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Oxidative\/nitrosative stress, inflammation, and impaired nitric oxide generation may contribute to such pathophysiology. We tested whether the antioxidant and anti\u2010inflammatory drug, tempol, may modify these responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Following unilateral nephrectomy, we inserted renal arterial catheters and laser\u2010Doppler\/oxygen\u2010sensing probes in the renal cortex and medulla. Noanesthetized sheep were administered intravenous (IV) <jats:italic>Escherichia coli<\/jats:italic> and, at sepsis onset, IV tempol (IVT; 30\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup>\u2009h<jats:sup>\u22121<\/jats:sup>), renal arterial tempol (RAT; 3\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup>\u2009h<jats:sup>\u22121<\/jats:sup>), or vehicle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Septic sheep receiving vehicle developed renal medullary hypoperfusion (76\u2009\u00b1\u200916% decrease in perfusion), hypoxia (70\u2009\u00b1\u200913% decrease in oxygenation), and AKI (87\u2009\u00b1\u20098% decrease in creatinine clearance) with similar changes during IVT. However, RAT preserved medullary perfusion (1072\u2009\u00b1\u2009307 to 1005\u2009\u00b1\u2009271\u2009units), oxygenation (46\u2009\u00b1\u20098 to 43\u2009\u00b1\u20096\u2009mmHg), and creatinine clearance (61\u2009\u00b1\u200910 to 66\u2009\u00b1\u200920\u2009mL\u2009min<jats:sup>\u22121<\/jats:sup>). Plasma, renal medullary, and cortical tissue malonaldehyde and medullary 3\u2010nitrotyrosine decreased significantly with sepsis but were unaffected by IVT or RAT. Consistent with decreased oxidative\/nitrosative stress markers, cortical and medullary nuclear factor\u2010erythroid\u2010related factor\u20102 increased significantly and were unaffected by IVT or RAT. However, RAT prevented sepsis\u2010induced overexpression of cortical tissue tumor necrosis factor alpha (TNF\u2010\u03b1; 51\u2009\u00b1\u200916% decrease; <jats:italic>p<\/jats:italic>\u2009=\u20090.003) and medullary Thr\u2010495 phosphorylation of endothelial nitric oxide synthase (eNOS; 63\u2009\u00b1\u200918% decrease; <jats:italic>p<\/jats:italic>\u2009=\u20090.015).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In ovine Gram\u2010negative sepsis, renal arterial infusion of tempol prevented renal medullary hypoperfusion and hypoxia and AKI and decreased TNF\u2010\u03b1 expression and uncoupling of eNOS. However, it did not affect markers of oxidative\/nitrosative stress, which were significantly decreased by Gram\u2010negative sepsis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.14025","type":"journal-article","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T11:35:23Z","timestamp":1691408123000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Renal arterial infusion of tempol prevents medullary hypoperfusion, hypoxia, and acute kidney injury in ovine Gram\u2010negative sepsis"],"prefix":"10.1111","volume":"239","author":[{"given":"Ashenafi H.","family":"Betrie","sequence":"first","affiliation":[{"name":"Preclinical Critical Care Unit, Florey Institute of Neuroscience and Mental Health The University of Melbourne  Melbourne Victoria Australia"},{"name":"Translational Neurodegeneration Laboratory, Florey Institute of Neuroscience and Mental Health The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Ma","sequence":"additional","affiliation":[{"name":"Preclinical Critical Care Unit, Florey Institute of Neuroscience and Mental Health The University of Melbourne  Melbourne Victoria Australia"},{"name":"Division of Nephrology, Shanghai Ninth People's Hospital Shanghai Jiaotong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie P. 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