (2) while unbalanced crystalloid resuscitation induced hyperchloremia and worsened metabolic acidosis in hemorrhaged rats, balanced crystalloid resuscitation prevented hyperchloremia, restored the acid-base balance, and preserved the anion gap and strong ion difference in these animals; (3) in addition balanced crystalloid resuscitation significantly improved renal oxygen consumption (increased VO2, decreased EFNa+); and (4) however neither balanced nor unbalanced crystalloid resuscitation could normalize systemic inflammation or oxidative stress. Functional immunohistochemistry biomarkers showed improvement in L-FABP in favor of balanced solutions in comparison to the hemorrhagic group although no such benefit was seen for renal tubular injury (measured by NGAL) by giving either unbalanced or balanced solutions. Conclusions: Although balanced crystalloid resuscitation seems superior to balanced crystalloid resuscitation in protecting the kidney after hemorrhagic shock and is certainly better than not applying fluid resuscitation, these solutions were not able to correct systemic inflammation or oxidative stress associated with hemorrhagic shock. (C) 2011 Elsevier Ireland Ltd. All rights reserved

Acute kidney injury (AKI) can occur after aortic clamping due to microvascular dysfunction leading to renal hypoxia. In this rat study, we have tested the hypothesis that the administration of the precursor of the nitric oxide synthase essential cofactor tetrahydrobiopterin (BH4) could restore renal oxygenation after ischemia reperfusion (I/R) and prevent AKI. We randomly distributed rats into 4 groups: sham group; ischemia-reperfusion group; I/R + sepiapterin, the precursor of BH4; and I/R + sepiapterin + methotrexate, an inhibitor of the pathway generating BH4 from sepiapterin. Cortical and outer medullary microvascular oxygen pressure, renal oxygen delivery, renal oxygen consumption were measured using dual-wavelength oxygen-dependent quenching phosphorescence techniques during ischemia and throughout 3 hours of reperfusion. Kidney injury was assessed using myeloperoxidase staining for leukocyte infiltration and urine neutrophil gelatinase-associated lipocalin levels. Ischemia reperfusion induced a drop in microvascular PO2 (P < 0.01 vs. Sham, both), which was prevented by the infusion of sepiapterin. Sepiapterin partially prevented the rise in renal oxygen extraction (P < 0.001 vs. I/R). Finally, treatment with sepiapterin prevented renal infiltration by inflammatory cells and decreased urine neutrophil gelatinase-associated lipocalin levels indicating a decrease of renal injury. These effects were blunted when adding methotrexate, except for myeloperoxidase. In conclusion, the administration of sepiapterin can prevent renal hypoxia and AKI after suprarenal aortic clamping in rats.

Even though renal hypoxia is believed to play a pivotal role in the development of acute kidney injury, no study has specifically addressed the alterations in renal oxygenation in the early onset of renal ischemia-reperfusion (I/R). Renal oxygenation depends on a balance between oxygen supply and consumption, with the nitric oxide (NO) as a major regulator of microvascular oxygen supply and oxygen consumption. The aim of this study was to investigate whether I/R induces inducible NO synthase (iNOS)-dependent early changes in renal oxygenation and the potential benefit of iNOS inhibitors on such alterations. Anesthetized Sprague-Dawley rats underwent a 30-min suprarenal aortic clamping with or without either the nonselective NO synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) or the selective iNOS inhibitor l- N6-(1-iminoethyl)lysine hydrochloride (l-NIL). Cortical (CμPo2) and outer medullary (MμPo2) microvascular oxygen pressure (μPo2), renal oxygen delivery (Do2ren), renal oxygen consumption (V̇o2ren), and renal oxygen extraction (O2ER) were measured by oxygen-dependent quenching phosphorescence techniques throughout 2 h of reperfusion. During reperfusion renal arterial resistance and oxygen shunting increased, whereas renal blood flow, CμPo2, and MμPo2(−70, −42, and −42%, respectively, P < 0.05), V̇o2ren, and Do2ren(−70%, P < 0.0001, and −28%, P < 0.05) dropped. Whereas l-NAME further decreased Do2ren, V̇o2ren, CμPo2, and MμPo2and deteriorated renal function, l-NIL partially prevented the drop of Do2renand μPo2, increased O2ER, restored V̇o2renand metabolic efficiency, and prevented deterioration of renal function. Our results demonstrate that renal I/R induces early iNOS-dependent microvascular hypoxia in disrupting the balance between microvascular oxygen supply and V̇o2ren, whereas endothelial NO synthase activity is compulsory for the maintenance of this balance. l-NIL can prevent ischemic-induced renal microvascular hypoxia.

Nitric oxide (NO) is known to be a messenger molecule that plays an important role in physiological and pathological conditions. It is synthesized by an enzyme called nitric oxide synthase (NOS). Inducible NOS (iNOS), one of the three isomers of NOS, has both protective and toxic properties. In this study, the role of NO has been evaluated by gastrointestinal symptoms induced by orlistat which is used in obesity treatment. Orlistat was given to Wistar rats with and without iNOS inhibition. The effects of orlistat and inhibition of NOS were studied. Glucose, urea, alanine transaminase (ALT), and gamma glutamil transpeptidase (GGT) were descreased after short- and long- term orlistat applications. Dexamethasone increased level of these enzymes. Cholesterol and triglyceride were increased in all experimental groups than the controls. This increment was more severe in animals received orlistat and dexamethasone together. Small intestinal tissue also were researched histologically and NADPH-diaphorase (NADPH-d) histochemistrically. Orlistat caused histological damages in brush border membranes, connective tissues of villi, and lymphocyte migration also increased. Dexamethasone treatment prevented these damages partially while orlistat increased the NOS distribution in the tissue sections. Dexamethasone, which is an iNOS inhibitor, decreased NADPH-d histochemistry. There was a similiar NOS distribution both in the control and orlistat+dexamethasone group. Hence, we concluded that long- term trials with orlistat and similar drugs are needed.