Methylprednisolone Increases Urinary Nitrate Concentrations and Reduces Subclinical Renal Injury During Infrarenal Aortic Ischemia Reperfusion.

Reactive vasoconstriction of the acutely ischemic kidney is harmful, first due at least in part to heightened endothelin-1 (ET-1) activity.1 Thus, bosentan, a dual endothelin (ET) receptor antagonist, reduces ischemia induced renal injury and protective effects of ischemic preconditioning against prolonged renal ischemia depend on endothelial nitric oxide synthase (eNOS). Second, ischemia reduces vasodilatory e-NOS, thus compounding ischemia-mediated renal injury through adversely altering the intrarenal ET-1/NO balance. Third, ischemia, by an NF kappa B-dependent mechanism, increases renal proinflammatory mediators, which may be renotoxic, indirectly by amplifying hypoxia-induced arterial vasoconstriction (through inhibition of vasodilatory e-NOS and promoting ET-1) and by direct renotoxic effects. A local renal proinflammatory response from localized hypoxia, superimposed upon a systemic proinflammatory response, may predispose to renal dysfunction. Measures to reduce the systemic proinflammatory response as well as heighten arterial eNOS might be expected to be renoprotective. Methylprednisolone (MP) reduces both plasma proinflammatory and urinary anti-inflammatory cytokines, suggesting reduced intrarenal proinflammatory activity. Moreover, steroids enhance arterial e-NOS activity, reducing vascular vasoconstriction in murine ischemic myocardium. Furthermore, dexamethasone lowers tumor necrosis factor (TNF)-mediated pulmonary ET-1. In renal damage, arising from vasoconstrictive effects of hypoxia and proinflammatory mediators, it is unknown if steroids favorably counter renal arterial eNOS/ET-1 imbalance as observed in myocardium and lung. This considers only vasoconstrictive effects of proinflammatory mediators on arterial eNOS. In contrast, intravenous IL-1 causes venodilation with increased venous eNOS expression. Thus, proinflammatory mediators increase venous e-NOS and impair arterial eNOS/ET-1 balance. Urinary nitrate reflects total eNOS activity of both arterial and venous vascular beds. We hypothesize that a proinflammatory response arising from infrarenal ischemia-reperfusion in a normotensive, normoxic subject increases overall urinary nitrate excretion, reflecting increased venous eNOS activity. We also hypothesized that MP may be renoprotective through further increasing urinary nitrate levels. The underlying reasoning is that higher urinary nitrate excretion would follow a MP-induced additional arterial contribution to urinary nitrate. Moreover, reducing vasoconstrictive renal damage in the MP group would enhance nitrate excretion and reduce subclinical renal injury as measured by urinary N-acetyl-beta-D-glucosaminidase (NAG)/creatinine (Cr) ratios.2–4 NAG is a proximal tubular lysosomal enzyme, neither filtered at the glomerulus nor absorbed nor secreted by tubules. Thus, urinary NAG arises from tubular cell damage.5,6