Abstract
Overproduction of reactive oxygen and nitrogen species leads to oxidative stress and decreased total antioxidant capacity, which is responsible for high mortality from several diseases such as endotoxic shock. Nitric oxide (NO) produced by inducible NO synthase (iNOS) during endotoxemia is the major cause of vascular hyporeactivity, hypotension and multiple organ failure. In this study, we investigated whether increased production of NO contributes to renal oxidative stress in endotoxemic rat. Saline (4 mL kgˉ1, i.p.), endotoxin (Escherichia coli lipopolysaccharide, O111:B4; 10 mg kgˉ1, i.p.) and/or selective iNOS inhibitor (1,3-PBIT; 10 mg kgˉ1, i.p.) were administered to conscious male Wistar rats and mean arterial blood pressure was recorded at 1, 2, 3 and 4 hr after injection. Nitrite and malondialdehyde (MDA) levels and myeloperoxidase (MPO) activity were measured in the sera and/or kidney homogenates at the end of the experiments. Administration of endotoxin caused hypotension associated with increased systemic and renal nitrite production. 1,3-PBIT prevented these effects of endotoxin at 1 hr after injection of endotoxin. Renal MPO activity was decreased by endotoxin which was not changed by 1,3-PBIT. Endotoxin caused a decrease in MDA levels in the renal tissue, which was prevented by 1,3-PBIT. These data suggest that overproduction of NO by iNOS during endotoxemia decreases renal oxidative stress and that inhibition of iNOS restores total renal antioxidant capacity.
Highlights
Oxidative stress results from an oxidant/antioxidant imbalance, an excess of oxidants and/or a depletion of antioxidants
This study demonstrates that increased systemic Nitric oxide (NO) production by inducible NO synthase (iNOS) 4 hr after endotoxin injection causes hypotension in conscious rats and NO-derived from renal tissue contributes to these effects of endotoxin
Expression of iNOS protein and mRNA expression approximately 3 hr after systemic endotoxin administration to animals has been reported in several tissues, such as blood vessels, heart, kidney and lung associated with significant increase in serum/plasma and tissue nitrite levels and decrease in mean arterial blood pressure (MAP)[7,17,18,19]
Summary
Oxidative stress results from an oxidant/antioxidant imbalance, an excess of oxidants and/or a depletion of antioxidants. The excessive production of reactive oxygen and nitrogen species (ROS and RNS, respectively) associated with inflammation leads to oxidative stress, which is involved with the high mortality from several diseases such as endotoxic shock[1,2,3,4]. It has been reported that endotoxemia increases markers of oxidative stress and tissue injury in different animal models and in humans. This effect of endotoxin has been found to be correlated with decreased total antioxidant capacity and blood levels of several antioxidants such as α-tocopherol, retinol, vitamin E, vitamin C and β-carotene in humans with sepsis and septic shock[1,2,3,4]. Since impairment of renal function during endotoxemia contributes to multiple organ failure[2], we investigated whether increased production of NO contributes to renal oxidative stress in endotoxemic rat
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