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Levosimendan protects against experimental endotoxemic acute renal failure

¹Department of Medicine, University of Washington, ²Fred Hutchinson Cancer Research Center, and ³Veterans Administration Puget Sound Health Care System, Seattle, Washington

Submitted 6 December 2005 ; accepted in final form 10 January 2006

Endotoxemia induces a hemodynamic form of acute renal failure (ARF; renal vasoconstriction ± reduced glomerular ultrafiltration coefficient, K_f; minimal/no histological damage). We tested whether levosimendan (LS), an ATP-sensitive K⁺ (K_ATP) channel opener with cardiac ionotropic and possible anti-inflammatory properties, might have utility in combating this form of ARF. CD-1 mice were injected with LPS ± LS. LS effects on LPS-induced systemic inflammation (plasma TNF-/MCP-1; cardiorenal mRNAs), plasma 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 ATP depletion injury were sought. Effects of diazoxide (another K_ATP channel agonist) and glibenclamide (a channel antagonist) on hypoxic tubular injury also were assessed. Finally, the ability of LS to alter rat mesangial cell (MC) contraction in response to ANG II (elevated in sepsis) was tested. LS conferred almost complete protection against LPS-induced ARF, 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 ANG II-induced MC contraction, an action likely to increase K_f. We concluded that 1) LS can confer marked protection against LPS-induced ARF; 2) this likely stems from vasoactive properties, rather than 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 (sepsis syndrome, heart failure) in which severe renal vasoconstriction might lead to ischemic ARF.

isolated tubules; HK-2 cells; glibenclamide; diazoxide; tetraethylammonium

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