Background: Endotoxemia induces a hemodynamic form of acute renal failure (ARF) [renal vasoconstriction ± reduced glomerular ultrafilitration coefficient, K_f; minimal / no histologic damage]. This study tested whether levosimendan (LS), a K_ATP channel opener with cardiac ionotropic and possible anti-inflammatory properties, might have utility in combating this form of ARF. Methods: CD-1 mice were injected with lipopolysaccharide (LPS) ± LS. LS effects on LPS- induced systemic inflammation (plasma TNF- / MCP-1; cardio-renal mRNAs), plasma nitric oxide (NO) levels, and azotemia were assessed. Because K_ATP channel opening has been reported to mediate hypoxic tubular injury, possible adverse LS effects on ischemic ARF, and on ATP depletion- injury, were sought (in HK-2 cells and isolated mouse proximal tubules). The impacts of diazoxide (another K_ATP channel agonist) and glibenclamide (a channel antagonist) on hypoxic tubular injury were also assessed. Finally, the ability of LS to alter rat mesangial cell (MC) contraction in response to angiotensin II (AII; elevated in sepsis) was tested. Results: LS conferred almost complete protection against LPS-induced ARF. This occurred without any apparent reduction in the LPS- induced inflammatory response. Neither LS nor diazoxide altered ATP depletion- mediated tubule injury (in vivo or in vitro). Conversely, glibenclamide induced a marked and direct cytotoxic effect. LS completely blocked AII- induced MC contraction, an action likely to increase K_f. Conclusions: 1) LS can confer marked protection against LPS- induced ARF; 2) This likely stems from its vasoactive properties, rather than from reductions in LPS induced inflammation; and 3) K_ATP channel agonists (but not antagonists) appear to be devoid of toxic proximal tubular cell effects. This suggests that LS, and other K_ATP channel agonists, have a margin of safety if employed in situations (e.g., sepsis syndrome, heart failure) in which severe renal vasoconstriction might lead to ischemic ARF